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Sample records for 17q23 q21 translocation

  1. PLZF-RAR[alpha] fusion proteins generated from the variant t(11; 17)(q23; q21) translocation in acute promyelocytic leukemia inhibit ligand-dependent transactivation of wild-type retinoic acid receptors

    SciTech Connect

    Chen, Zhu; Chen, Sai-Juan; Wang, Zhen-Yi ); Guidez, F.; Rousselot, P.; Agadir, A.; Degos, L.; Chomienne, C. ); Zelent, A. ); Waxman, S. )

    1994-02-01

    Recently, the authors described a recurrent variant translocation, t(11;17)(q23;q21), in acute promyelocytic leukemia (APL) which juxtaposes PLZF, a gene encoding a zinc finger protein, to RARA, encoding retinoic acid receptor [alpha] (RAR[alpha]). They have now cloned cDNAs encoding PLZF-RAR[alpha] chimeric proteins and studied their transactivating activities. In transient-expression assays, both the PLZF(A)-RAR[alpha] and PLZF(B)-RAR[alpha] fusion proteins like the PML-RAR[alpha] protein resulting from the well-known t(15;17) translocation in APL, antagonized endogenous and transfected wild-type RAR[alpha] in the presence of retinoic acid. Cotransfection assays showed that a significant repression of RAR[alpha] transactivation activity was obtained even with a very low PLZF-RAR[alpha]-expressing plasmid concentration. A [open quotes]dominant negative[close quotes] effect was observed with vectors expressing RAR[alpha] and retinoid X receptor [alpha] (RXR[alpha]). These abnormal transactivation properties observed in retinoic acid-sensitive myeloid cells strongly implicate the PLZF-RAR[alpha] fusion proteins in the molecular pathogenesis of APL.

  2. PLZF-RAR alpha fusion proteins generated from the variant t(11;17)(q23;q21) translocation in acute promyelocytic leukemia inhibit ligand-dependent transactivation of wild-type retinoic acid receptors.

    PubMed Central

    Chen, Z; Guidez, F; Rousselot, P; Agadir, A; Chen, S J; Wang, Z Y; Degos, L; Zelent, A; Waxman, S; Chomienne, C

    1994-01-01

    Recently, we described a recurrent variant translocation, t(11;17)(q23;q21), in acute promyelocytic leukemia (APL) which juxtaposes PLZF, a gene encoding a zinc finger protein, to RARA, encoding retinoic acid receptor alpha (RAR alpha). We have now cloned cDNAs encoding PLZF-RAR alpha chimeric proteins and studied their transactivating activities. In transient-expression assays, both the PLZF(A)-RAR alpha and PLZF(B)-RAR alpha fusion proteins like the PML-RAR alpha protein resulting from the well-known t(15;17) translocation in APL, antagonized endogenous and transfected wild-type RAR alpha in the presence of retinoic acid. Cotransfection assays showed that a significant repression of RAR alpha transactivation activity was obtained even with a very low PLZF-RAR alpha-expressing plasmid concentration. A "dominant negative" effect was observed when PLZF-RAR alpha fusion proteins were cotransfected with vectors expressing RAR alpha and retinoid X receptor alpha (RXR alpha). These abnormal transactivation properties observed in retinoic acid-sensitive myeloid cells strongly implicate the PLZF-RAR alpha fusion proteins in the molecular pathogenesis of APL. Images PMID:8302850

  3. De novo apparently balanced reciprocal translocation between 5q11.2 and 17q23 associated with Klippel-Feil anomaly and type A1 brachydactyly

    SciTech Connect

    Fukushima, Yoshimitsu; Ohashi, Hirofumi; Wakui, Keiko

    1995-07-03

    We report on a girl with Klippel-Feil anomaly, type A1 brachydactyly, and minor facial anomalies. She has an apparently balanced de novo reciprocal translocation between 5q11.2 and 17q23. The possible significance of this chromosomal abnormality is discussed. 7 refs., 3 figs.

  4. The human PECAM1 gene maps to 17q23

    SciTech Connect

    Gumina, R.J.; Rao, P.N.; Tuinen, P. van

    1996-06-01

    We have determined the chromosomal and regional location of the gene encoding PECAM-1 (termed PECAM1 by GBI) nomenclature using a polymerase chain reaction (PCR)-based analysis of somatic cell hybrids. Analysis of a somatic cell hybrid chromosome panel established that the PECAM1 gene is on chromosome 17. Interestingly, several adhesion molecules expressed on platelets and endothelium also localize to chromosome 17: the GP1BA locus (glycoprotein (GP) Ib{alpha}) has been provisionally mapped to the region 17p12-pter, the ITGA2b (GPIIb) and the ITGB3 (GPI-IIa) loci have been confirmed to the region 17q21.32; and the ICAM2 locus has been provisionally mapped to the region 17q23-q25. To determine if the PECAM1 locus colocalizes with any of the loci for these adhesion molecules, PCR-based analysis of a regional mapping panel for human chromosome 17 was conducted. We found that the PECAM1 locus is on the long arm of chromosome 17, i the region q23-qter. To confirm this observation and obtain a more precise localization of the PECAM1 locus, fluorescence in situ hybridization was conducted. Together our data allowed assignment of the PECAM1 locus to the region 17q23. 18 refs., 2 figs.

  5. Physical localisation of the breakpoints of a constitutional translocation t(5;6)(q21;q21) in a child with bilateral Wilms' tumour.

    PubMed Central

    Hoban, P R; Cowen, R L; Mitchell, E L; Evans, D G; Kelly, M; Howard, P J; Heighway, J

    1997-01-01

    A 6 month old boy presented with bilateral Wilms' tumour. Cytogenetic analysis of the lymphocytes from the patient showed a de novo balanced translocation t(5;6)(q21;q21), which was also present in the tumour material as the sole cytogenetic abnormality. To facilitate the identification of the translocation breakpoints, we have established a lymphoblastoid cell line (MA214L) from the patient which maintains the translocation in culture. We have used Genethon microsatellite markers as sequence tagged sites (STSs) to isolate yeast artificial chromosome (YAC) clones to 5q and 6q from human genomic libraries. Using fluorescence in situ hybridisation (FISH) on metaphase preparations of MA214L, we have physically defined the translocation breakpoints between YAC clones on each chromosome arm. The genetic distance separating the flanking YACs on 6q21 is 3 cM, while that on 5q21 is 4 cM. To date this is the first report of these chromosomal regions being implicated in Wilms' tumourigenesis. Images PMID:9138163

  6. Molecular characterization of the rare translocation t(3;10)(q26;q21) in an acute myeloid leukemia patient

    PubMed Central

    2014-01-01

    Background In acute myeloid leukemia (AML), the MDS1 and EVI1 complex locus - MECOM, also known as the ecotropic virus integration site 1 - EVI1, located in band 3q26, can be rearranged with a variety of partner chromosomes and partner genes. Here we report on a 57-year-old female with AML who presented with the rare translocation t(3;10)(q26;q21) involving the MECOM gene. Our aim was to identify the fusion partner on chromosome 10q21 and to characterize the precise nucleotide sequence of the chromosomal breakpoint. Methods Cytogenetic and molecular-cytogenetic techniques, chromosome microdissection, next generation sequencing, long-range PCR and direct Sanger sequencing were used to map the chromosomal translocation. Results Using a combination of cytogenetic and molecular approaches, we mapped the t(3;10)(q26;q21) to the single nucleotide level, revealing a fusion of the MECOM gene (3q26.2) and C10orf107 (10q21.2). Conclusions The approach described here opens up new possibilities in characterizing acquired as well as congenital chromosomal aberrations. In addition, DNA sequences of chromosomal breakpoints may be a useful tool for unique molecular minimal residual disease target identification in acute leukemia patients. PMID:25071866

  7. Translocation t(2;7)(p11;q21) associated with the CDK6/IGK rearrangement is a rare but recurrent abnormality in B-cell lymphoproliferative malignancies.

    PubMed

    Douet-Guilbert, Nathalie; Tous, Corinne; Le Flahec, Glen; Bovo, Clément; Le Bris, Marie-Josée; Basinko, Audrey; Morel, Frédéric; De Braekeleer, Marc

    2014-03-01

    Structural abnormalities of chromosome 7q have been regularly reported in chronic B-cell lymphoproliferative disorders. They include chromosomal translocations involving 7q21, leading to overexpression of the CDK6 gene. Three different translocations, t(7;14)(q21;q32), t(7;22)(q21;q11), and t(2;7)(p11;q21), leading to the juxtaposition of the CDK6 gene with a immunoglobulin gene enhancer during B-cell differentiation, have been described. In the past 2 years, we identified three patients with lymphoproliferative malignancy associated with a t(2;7)(p11;q21). Fluorescent in situ hybridization using an IGK probe and a library of bacterial artificial chromosome (BAC) clones located in bands 7q21.2 and 7q21.3, containing CDK6, revealed that the telomeric part of the IGK probe was translocated on the der(7) within a 51-kb region upstream of the transcriptional start site of CDK6. A total of 23 patients with indolent B-cell lymphoproliferative disorders and juxtaposition of the IG and CDK6 genes, including 20 with IGK and CDK6 juxtaposition, have been reported thus far. This rearrangement leads to the overexpression of CDK6, which encodes a cyclin-dependent protein kinase involved in cell cycle G1 phase progression and G1/S transition. PMID:24726269

  8. Ulnar ray defect in an infant with a 6q21;7q31.2 translocation: Further evidence of the existence of a limb defect gene in 6q21

    SciTech Connect

    Gurrieri, F.; Genuardi, M.; Pomponi, M.G.

    1995-01-30

    Ectrodactyly is a developmental defect of the distal limbs characterized by marked clinical variability and genetic heterogeneity, also reflected in the observation of different chromosome abnormalities nonrandomly associated with longitudinal postaxial limb deficiencies. The one most frequently found in patients with split hand-split foot (SHSF) involves chromosome band 7q22. Recently, structural anomalies of chromosome 6q21 have been reported in 2 unrelated patients with SHSF, suggesting that this region may also contain genes responsible for limb development. We report on a third patient who had a de novo, apparently balanced t(6;7)(q21;q31.2) translocation and bilateral ulnar aplasia with postaxial oligodactyly. In spite of the different phenotypic effects observed in these 3 patients, we consider our case as further evidence that genes in 6q21 may play a role in distal limb development. 8 refs., 3 figs.

  9. Novel t(1;3)(q21,p21) translocation in a basal cell adenocarcinoma of the parotid gland: potential association with tumorigenesis.

    PubMed

    Saluja, Karan; Rao, Pulivarthi H; Myers, Jeffery N; El-Naggar, Adel K

    2016-08-01

    We report a rare translocation involving chromosomes 1q23 and 3p21 regions in a basaloid salivary carcinoma. Our case together with a previously reported instance of translocation involving chromosome 1q 21-24 region defines a specific chromosomal segment that may house a gene associated with the development of a subset of basaloid salivary tumors. PMID:27085552

  10. Localization of the chromosome 11 breakpoint in a translocation t(4;11)(q21;p15) in T cell acute lymphocytic leukemia (T-ALL)

    SciTech Connect

    Dobrovic, A.; Peters, G.B.; Finch, J.

    1994-09-01

    The identification of genes located at the breakpoints of chromosomal translocations has been invaluable in determining the pathogenesis of hematogical malignancies. We have investigated the translocation, t(4;11)(q21;p14-15) in a T-ALL patient. Four cases with a similar translocation have been reported; three at diagnosis and one as a secondary cytogenetic change. As a first step towards cloning of the breakpoint sequences, we isolated a somatic cell hybrid containing the der(4) translocation chromosome. The hybrid allowed us to determine the markers flanking the chromosome 11 breakpoint position. The breakpoint was localized to band 11p15.5 between the genes for interferon-like growth factor II (IGF2) and the M1 subunit of ribonucleotide reductase (RRM1) by PCR. Cosmid probes from this region were then used to further localize the breakpoint to a region adjacent to RRM1 by fluorescent in situ hybridization (FISH).

  11. A Non-Reciprocal Autosomal Translocation 64,XX, t(4;10)(q21;p15) in an Arabian Mare with Repeated Early Embryonic Loss.

    PubMed

    Ghosh, S; Das, P J; Avila, F; Thwaits, B K; Chowdhary, B P; Raudsepp, T

    2016-02-01

    Balanced autosomal translocations are a known cause for repeated early embryonic loss (REEL) in horses. In most cases, carriers of such translocations are phenotypically normal, but the chromosomal aberration negatively affects gametogenesis giving rise to both genetically balanced and unbalanced gametes. The latter, if involved in fertilization, result in REEL, whereas gametes with the balanced form of translocation will pass the defect into next generation. Therefore, in order to reduce the incidence of REEL, identification of translocation carriers is critical. Here, we report about a phenotypically normal 3-year-old Arabian mare that had repeated resorption of conceptuses prior to day 45 of gestation and was diagnosed with REEL. Conventional and molecular cytogenetic analyses revealed that the mare had normal chromosome number 64,XX but carried a non-mosaic and non-reciprocal autosomal translocation t(4;10)(q21;p15). This is a novel translocation described in horses with REEL and the first such report in Arabians. Previous cases of REEL due to autosomal translocations have exclusively involved Thoroughbreds. The findings underscore the importance of routine cytogenetic screening of breeding animals. PMID:26547799

  12. Schizophrenia-associated chromosome 11q21 translocation: Identification of flanking markers and development of chromosome 11q fragment hybrids as cloning and mapping resources

    SciTech Connect

    Fletcher, J.M.; Evans, K.; Baillie, D.; Byrd, P.; Hanratty, D.; Leach, S.; Gosden, J.R.; Muir, W.; Porteous, D.J.; St. Clair, D.; Heyningen, V. van ); Julier, C. )

    1993-03-01

    Genetic linkage, molecular analysis, and in situ hybridization have identified TYR and D11S388 as markers flanking the chromosome 11 breakpoint in a large pedigree where a balanced translocation, t(1;11)(q43;q21), segregates with schizophrenia and related affective disorders. Somatic cell hybrids, separating the two translocation chromosomes from each other and from the normal homologues, have been produced with the aid of immunomagnetic sorting for chromosome 1- and chromosome 11-encoded cell-surface antigens. The genes for two of these antigens map on either side of the 11q breakpoint. Immunomagnetic bead sorting was also used to isolate two stable X-irradiation hybrids for each cells-surface antigen. Each hybrid carriers only chromosome 11 fragments. Translocation and X-irradiation hybrids were analyzed, mainly by PCR, for the presence of 19 chromosome 11 and 4 chromosome 1 markers. Ten newly designed primers are reported. The X-irradiation hybrids were also studied cytogenetically, for human DNA content, by in situ Cot1 DNA hybridization and by painting the Alu-PCR products from these four lines back onto normal human metaphases. The generation of the translocation hybrids and of the chromosome 11q fragment hybrids is a necessary preliminary to determining whether a achizophrenia-predisposition gene SCZD2 is encoded at this site. 56 refs., 4 figs., 2 tabs.

  13. Recurrent translocation t(10;17)(p15;q21) in minimally differentiated acute myeloid leukemia results in ZMYND11/MBTD1 fusion.

    PubMed

    de Rooij, Jasmijn D E; van den Heuvel-Eibrink, Marry M; Kollen, Wouter J W; Sonneveld, Edwin; Kaspers, Gertjan J L; Beverloo, H Berna; Fornerod, Maarten; Pieters, Rob; Zwaan, C Michel

    2016-03-01

    Pediatric acute myeloid leukemia (AML) is a heterogeneous disease, characterized by different collaborating karyotypic and molecular abnormalities, which are used in risk group stratification. In ∼20% of the pediatric AML cases a specific genetic aberration is still unknown. Minimally differentiated myeloid leukemia or FAB-type M0 is a rare morphological subtype of AML. The translocation t(10;17)(p15;q21) is described to be recurrent in minimally differentiated AML, but the involved genes and location of the breakpoints have so far not been identified. In this study, we show that this translocation results in an in-frame translocation fusing exon 12 of the tumor suppressor gene ZMYND11 to exon 3 of the chromatin protein MBTD1, encoding a protein of 1,054 amino acids, while the reciprocal fusion product is predicted to lack a productive start codon. Gene expression profiling of the leukemic cells showed high HOXA expression. ZMYND11, also known as BS69, is a tumor suppressor that specifically recognizes H3K36me3, which is linked to aberrant HOXA expression in leukemogenesis. Aberrant expression of the genes involved in this fusion may thus contribute to the HOXA-phenotype observed with gene expression profiling. PMID:26608508

  14. Establishment of a human cell line (SKI-DLCL-1) with a t(1;14)(q21;q32) translocation from the ascites of a patient with diffuse large cell lymphoma.

    PubMed

    Goy, A; Gilles, F; Remache, Y; Filippa, D; Portlock, C S; Jhanwar, S C; Zelenetz, A D

    2001-01-01

    Cytogenetic abnormalities at chromosome 1q21 are among the most common second genetic events observed in Non-Hodgkin's Lymphomas and have prognostic significance. Recently, BCL9 has been cloned from a pre-B-cell lymphoblastic leukemia cell line, which carried a t(1:14)(q21;q32). However, among a panel of 39 B-cell malignancies with 1q21 translocation, only two cases showed rearrangement for the BCL9 gene. We report the establishment of a new lymphoma cell line from a patient with relapsed diffuse large cell lymphoma. This cell line SKI-DLCL-1 showed cell surface antigens identical to the original tumor and demonstrated the profile of a mature B-cell phenotype: CD19 and CD20 positive, CD5 and C10 negative. It carried a t(1;14)(q21;q32) translocation identical to the original tumor. Although the clinical presentation was an isolated effusion lymphoma, studies for HIV-1, HHV8 and EBV were all negative. Southern blot analysis demonstrated that BCL9 was not rearranged in the SKI-DLCL-1 cell line. In addition, the BCL9 gene was not over-expressed in SKI-DLCL-1 cell line. The identification of a new locus at 1q21 will help clarify the pathogenesis of B-cell malignancies with a translocation involving this locus. PMID:11426565

  15. The Ah receptor nuclear translocator gene (ARNT) is located on q21 of human chromosome 1 and on mouse chromosome 3 near Cf-3

    SciTech Connect

    Johnson, B.; Brooks, B.A.; Heinzmann, C. ); Mohandas, T. )

    1993-09-01

    The authors have mapped the Ah (aryl hydrocarbon) receptor nuclear translocator (ARNT) gene to a conserved linkage group located on mouse chromosome 3 and human chromosome 1. EcoRi-digested DNA from a panel of 17 human x mouse somatic cell hybrids was probed with a cDNA fragment of the human ARNT gene. Six of the 17 independent mouse x human hybrids were positive for human bands. Human chromosome 1 showed complete cosegregation with the gene, whereas discordant segregation was observed for all other human chromosomes. The human gene was localized to 1q21 by using DNA from mouse x human hybrid clones that retain translocations involving human chromosome 1, by segregation analysis in nine informative CEPH families, and by in situ hybridization. The mouse homologue was mapped to mouse chromosome 3 using a panel of 16 hamster x mouse somatic cell hybrids. Six of 16 mouse x hamster hybrids were positive for mouse bands, showing complete concordance with mouse chromosome 3. The mouse Arnt gene was regionally mapped on chromosome 3, using linkage analysis in an interspecific backcross. The results indicate that the mouse gene resides about 40 cM from the centromere and about 10 cM proximal to Cf-3, the gene for tissue factor. 41 refs., 4 figs., 5 tabs.

  16. Soft-tissue aneurysmal bone cyst with translocation t(17;17)(p13;q21) corresponding to COL1A1 and USP6 loci.

    PubMed

    Jacquot, Cyril; Szymanska, Jadwiga; Nemana, Lakshmi J; Steinbach, Lynne S; Horvai, Andrew E

    2015-11-01

    We present the case of a 46-year-old woman with no significant past medical history who developed left mid-thigh pain and fullness. Imaging demonstrated a mineralized soft-tissue mass, which increased in size during a year of monitoring, but retained a circumscribed appearance. The mass was located in the medial soft tissues of the thigh, separate from the bone on imaging studies, and this finding was confirmed during excision. The mass showed gross and microscopic features of an aneurysmal bone cyst. This diagnosis was supported by cytogenetic analysis revealing a t(17;17)(p13;q21) translocation corresponding to the USP6 and COL1A1 loci. Soft-tissue aneurysmal bone cyst is a rare entity, with fewer than 25 reports in the literature. Limited cytogenetic information about these tumors is available. To our knowledge, the USP6 and COL1A1 rearrangement has only previously been described in a pediatric soft-tissue aneurysmal bone cyst. We also discuss the differential diagnosis of ossifying soft-tissue lesions. PMID:26142538

  17. Familial microduplication of 17q23.1–q23.2 involving TBX4 is associated with congenital clubfoot and reduced penetrance in females.

    PubMed

    Peterson, Jess F; Ghaloul-Gonzalez, Lina; Madan-Khetarpal, Suneeta; Hartman, Jessica; Surti, Urvashi; Rajkovic, Aleksandar; Yatsenko, Svetlana A

    2014-02-01

    Congenital clubfoot is a heterogeneous disorder that can result in functional disability, deformity, and pain if left untreated. Although the etiology is considered multifactorial in the majority of cases, a 17q23.1–q23.2 duplication has been reported in families with congenital clubfoot characterized by variable expressivity and incomplete penetrance. The candidate gene within the duplicated region is TBX4, a T-box transcription factor required for normal hind limb development. We describe a familial 2.15 Mb duplication in the 17q23.1–q23.2 region identified in a mother, daughter, and two sons. The male proband was referred for genetic evaluation due to multiple congenital anomalies including bilateral clubfoot, dysplastic hips, multiple heart defects, microcephaly, midfacial hypoplasia, brain anomalies on MRI scan, seizure disorder, optic nerve hypoplasia, hearing loss, and bilateral vocal cord paralysis. Cytogenetic testing on family members identified the 17q23.1–q23.2 duplication in both older siblings and the mother. In this family both male siblings had clubfoot, while females were phenotypically normal. Although TBX4 remains the candidate gene for congenital clubfoot involving 17q23.1–q23.2 duplications, the explanation for variable expressivity and penetrance remains unknown. PMID:24592505

  18. De novo t(12;17)(p13.3;q21.3) translocation with a breakpoint near the 5' end of the HOXB gene cluster in a patient with developmental delay and skeletal malformations.

    PubMed

    Yue, Ying; Farcas, Ruxandra; Thiel, Gundula; Bommer, Christiane; Grossmann, Bärbel; Galetzka, Danuta; Kelbova, Christina; Küpferling, Peter; Daser, Angelika; Zechner, Ulrich; Haaf, Thomas

    2007-05-01

    A boy with severe mental retardation, funnel chest, bell-shaped thorax, and hexadactyly of both feet was found to have a balanced de novo t(12;17)(p13.3;q21.3) translocation. FISH with BAC clones and long-range PCR products assessed in the human genome sequence localized the breakpoint on chromosome 17q21.3 to a 21-kb segment that lies <30 kb upstream of the HOXB gene cluster and immediately adjacent to the 3' end of the TTLL6 gene. The breakpoint on chromosome 12 occurred within telomeric hexamer repeats and, therefore, is not likely to affect gene function directly. We propose that juxtaposition of the HOXB cluster to a repetitive DNA domain and/or separation from required cis-regulatory elements gave rise to a position effect. PMID:17327879

  19. Prenatal diagnosis of del(15)(q26.1) and del(18)(q21.3) due to an unbalanced de novo translocation: ultrasound, molecular cytogenetic and autopsy findings.

    PubMed

    Froster, U G; Horn, L C; Holland, H; Strenge, S; Faber, R

    2000-12-01

    A case of partial deletion of the distal parts of chromosomes 15 and 18 [(15)(q26.1)(18)(q21.3)] due to a de novo translocation is reported. Cordocentesis and fetal karyotyping was done because of severe oligohydramnios and bilateral absence of kidneys. Renal defects are a frequent finding in fetuses with different chromosomal anomalies; this particular chromosomal rearrangement however has not been reported yet in a fetus with bilateral renal agenesis. FISH was performed for detailed clarification of the chromosomal anomaly. Prenatal karyotyping appears to be important in fetuses with renal agenesis. PMID:11113912

  20. Unique de novo interstitial deletion of chromosome 17, del(17) (q23.2q24.3) in a female newborn with multiple congenital anomalies

    SciTech Connect

    Levin, M.L.; Shaffer, L.G.; Lewis, R.L.

    1995-01-02

    We describe a newborn with a novel interstitial deletion of the long arm of chromosome 17 (del(17) (q23.2q24.3)) who died on day of life 17 during a recurrent apneic episode. Her phenotype included severe growth retardation, multiple facial anomalies, maldeveloped oralpharyngeal structures, and digital and widespread skeletal anomalies. This patient`s phenotype was compared to two other reported patients with deletion 17q with minor clinical overlap consistent with a unique deletion. 9 refs., 2 figs.

  1. Coexistence of alternative MLL-SEPT9 fusion transcripts in an acute myeloid leukemia with t(11;17)(q23;q25).

    PubMed

    Santos, Joana; Cerveira, Nuno; Correia, Cecília; Lisboa, Susana; Pinheiro, Manuela; Torres, Lurdes; Bizarro, Susana; Vieira, Joana; Viterbo, Luisa; Mariz, José M; Teixeira, Manuel R

    2010-02-01

    We present the characterization at the RNA level of an acute myeloid leukemia with a t(11;17)(q23;q25) and a MLL rearrangement demonstrated by FISH. Molecular analysis led to the identification of two coexistent in-frame MLL-SEPT9 fusion transcripts (variants 1 and 2), presumably resulting from alternative splicing. Real-time quantitative RT-PCR analysis showed that the relative expression of the MLL-SEPT9 fusion variant 2 was 1.88 fold higher than the relative expression of MLL-SEPT9 fusion variant 1. This is the first description of a MLL-SEPT9 fusion resulting in coexistence of two alternative splicing variants, each of which previously found isolated in myeloid leukemias. PMID:20113838

  2. A unique de novo interstitial deletion of chromosome 17, del(17)(q23.2q24.3) in a female newborn with multiple congenital anomalies

    SciTech Connect

    Levin, M.L.; Shaffer, L.G.; Lewis, R.A.

    1994-09-01

    Contiguous gene or microdeletion syndromes occurring on chromosome 17p include the Smith-Magenis and Miller-Dieker syndromes associated with interstitial deletions of 17p11.2 and 17p13.3, respectively. Other cytogenetically visible interstitial deletions on chromosome 17 are quite rare or unique. We describe a newborn with a novel interstitial deletion of the long arm of chromosome 17 [del(17)(q23.2q24.3)] who died on day of life 17 during a recurrent apneic episode. We have compared our patient`s phenotype and karyotype to two reported patients with deletion 17q with minor clinical overlap. The most striking clinical features of this patient were severe intrauterine growth retardation, widespread skeletal malformations (split sutures, hypoplastic acetabulae and scapulae, vertebral anomalies, and digital hypoplasia), cutis verticis gyrata, dysmorphic facial features, and oropharyngeal malformations (absent uvula and submucous cleft palate). Mild congenital heart disease and anomalous optic nerves were also present. Parental karyotyps were normal. DNA from parents and patient has been collected and cell lines established on both parents. Genes which have been previously mapped to the region that is apparently deleted in this patient include: chorionic somatomammotropin A, growth hormone (normal), acid alpha-glucosidase, apolipoprotein H, and the alpha peptide of type 4 voltage gated sodium channel. As in other clinical cytogenetic syndromes, further descriptions of patients with similar or overlapping rearrangements in this region will be necessary to delineate genotype/phenotype correlations for chromosome 17.

  3. Leukemia breakpoint region in 3q21 is gene rich.

    PubMed

    Rynditch, A; Pekarsky, Y; Schnittger, S; Gardiner, K

    1997-07-01

    Rearrangements of the long arm of human chromosome 3, including reciprocal translocations, inversions and deletion/duplication of bands 3q21-3q26, as well as deletions of 3q21 and reciprocal translocations between 3q21 and other chromosomes, are well documented in leukemia. Previous studies showed that the breakpoints within 3q21 cluster within a 10-40 kb region but no candidate genes were described. In this work, we have identified partial cDNAs corresponding to five to nine new transcripts from an 80 kb P1 clone that spans ten breakpoints. These transcripts, with one exception, appear to be expressed only at low levels in the set of cancer cell lines examined. Four transcripts are located between the previously mapped Ribophorin I gene and the most centromeric breakpoint; three map directly within the 20 kb spanning nine independent breakpoints. These data (i) show that among characterized leukemia breakpoint regions 3q21 is unusually gene rich, (ii) provide new candidates for relevance to leukemia in 3q21, and (iii) suggest possibilities for chromatin configuration effects. PMID:9249066

  4. Severe Progressive Autism Associated with Two de novo Changes: A 2.6-Mb 2q31.1 Deletion and a Balanced t(14;21)(q21.1;p11.2) Translocation with Long-Range Epigenetic Silencing of LRFN5 Expression.

    PubMed

    de Bruijn, D R H; van Dijk, A H A; Pfundt, R; Hoischen, A; Merkx, G F M; Gradek, G A; Lybæk, H; Stray-Pedersen, A; Brunner, H G; Houge, G

    2010-02-01

    In a 19-year-old severely autistic and mentally retarded girl, a balanced de novo t(14;21)(q21.1;p11.2) translocation was found in addition to a de novo 2.6-Mb 2q31.1 deletion containing 15 protein-encoding genes. To investigate if the translocation might contribute to developmental stagnation at the age of 2 years with later regression of skills, i.e. a more severe phenotype than expected from the 2q31.1 deletion, the epigenetic status and expression of genes proximal and distal to the 14q21.1 breakpoint were investigated in Ebstein Barr Virus-transformed lymphoblast and primary skin fibroblast cells. The 14q21.1 breakpoint was found to be located between a cluster of 7 genes 0.1 Mb upstream, starting with FBXO33, and the single and isolated LRFN5 gene 2.1 Mb downstream. Only expression of LRFN5 appeared to be affected by its novel genomic context. In patient fibroblasts, LRFN5 expression was 10-fold reduced compared to LRFN5 expressed in control fibroblasts. In addition, a relative increase in trimethylated histone H3 lysine 9 (H3K9M3)-associated DNA starting exactly at the translocation breakpoint and going 2.5 Mb beyond the LRFN5 gene was found. At the LRFN5 promoter, there was a distinct peak of trimethylated histone H3 lysine 27 (H3K27M3)-associated DNA in addition to a diminished trimethylated histone H3 lysine 4 (H3K4M3) level. We speculate that dysregulation of LRFN5, a postsynaptic density-associated gene, may contribute to the patient's autism, even though 2 other patients with 14q13.2q21.3 deletions that included LRFN5 were not autistic. More significantly, we have shown that translocations may influence gene expression more than 2 Mb away from the translocation breakpoint. PMID:20648246

  5. MSF (MLL septin-like fusion), a fusion partner gene of MLL, in a therapy-related acute myeloid leukemia with a t(11;17)(q23;q25)

    PubMed Central

    Osaka, Mitsuhiko; Rowley, Janet D.; Zeleznik-Le, Nancy J.

    1999-01-01

    MLL (ALL1, Htrx, HRX), which is located on chromosome band 11q23, frequently is rearranged in patients with therapy-related acute myeloid leukemia who previously were treated with DNA topoisomerase II inhibitors. In this study, we have identified a fusion partner of MLL in a 10-year-old female who developed therapy-related acute myeloid leukemia 17 months after treatment for Hodgkin’s disease. Leukemia cells of this patient had a t(11;17)(q23;q25), which involved MLL as demonstrated by Southern blot analysis. The partner gene was cloned from cDNA of the leukemia cells by use of a combination of adapter reverse transcriptase–PCR, rapid amplification of 5′ cDNA ends, and blast database analysis to identify expressed sequence tags. The full-length cDNA of 2.8 kb was found to be an additional member of the septin family, therefore it was named MSF (MLL septin-like fusion). Members of the septin family conserve the GTP binding domain, localize in the cytoplasm, and interact with cytoskeletal filaments. A major 4-kb transcript of MSF was expressed ubiquitously; a 1.7-kb transcript was found in most tissues. An additional 3-kb transcript was found only in hematopoietic tissues. By amplification with MLL exon 5 forward primer and reverse primers in MSF, the appropriately sized products were obtained. MSF is highly homologous to hCDCrel-1, which is a partner gene of MLL in leukemias with a t(11;22)(q23;q11.2). Further analysis of MSF may help to delineate the function of MLL partner genes in leukemia, particularly in therapy-related leukemia. PMID:10339604

  6. Molecular cloning and characterization of 3q21 breakpoints from leukemia-associated t(3;3)(q21;q26)

    SciTech Connect

    Gardiner, K.; Pekarsky, Y.; Zabarovsky, E.

    1994-09-01

    A variety of rearrangements of 3q21, including deletion, translocation with 3q26 and other chromosomes, and inversion of 3q21-3q26, have been associated with hematological malignancy. To begin characterization of the 3q21 breakpoint region, the der3q- and der3q+ chromosomes from 2 separate leukemia patients carrying t(3;3)(q21;q26) have been isolated in hybrid cell lines, and the der3q- chromosomes analyzed extensively. In both cases, the 3q26 breakpoints occur between the EAP and EVI1 genes without direct rearrangement of either gene. In 3q21, 2 NotI linking clones have been identified that are physically linked on a 50 kb NotI fragment that spans both 3q21 breakpoints. To characterize this region further, an 80 kb P1 clone containing both NotI clones has been isolated from the Dupont total human P1 library. The breakpoints have been localized within this clone to SacI fragments of 1 kb and 0.8 kb that are separated by 9 kb. This is preliminary evidence suggesting that the 3q21 leukemia breakpoints may be generally more clustered than those within 3q26. Rare restriction site mapping of the P1 clone shows a high density of sites and suggests a GC-rich and therefore potentially gene-rich region. Sequence analysis of the breakpoint fragments has so far yielded no homologies with known genes; however, preliminary analysis around the NotI site 35 kb centromeric to the breakpoints shows homology with several transcription factor genes. Isolation of all genes within the P1 clone is in progress.

  7. Characterization of a 16 Mb interstitial chromosome 7q21 deletion by tiling path array CGH.

    PubMed

    Tzschach, Andreas; Menzel, Corinna; Erdogan, Fikret; Schubert, Marei; Hoeltzenbein, Maria; Barbi, Gotthold; Petzenhauser, Christine; Ropers, Hans-Hilger; Ullmann, Reinhard; Kalscheuer, Vera

    2007-02-15

    We report on a 42-year-old female patient with an interstitial 16 Mb deletion in 7q21.1-21.3 and a balanced reciprocal translocation between chromosomes 6 and 7 [karyotype 46,XX,t(6;7)(q23.3;q32.3)del(7)(q21.1q21.3)de novo]. We characterized the size and position of the deletion by tiling path array comparative genomic hybridization (CGH), and we mapped the translocation breakpoints on chromosomes 6 and 7 by FISH. The clinical features of this patient-severe mental retardation, short stature, microcephaly and deafness-are in accordance with previously reported patients with 7q21 deletions. Chromosome band 7q21.3 harbors a locus for split hand/split foot malformation (SHFM1), and part of this locus, including the SHFM1 candidate genes SHFM1, DLX5, and DLX6, is deleted. The absence of limb abnormalities in this patient suggests either a location of the SHFM1 causing factor distal to this deletion, or reduced penetrance of haploinsufficiency of a SHFM1 factor within the deleted interval. PMID:17230488

  8. Genetics Home Reference: 1q21.1 microduplication

    MedlinePlus

    ... Genetics Home Health Conditions 1q21.1 microduplication 1q21.1 microduplication Enable Javascript to view the expand/collapse ... Download PDF Open All Close All Description 1q21.1 microduplication is a chromosomal change in which a ...

  9. Unusually mild manifestations of dup(15) (q21.2-qter) in a patient with an unbalanced t(X;15) (q26;q21.2)

    SciTech Connect

    Bawle, E.V.; Conard, J.V.; Ebrahim, S.A.D.

    1994-09-01

    A 4.5 year old girl was noted to have seizures from age 6 months to 18 months. Delayed psychomotor development was noted by 14 months. At 4.5 years of age, she functioned at 2.5-3 year old level. Her gross motor skills were at 4 year level but expressive language was at 1 year level. Clinical manifestations at 4.5 years included normal physical growth (the weight, height, head circumference were consistently at 50th centile since birth), mild micrognathia, alternating esotropia, deeply grooved philtrum like her mother, slightly low set ears, clinodactyly of left 5th finger and 2nd toes. EEG repeatedly showed generalized paroxysmal activity although no more clinical seizures were noted. Karyotype showed 46,X,der(X)t(X;15)(q26.1;q21.2)mat chromosome consititution resulting in a net duplication of 15q21.2-qter and deletion of Xq26-qter. Karyotypes of the mother and maternal grandmother were 46,X,t(X;15)(q26;q21.2). Review of the literature showed about 38 cases of duplication of distal 15q, only 1 of which involved an X;autosome translocation. These showed moderate to severe mental deficiency and significant dysmorphic features. X inactivation studies using R-banding after BrDU incorporation showed the der(X) to be late replicating (genetically active). In the mother, the normal X appeared to be late replicating. The milder phenotype of the proband suggests that the preferential inactivation of the der(X) spread to the 15q portion even though the autosomal segment was not late replicating. Thus the replication pattern of der(X) in unbalanced X-autosome translocations may be independent of activation or inactivation of autosomal genes.

  10. Complex Phenotype Associated with 17q21.31 Microdeletion

    PubMed Central

    Dornelles-Wawruk, H.; Pic-Taylor, A.; Rosenberg, C.; Krepischi, A.C.V.; Safatle, H.P.N.; Ferrari, I.; Mazzeu, J.F.

    2013-01-01

    We report on a patient carrying a 17q21.31 microdeletion and exhibiting many common syndrome features, together with other clinical signs which have rarely or never been described to date. The detected 695-kb 17q21.31 deletion is larger than in most previously reported cases but is still probably the result of recombination between flanking low-copy repeats. Due to the complexity of the patient's clinical condition, together with the presence of 3 previously unreported symptoms, namely chronic anemia, cervical vertebrae arthrosis and vertebrae fusion, this case is an important addition to the existing knowledge about the 17q21.31 microdeletion syndrome. PMID:24167466

  11. Genetics Home Reference: 1q21.1 microdeletion

    MedlinePlus

    ... 1 region may also be risk factors for schizophrenia. Some people with a 1q21.1 microdeletion do ... D, Stefansson K. Large recurrent microdeletions associated with schizophrenia. Nature. 2008 Sep 11;455(7210):232-6. ...

  12. A der(11)t(4;11)(q21;p15) in a T-ALL/LBL patient.

    PubMed

    Colli, Sandra; Furforo, Lilian; Rojo Pisarello, Eduardo; Maidana, Marcela; Martín, Carlos; Bordone, Javier; Slavutsky, Irma

    2016-04-01

    Translocation t(4;11)(q21;p15) is a rare recurrent change associated to T-cell acute leukemia. In most cases, this alteration appears as the only abnormality or as part of a simple karyotype. In this report, we present the first case of T acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) with the unbalanced translocation der(11)t(4;11)(q21;p15) as part of a very complex karyotype with multiple chromosome abnormalities, most of them not previously described in the literature. FISH (fluorescence in situ hybridization) and spectral karyotype (HiSKY) analysis confirmed the presence of complex alterations. The patient, a 16-year-old male, showed poor response to treatment and short survival (11 months). A detailed review of previously reported cases with t(4;11)(q21;p15) is also provided. The description of this type of alterations may contribute to the identification of new molecular mechanism associated to neoplastic development. PMID:26883452

  13. Deletion (11)(q14.1q21)

    SciTech Connect

    Stratton, R.F.; Lazarus, K.H.; Ritchie, E.J.L.; Bell, A.M.

    1994-02-01

    The authors report on a 4-year-old girl with moderate development delay, horseshoe kidney, bilateral duplication of the ureters with right upper pole obstruction, hydronephrosis and nonfunction, and subsequent Wilms tumor of the right lower pole. She had an interstitial deletion of the long arm of chromosome 11 involving the region 11(q14.1q21). 22 refs., 2 figs., 1 tab.

  14. Focal cortical dysplasia, microcephaly and epilepsy in a boy with 1q21.1-q21.3 duplication.

    PubMed

    Milone, Roberta; Valetto, Angelo; Battini, Roberta; Bertini, Veronica; Valvo, Giulia; Cioni, Giovanni; Sicca, Federico

    2016-05-01

    The recent advance of new molecular technologies like array - Comparative Genomic Hybridization has fostered the detection of genomic imbalances in subjects with intellectual disability, epilepsy, and/or congenital anomalies. Though some of the rearrangements are relatively frequent, their consequences on phenotypes can be strongly variable. We report on a boy harbouring a de novo 8.3 Mb duplication of chromosome 1q21.1-q21.3 whose complex unusual phenotype deserves attention, due to the presence of focal cortical dysplasia, microcephaly, and epilepsy. Loss-of-function (LOF) effects of genes associated with human disease involved in the rearrangement have been only partially established, and have not been previously associated with brain malformations in several deletion syndromes. Less is known, instead, about the consequences of their duplication on neuronal migration and brain development process. Further advance in neuroimaging and genetic research will help in defining their actual role in neurodevelopment and cerebral cortex malformations. PMID:26975584

  15. Agnathia-holoprosencephaly associated with a 46,XY,-21,+t(21q;21q) karyotype

    SciTech Connect

    Niedermeyer, K.K.; McCorquodale, M.M.; Burton, B.K.

    1994-09-01

    We report an unusual case of agnathia-holoprosencephaly associated with Down syndrome due to a 21/21 translocation. The patient presented prenatally at 21 wks gestation. A fetal ultrasound revealed multiple CNS anomalies including hydrocephalus, compressed cerebellum, absent septum pellucidum and possible cranial meningocele or encephalocele. High resolution ultrasound & fetal karyotype were recommended. The patient refused & elected to have a pregnancy termination. Chromosomal analysis performed on products of conception revealed a 46,XY,-21,+t(21q;21q) karyotype. Fluorescence in situ hybridization was performed and confirmed the 21/21 translocation chromosome. An autopsy revealed agnathia and multiple CNS anomalies including absence of the septum pellucidum, absence of the corpus callosum, arhinencephaly, an occiptal meningoencephalocele, dilation of the lateral ventricles, and extensive dysgenesis & heterotopias of the central cerebrum & mid-brain. Additional abnormalities included a persistent left superior vena cava, atrial & ventricular septal defects, irregular length of the fingers with absence of the middle phalanges of the right 2nd and 5th & left 5th digits and bilateral simian creases. Agnathia can be an isolated abnormality but often is associated with holoprosencephaly and/or situs inversus. The majority of familial case of agnathis-holoprosencephaly was caused by an inherited unbalanced translocation resulting in duplication of 6p and monosomy of 18p. Our patient had a translocation form of trisomy 21 but did not have a phenotype consistent with Down syndrome. Trisomy 21 has not been previously reported in other cases of agnathia-holoprosencephaly. Whether the chromosomal abnormality caused the phenotypic abnormalities or if it is a coincidental finding cannot be determined.

  16. The t(14;18)(q32;q21) with extra MYC signal - is it a gray zone lymphoma?

    PubMed Central

    Chang, Qin A; Qasem, Abdulraheem; Madhusudhana, Sheshadri; Glazyrin, Alexey

    2015-01-01

    Double-hit lymphomas (DHL) are defined as B-cell lymphoma with a chromosomal breakpoint affecting the MYC/8q24 locus in combination with rearrangement at (14;18)(q32;q21). We recently observed three cases of B-cell lymphoma with an extra intact MYC signal in association with the t(14;18)(q32;q21) translocation. The impact of an extra copy of MYC to the clinical course and prognosis of one patient with Diffuse Large B Cell Lymphoma (DLBCL) and two patients with Follicular Lymphoma (FL) was evaluated. Flow cytometry in all cases demonstrated lambda- or kappa-light chain restricted CD20 and CD10 positive neoplastic B cells. FISH analysis was negative for MYC gene rearrangement but demonstrated an extra copy of intact MYC. Tissue sections displayed typical starry sky “gray zone” lymphoma morphology in case of DLBCL and FL morphology in cases 2 and 3, with high Ki67 labeling in all three cases. All patients responded well to initial chemotherapy although displayed variant outcome after initial remission. The patient with DLBCL deceased within a year of diagnosis while the other two patients with FL showed much better overall survival. Our limited experience showed that additional copy of intact MYC may be equivalent to “classic” DHL on the background of DLBCL with additional cytogenetic abnormalities, however isolated t(14;18)(q32;q21) translocation in combination with additional copy of intact MYC may demonstrate histology and clinical outcome more comparable with “classic” low grade follicular lymphoma, albeit with more aggressive morphology. PMID:26464726

  17. Isolated trisomy 7q21.2-31.31 resulting from a complex familial rearrangement involving chromosomes 7, 9 and 10

    PubMed Central

    2011-01-01

    Background Genotype-phenotype correlations for chromosomal imbalances are often limited by overlapping effects of partial trisomy and monosomy resulting from unbalanced translocations and by poor resolution of banding analysis for breakpoint designation. Here we report the clinical features of isolated partial trisomy 7q21.2 to 7q31.31 without overlapping phenotypic effects of partial monosomy in an 8 years old girl. The breakpoints of the unbalanced rearranged chromosome 7 could be defined precisely by array-CGH and a further imbalance could be excluded. The breakpoints of the balanced rearranged chromosomes 9 and 10 were identified by microdissection of fluorescence labelled derivative chromosomes 9 and 10. Results The proband's mother showed a complex balanced translocation t(9;10)(p13;q23) with insertion of 7q21.2-31.31 at the translocation breakpoint at 9p13. The daughter inherited the rearranged chromosomes 9 and 10 but the normal chromosome 7 from her mother, resulting in partial trisomy 7q21.2 to 7q31.31. The phenotype of the patient consisted of marked developmental retardation, facial dysmorphism, short stature, strabism, and hyperextensible metacarpophalangeal joints. Discussion For better understanding of genotype-phenotype correlation a new classification of 7q duplications which will be based on findings of molecular karyotyping is needed. Therefore, the description of well-defined patients is valuable. This case shows that FISH-microdissection is of great benefit for precise breakpoint designation in balanced rearrangements. PMID:22136633

  18. Sequencing and Analyzing the "t" (1;7) Reciprocal Translocation Breakpoints Associated with a Case of Childhood-Onset Schizophrenia/Autistic Disorder

    ERIC Educational Resources Information Center

    Idol, Jacquelyn R.; Addington, Anjene M.; Long, Robert T.; Rapoport, Judith L.; Green, Eric D.

    2008-01-01

    We characterized a "t"(1;7)(p22;q21) reciprocal translocation in a patient with childhood-onset schizophrenia (COS) and autism using genome mapping and sequencing methods. Based on genomic maps of human chromosome 7 and fluorescence in situ hybridization (FISH) studies, we delimited the region of 7q21 harboring the translocation breakpoint to a…

  19. Interstitial deletion of 6q21-q23 associated with split hand

    SciTech Connect

    Tsukahara, Masato; Yoneda, Junko; Azuma, Reiko

    1997-03-31

    We report on a 7-month-old boy with interstitial deletion of 6q21-q23 and split-hand defect. He died at 7 months. This is the fifth patient with distal limb anomaly associated with a rearrangement of 6q21 region, and supports previous suggestions that there may be candidate gene(s) for distal limb development in the 6q21 region. 10 refs., 3 figs., 1 tab.

  20. A new mosaic der(18)t(1;18)(q32.1;q21.3) with developmental delay and facial dysmorphism.

    PubMed

    Choi, Young-Jin; Shin, Eunsim; Jo, Tae Sik; Moon, Jin-Hwa; Lee, Se-Min; Kim, Joo-Hwa; Oh, Jae-Won; Kim, Chang-Ryul; Seol, In Joon

    2016-02-01

    We report the case of a 22-month-old boy with a new mosaic partial unbalanced translocation of 1q and 18q. The patient was referred to our Pediatric Department for developmental delay. He showed mild facial dysmorphism, physical growth retardation, a hearing disability, and had a history of patent ductus arteriosus. White matter abnormality on brain magnetic resonance images was also noted. His initial routine chromosomal analysis revealed a normal 46,XY karyotype. In a microarray-based comparative genomic hybridization (aCGH) analysis, subtle copy number changes in 1q32.1-q44 (copy gain) and 18q21.33-18q23 (copy loss) suggested an unbalanced translocation of t(1;18). Repeated chromosomal analysis revealed a low-level mosaic translocation karyotype of 46,XY,der(18)t(1;18)(q32.1;q21.3)[12]/46,XY[152]. Because his parents had normal karyotypes, his translocation was considered to be de novo. The abnormalities observed in aCGH were confirmed by metaphase fluorescent in situ hybridization. We report this patient as a new karyotype presenting developmental delay, facial dysmorphism, cerebral dysmyelination, and other abnormalities. PMID:26958068

  1. A new mosaic der(18)t(1;18)(q32.1;q21.3) with developmental delay and facial dysmorphism

    PubMed Central

    Choi, Young-Jin; Shin, Eunsim; Jo, Tae Sik; Lee, Se-Min; Kim, Joo-Hwa; Oh, Jae-Won; Kim, Chang-Ryul; Seol, In Joon

    2016-01-01

    We report the case of a 22-month-old boy with a new mosaic partial unbalanced translocation of 1q and 18q. The patient was referred to our Pediatric Department for developmental delay. He showed mild facial dysmorphism, physical growth retardation, a hearing disability, and had a history of patent ductus arteriosus. White matter abnormality on brain magnetic resonance images was also noted. His initial routine chromosomal analysis revealed a normal 46,XY karyotype. In a microarray-based comparative genomic hybridization (aCGH) analysis, subtle copy number changes in 1q32.1–q44 (copy gain) and 18q21.33–18q23 (copy loss) suggested an unbalanced translocation of t(1;18). Repeated chromosomal analysis revealed a low-level mosaic translocation karyotype of 46,XY,der(18)t(1;18)(q32.1;q21.3)[12]/46,XY[152]. Because his parents had normal karyotypes, his translocation was considered to be de novo. The abnormalities observed in aCGH were confirmed by metaphase fluorescent in situ hybridization. We report this patient as a new karyotype presenting developmental delay, facial dysmorphism, cerebral dysmyelination, and other abnormalities. PMID:26958068

  2. Fine mapping of the autosomal dominant split hand/split foot locus on chromosome 7, band q21. 3-q. 22. 1

    SciTech Connect

    Scherer, S.W.; Tsui, L.C. ); Allen, T.; Kim, J.; Soder, S. ); Poorkaj, P.; Geshuri, D.; Nunes, M.; Stephens, K.; Pagon, R.A. )

    1994-07-01

    Split hand/split foot (SHFD) is a human developmental defect characterized by missing digits, fusion of remaining digits, and a deep median cleft in the hands and feet. Cytogenetic studies of deletions and translocations associated with this disorder have indicated that an autosomal dominant split hand/split foot locus (gene SHFD1) maps to 7q21-q22. To characterize the SHFD1 locus, somatic cell hybrid lines were constructed from cytogenetically abnormal individuals with SHFD. Molecular analysis resulted in the localization of 93 DNA markers to one of 10 intervals surrounding the SHFD1 locus. The translocation breakpoints in four SHFD patients were encompassed by the smallest region of overlap among the SHFD-associated deletions. The order of DNA markers in the SHFD1 critical region has been defined as PON-D7S812-SHFD1-D7S811-ASNS. One DNA marker, D7S811, detected altered restriction enzyme fragments in three patients with translocations when examined by pulsed-field gel electrophoresis (PFGE). These data map SHFD1, a gene that is crucial for human limb differentiation, to a small interval in the q21.3-q.22.1 region of human chromosome 7. 54 refs., 4 figs., 2 tabs.

  3. Proximal microdeletions and microduplications of 1q21.1 contribute to variable abnormal phenotypes

    PubMed Central

    Rosenfeld, Jill A; Traylor, Ryan N; Schaefer, G Bradley; McPherson, Elizabeth W; Ballif, Blake C; Klopocki, Eva; Mundlos, Stefan; Shaffer, Lisa G; Aylsworth, Arthur S

    2012-01-01

    Chromosomal band 1q21.1 can be divided into two distinct regions, proximal and distal, based on segmental duplications that mediate recurrent rearrangements. Microdeletions and microduplications of the distal region within 1q21.1, which are susceptibility factors for a variety of neurodevelopmental phenotypes, have been more extensively studied than proximal microdeletions and microduplications. Proximal microdeletions are known as a susceptibility factor for thrombocytopenia-absent radius (TAR) syndrome, but it is unclear if these proximal microdeletions have other phenotypic consequences. Therefore, to elucidate the clinical significance of rearrangements of the proximal 1q21.1 region, we evaluated the phenotypes in patients identified with 1q21.1 rearrangements after referral for clinical microarray testing. We report clinical information for 55 probands with copy number variations (CNVs) involving proximal 1q21.1: 22 microdeletions and 20 reciprocal microduplications limited to proximal 1q21.1 and 13 microdeletions that include both the proximal and distal regions. Six individuals with proximal microdeletions have TAR syndrome. Three individuals with proximal microdeletions and two individuals with larger microdeletions of proximal and distal 1q21.1 have a ‘partial' TAR phenotype. Furthermore, one subject with TAR syndrome has a smaller, atypical deletion, narrowing the critical deletion region for the syndrome. Otherwise, phenotypic features varied among individuals with these microdeletions and microduplications. The recurrent, proximal 1q21.1 microduplications are enriched in our population undergoing genetic testing compared with control populations. Therefore, CNVs in proximal 1q21.1 can be a contributing factor for the development of abnormal phenotypes in some carriers. PMID:22317977

  4. BCL10 nuclear expression and t(11;18)(q21;q21) indicate nonresponsiveness to Helicobacter pylori eradication of Chinese primary gastric MALT lymphoma.

    PubMed

    Dong, Gehong; Liu, Cuiling; Ye, Hongtao; Gong, Liping; Zheng, Jie; Li, Min; Huang, Xin; Huang, Xuebiao; Huang, Yuanjie; Shi, Yunfei; Yin, Wenjuan; Gao, Zifen

    2008-12-01

    The eradication of Helicobacter pylori (H. pylori) with antibiotics induces complete remission in 75% of patients with gastric MALT lymphoma. We investigated the efficacy of H. pylori eradication and assessed the predictive value of BCL10 nuclear expression and t(11;18)(q21;q21) regarding resistance to H. pylori eradication in primary gastric mucosa-associated lymphoid tissue lymphoma (MALT lymphoma) patients from mainland China. Twenty-two gastric MALT cases (Stage I(E)) underwent H. pylori eradication with antibiotics, and sequential endoscopic-bioptic follow-ups were performed and assessed with regular morphologic and immunohistochemical examinations. BCL10 nuclear expression and interphase fluorescence in situ hybridization (FISH) for MALT1 and API2/MALT1 were tested. Thirteen out of the 22 cases (59.1%) achieved complete regression (CR) after the eradication of H. pylori. The longest follow-up period in the 22 patients was 68 months, with 12 patients longer than 24 months. For the 13 CR patients, the longest follow-up period after H. pylori eradication was 53 months, with 6 patients longer than 24 months. BCL10 nuclear expression was detected by immunohistochemical staining in 9 cases, including 7 (77.8%) of 9 cases who showed no response (NR) and 2 (15.4%) of 13 patients who achieved CR following eradication therapy (P < 0.05). t(11;18)(q21;q21) was evaluated by interphase FISH in 18 cases including 11 CR and 7 NR patients after H. pylori eradication. t(11;18)(q21;q21) was found in 4 (57.1%) of 7 patients who showed NR following H. pylori eradication, but one in 11 CR patients (P < 0.05). A total of 59.1% of patients with early gastric MALT lymphoma recruited in this study achieved CR after H. pylori eradication. BCL10 nuclear expression and t(11;18)(q21;q21)-positive gastric MALT lymphomas are likely to be related to a failure to respond to H. pylori eradication in Chinese patients. PMID:18949449

  5. 8q21.11 microdeletion in two patients with syndromic peters anomaly.

    PubMed

    Happ, Hannah; Schilter, Kala F; Weh, Eric; Reis, Linda M; Semina, Elena V

    2016-09-01

    Peters anomaly is a form of anterior segment dysgenesis characterized by central ocular opacity and corneo-lenticular adhesions. Isolated and syndromic Peters anomaly can be observed and demonstrate significant genetic heterogeneity. We report the identification of overlapping 8q21.11 deletions in two patients with syndromic Peters anomaly via whole exome sequencing and chromosomal microarray analyses. Microdeletions of 8q21.11 were recently reported in 10 patients with highly variable phenotypes involving craniofacial features, ptosis, intellectual disability, abnormalities of the hands/feet and other defects; sclerocornea and/or microphthalmia were reported in three cases. The two additional cases presented in this report expand the phenotypic spectrum of 8q21.11 microdeletions to include Peters anomaly (seen in both patients) and persistent primary dentition (seen in one patient with a larger deletion). The two novel deletions include the ZFHX4 and PEX2 genes, which were also affected in all three previous cases involving ocular anomalies. Screening of the remaining alleles of ZFHX4 and PEX2 did not identify any additional likely pathogenic variants in either patient, suggesting a dominant mechanism (haploinsufficiency) for the identified deletion. This report provides further insight into the phenotypes associated with 8q21.11 deletions and, for the first time, reports Peters anomaly as an additional ocular feature; screening for copy number variations of the 8q21.11 region should be considered in patients with Peters anomaly and related syndromic features. © 2016 Wiley Periodicals, Inc. PMID:27378168

  6. Split Hand/Foot Malformation Associated with 7q21.3 Microdeletion: A Case Report.

    PubMed

    Sivasankaran, Aswini; Srikanth, Ambika; Kulshreshtha, Pooja S; Anuradha, Deenadayalu; Kadandale, Jayarama S; Samuel, Chandra R

    2016-02-01

    Split hand/foot malformation (SHFM) or ectrodactyly is a rare genetic condition affecting limb development. SHFM shows clinical and genetic heterogeneity. It can present as an isolated form or in combination with additional anomalies affecting the long bones (nonsyndromic form) or other organ systems including the craniofacial, genitourinary and ectodermal structures (syndromic ectrodactyly). This study reports a girl with SHFM who also exhibited developmental delay, mild dysmorphic facial features and sensorineural hearing loss. High-resolution banding analysis indicated an interstitial deletion within the 7q21 band. FISH using locus-specific BAC probes confirmed the microdeletion of 7q21.3. Chromosomal microarray analysis also revealed a microdeletion of 1.856 Mb in 7q21.3. However, a larger 8.44-Mb deletion involving bands 7q21.11q21.2 was observed, and the breakpoints were refined. The phenotype and the candidate genes underlying the pathogenesis of this disorder are discussed. PMID:27022330

  7. Split Hand/Foot Malformation Associated with 7q21.3 Microdeletion: A Case Report

    PubMed Central

    Sivasankaran, Aswini; Srikanth, Ambika; Kulshreshtha, Pooja S.; Anuradha, Deenadayalu; Kadandale, Jayarama S.; Samuel, Chandra R.

    2016-01-01

    Split hand/foot malformation (SHFM) or ectrodactyly is a rare genetic condition affecting limb development. SHFM shows clinical and genetic heterogeneity. It can present as an isolated form or in combination with additional anomalies affecting the long bones (nonsyndromic form) or other organ systems including the craniofacial, genitourinary and ectodermal structures (syndromic ectrodactyly). This study reports a girl with SHFM who also exhibited developmental delay, mild dysmorphic facial features and sensorineural hearing loss. High-resolution banding analysis indicated an interstitial deletion within the 7q21 band. FISH using locus-specific BAC probes confirmed the microdeletion of 7q21.3. Chromosomal microarray analysis also revealed a microdeletion of 1.856 Mb in 7q21.3. However, a larger 8.44-Mb deletion involving bands 7q21.11q21.2 was observed, and the breakpoints were refined. The phenotype and the candidate genes underlying the pathogenesis of this disorder are discussed. PMID:27022330

  8. 17q21 variants modify the association between early respiratory infections and asthma.

    PubMed

    Smit, L A M; Bouzigon, E; Pin, I; Siroux, V; Monier, F; Aschard, H; Bousquet, J; Gormand, F; Just, J; Le Moual, N; Nadif, R; Scheinmann, P; Vervloet, D; Lathrop, M; Demenais, F; Kauffmann, F

    2010-07-01

    Single nucleotide polymorphisms (SNPs) at chromosome 17q21 confer an increased risk of early-onset asthma. The objective was to study whether 17q21 SNPs modify associations between early respiratory infections and asthma. Association analysis was conducted in 499 children (268 with asthma, median age 11 yrs) from the Epidemiological Study on the Genetics and Environment of Asthma (EGEA). The 12-yr follow-up data were used to assess persistent or remittent asthma in young adulthood. Respiratory infection before 2 yrs of age was assessed retrospectively. For the 12 17q21 SNPs studied, the odds ratios (OR) for association between infection and early-onset asthma (age at onset q21 risk genotypes and early-life environmental tobacco smoke (ETS) exposure, associations between infection and asthma were further enhanced. 17q21 genetic variants and early ETS exposure enhance the association between early respiratory infections and early-onset asthma and childhood asthma that remits in adulthood. PMID:20032010

  9. t(11;18)(q21;q21)-positive advanced-stage MALT lymphoma associated with monoclonal gammopathy: resistance to rituximab or rituximab-containing chemotherapy.

    PubMed

    Ohno, Hitoshi; Isoda, Kotaro

    2008-11-01

    Here we describe two cases of mucosa-associated lymphoid tissue (MALT) lymphoma with monoclonal immunoglobulins (Igs). The first case was a 77-year-old man with primary lymphoma of the lung. Immunoelectrophoresis detected IgM-kappa in serum and kappa light chain excretion into urine. Three months after treatment with single-agent rituximab, a large amount of pleural fluid was found to have accumulated. The fluid contained CD5(-), CD10(-), CD19(+), CD38(+) and CD138(-/+) lymphoma cells with lymphoplasmacytoid appearance. Although a small fraction of the cells were CD20(+), the majority of the lymphoma cells were negative and expressed surface-membrane IgM-kappa at low levels. The cells possessed a karyotype of 46, XY, t(11;18)(q21;q21). The second case was a 55-year-old man who underwent total gastrectomy due to gastric perforation. Surgical specimens demonstrated the histopathological features of MALT lymphoma associated with plasma cell differentiation. The lymphoma cells had a 46, XY, t(11;18)(q21;q21) karyotype. Monoclonal Igs detected were serum IgA (M)-kappa and urinary kappa light chain. The patient was subsequently treated with six cycles of R-CVP (rituximab, cyclophosphamide, vincristine and prednisolone) ; however, serum monoclonal Ig levels were not affected. The lymphoma cells in both cases may have contained two populations, a rituximab-sensitive CD20(+) population and a rituximab-resistant population that had differentiated into the Ig-secreting plasma cell stage. PMID:19039196

  10. 1q21.1 microduplication in a patient with mental impairment and congenital heart defect.

    PubMed

    Sun, Guowen; Tan, Zhiping; Fan, Liangliang; Wang, Jian; Yang, Yifeng; Zhang, Weizhi

    2015-10-01

    1q21.1 duplication is a rare copy number variant with multiple congenital malformations, including developmental delay, autism spectrum disorder, dysmorphic features and congenital heart anomalies. The present study described a Chinese female patient (age, four years and eight months) with multiple malformations, including congenital heart defect, mental impairment and developmental delay. The parents and the monozygotic twin sister of the patient, however, were physically and psychologically normal. High‑resolution genome‑wide single nucleotide polymorphism array revealed a 1.6‑Mb duplication in chromosome region 1q21.1. This chromosome region contained HFE2, a critical gene involved in hereditary hemochromatosis. However, the parents and monozygotic twin sister of the patient did not carry this genomic lesion. To the best of our knowledge, the present study was the first to report on a 1q21.1 duplication patient in mainland China. PMID:26238956

  11. [Turner's syndrome 45,X/46Xdel(X)(q21): a case report].

    PubMed

    Aiassa, Delia; Bosch, Beatriz; Castellano, Mónica

    2013-01-01

    Turner's syndrome was described by Otto Ullrich (1930) and Henry Turner (1938). An estimated 1 from 2,000 to 3,000 female babies and 1% of the conceptions of female embryos and fetuses have this condition, and 95 to 99% of them result in miscarriage during the first trimester. The case presented concerns a 15 y/o girl who consulted due to primary amenorrhea. The karyotype was 45,X[6]/46Xdel(X)(q21)[14]. Her mother had experienced premature ovarian failure and her karyotype was: 46Xdel(X)(q21)[3]/46,XX[35]. PMID:23381712

  12. De novo interstitial deletion q16.2q21 on chromosome 6

    SciTech Connect

    Villa, A.; Urioste, M.; Luisa, M.

    1995-01-30

    A de novo interstitial deletion of 6q16.2q21 was observed in a 23-month-old boy with mental and psychomotor delay, obese appearance, minor craniofacial anomalies, and brain anomalies. We compare clinical manifestations of this patient with those observed in previously reported cases with similar 6q interstitial deletions. It is interesting to note the clinical similarities between some patients with interstitial deletions of 6q16 or q21 bands and patients with Prader-Willi syndrome (PWS) and it may help to keep in mind cytogenetic studies of patients with some PWS findings. 24 refs., 3 figs., 2 tabs.

  13. Reciprocal translocations

    SciTech Connect

    1993-12-31

    Chapter 26, describes reciprocal translocations of chromosomes: their occurrence, breakpoints, and multiple rearrangements. In addition, phenotypes of balanced and unbalanced translocation carriers and fetal death are discussed. Examples of translocation families are given. Meiosis and genetic risk in translocation carriers is presented. Finally, sperm chromosomes in meiotic segregation analysis is mentioned. 39 refs., 3 figs., 1 tab.

  14. Understanding the impact of 1q21.1 copy number variant

    PubMed Central

    2011-01-01

    Background 1q21.1 Copy Number Variant (CNV) is associated with a highly variable phenotype ranging from congenital anomalies, learning deficits/intellectual disability (ID), to a normal phenotype. Hence, the clinical significance of this CNV can be difficult to evaluate. Here we described the consequences of the 1q21.1 CNV on genome-wide gene expression and function of selected candidate genes within 1q21.1 using cell lines from clinically well described subjects. Methods and Results Eight subjects from 3 families were included in the study: six with a 1q21.1 deletion and two with a 1q21.1 duplication. High resolution Affymetrix 2.7M array was used to refine the 1q21.1 CNV breakpoints and exclude the presence of secondary CNVs of pathogenic relevance. Whole genome expression profiling, studied in lymphoblast cell lines (LBCs) from 5 subjects, showed enrichment of genes from 1q21.1 in the top 100 genes ranked based on correlation of expression with 1q21.1 copy number. The function of two top genes from 1q21.1, CHD1L/ALC1 and PRKAB2, was studied in detail in LBCs from a deletion and a duplication carrier. CHD1L/ALC1 is an enzyme with a role in chromatin modification and DNA damage response while PRKAB2 is a member of the AMP kinase complex, which senses and maintains systemic and cellular energy balance. The protein levels for CHD1L/ALC1 and PRKAB2 were changed in concordance with their copy number in both LBCs. A defect in chromatin remodeling was documented based on impaired decatenation (chromatid untangling) checkpoint (DCC) in both LBCs. This defect, reproduced by CHD1L/ALC1 siRNA, identifies a new role of CHD1L/ALC1 in DCC. Both LBCs also showed elevated levels of micronuclei following treatment with a Topoisomerase II inhibitor suggesting increased DNA breaks. AMP kinase function, specifically in the deletion containing LBCs, was attenuated. Conclusion Our studies are unique as they show for the first time that the 1q21.1 CNV not only causes changes in the

  15. The amplification of 1q21 is an adverse prognostic factor in patients with multiple myeloma in a Chinese population

    PubMed Central

    Yu, Wenjun; Guo, Rui; Qu, Xiaoyan; Qiu, Hairong; Li, Jianyong; Zhang, Run; Chen, Lijuan

    2016-01-01

    The prognostic heterogeneity of multiple myeloma (MM) is largely due to different genetic abnormalities. Cytogenetic analysis has revealed that most of MM harbor chromosome aberrations. Amplification of 1q21 is one of the most common chromosomal aberrations. Interphase fluorescence in situ hybridization was applied to detect the 1q21 amplification in 86 Chinese patients with newly diagnosed MM. Amp(1q21) was found in totally 40 of 86 (46.5%) cases, among which 29 with three copies of 1q21 and eleven with at least four copies of 1q21. Further analysis revealed a significant difference of overall survival and progression-free survival among the three arms (P<0.05). Bortezomib could not significantly improve the overall survival for patients with 1q21 amplification (P>0.05). These findings suggest that 1q21 amplification with four copies or more is prognostic factor for adverse outcomes of MM patients. Furthermore, chromosome 1q21 gains predicted a poor overall survival even in those receiving bortezomib-based regimens. PMID:26834489

  16. Ectrodactyly and tetralogy of Fallot in a fetus with del(6)(q21q23).

    PubMed

    Novikova, I V; Lazarevich, A A; Egorova, T M; Solovyeva, I V; Golovataja, E I; Plevako, T A; Mikheeva, N G; Lurie, I W

    2014-01-01

    We report a fetus with del(6)(q21q23) who had tetralogy of Fallot and ectrodactyly of the right hand. Analysis of the literature showed that both these defects were reported in several patients with similar deletions. The minimal segment responsible for ectrodactyly may be limited to 7.35 Mb (106.650.000-114.600.000). However 1) significant number of patients with this deletion but without ectrodactyly or other defects of extremities, and 2) wide range of unusual birth defects in some persons with deletions of the critical segment allow to propose involvement of regulatory element(s) necessary for the occurrence of ectrodactyly in patients with del 6q21. PMID:24783651

  17. Genetic Mapping of the BRCA1 Region on Chromosome 17q21

    PubMed Central

    Albertsen, Hans; Plaetke, Rosemarie; Ballard, Linda; Fujimoto, Esther; Connolly, Judith; Lawrence, Elizabeth; Rodriguez, Pilar; Robertson, Margaret; Bradley, Paige; Milner, Bruce; Fuhrman, David; Marks, Andy; Sargent, Robert; Cartwright, Peter; Matsunami, Nori; White, Ray

    1994-01-01

    Chromosome 17q21 harbors a gene (BRCA1) associated with a hereditary form of breast cancer. As a step toward identification of this gene itself we developed a number of simple-sequence-repeat (SSR) markers for chromosome 17 and constructed a high-resolution genetic map of a 40-cM region around 17q21. As part of this effort we captured genotypes from five of the markers by using an ABI sequencing instrument and stored them in a locally developed database, as a step toward automated genotyping. In addition, YACs that physically link some of the SSR markers were identified. The results provided by this study should facilitate physical mapping of the BRCA1 region and isolation of the BRCA1 gene. ImagesFigure 2Figure 1 PMID:8116621

  18. The prostatic acid phosphatase (ACPP) gene is localized to human chromosome 3q21-q23

    SciTech Connect

    Li, S.S.L.; Sharief, F.S. )

    1993-09-01

    Human prostatic acid phosphatase (ACPP) has been used as a diagnostic marker for prostate cancer. It is synthesized under androgen regulation and secreted by the epithelial cells of the prostate gland. The authors have confirmed the previous assignment of the ACPP gene to chromosome 3 by probing a panel of 25 human-Chinese hamster somatic cell hybrids, and they have further localized the ACPP gene to chromosome 3q21-q23 by fluorescence in situ hybridization. 10 refs., 1 fig.

  19. De novo interstitial tandem duplication of chromosome 4(q21-q28)

    SciTech Connect

    Navarro, E.G.; Ramon, F.J.H.; Jimenez, R.D.

    1996-03-29

    We describe a girl with a previously unreported de novo duplication of chromosome 4q involving segment q21-q28. Clinical manifestations included growth and psychomotor retardation, facial asymmetry, hypotelorism, epicanthic folds, mongoloid slant of palpebral fissures, apparently low-set auricles, high nasal bridge, long philtrum, small mouth, short neck, low-set thumbs, and bilateral club foot. This phenotype is compared with that of previously reported cases of duplication 4q. 12 refs., 3 figs., 1 tab.

  20. Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2

    PubMed Central

    Ahmed, Shahana; Thomas, Gilles; Ghoussaini, Maya; Healey, Catherine S; Humphreys, Manjeet K; Platte, Radka; Morrison, Jonathan; Maranian, Melanie; Pooley, Karen A; Luben, Robert; Eccles, Diana; Evans, D Gareth; Fletcher, Olivia; Johnson, Nichola; Silva, Isabel dos Santos; Peto, Julian; Stratton, Michael R; Rahman, Nazneen; Jacobs, Kevin; Prentice, Ross; Anderson, Garnet L; Rajkovic, Aleksandar; Curb, J David; Ziegler, Regina G; Berg, Christine D; Buys, Saundra S; McCarty, Catherine A; Feigelson, Heather Spencer; Calle, Eugenia E; Thun, Michael J; Diver, W Ryan; Bojesen, Stig; Nordestgaard, Børge G; Flyger, Henrik; Dörk, Thilo; Schürmann, Peter; Hillemanns, Peter; Karstens, Johann H; Bogdanova, Natalia V; Antonenkova, Natalia N; Zalutsky, Iosif V; Bermisheva, Marina; Fedorova, Sardana; Khusnutdinova, Elza; Kang, Daehee; Yoo, Keun-Young; Noh, Dong Young; Ahn, Sei-Hyun; Devilee, Peter; van Asperen, Christi J; Tollenaar, R A E M; Seynaeve, Caroline; Garcia-Closas, Montserrat; Lissowska, Jolanta; Brinton, Louise; Peplonska, Beata; Nevanlinna, Heli; Heikkinen, Tuomas; Aittomäki, Kristiina; Blomqvist, Carl; Hopper, John L; Southey, Melissa C; Smith, Letitia; Spurdle, Amanda B; Schmidt, Marjanka K; Broeks, Annegien; van Hien, Richard R; Cornelissen, Sten; Milne, Roger L; Ribas, Gloria; González-Neira, Anna; Benitez, Javier; Schmutzler, Rita K; Burwinkel, Barbara; Bartram, Claus R; Meindl, Alfons; Brauch, Hiltrud; Justenhoven, Christina; Hamann, Ute; Chang-Claude, Jenny; Hein, Rebecca; Wang-Gohrke, Shan; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kosma, Veli-Matti; Kataja, Vesa; Olson, Janet E; Wang, Xianshu; Fredericksen, Zachary; Giles, Graham G; Severi, Gianluca; Baglietto, Laura; English, Dallas R; Hankinson, Susan E; Cox, David G; Kraft, Peter; Vatten, Lars J; Hveem, Kristian; Kumle, Merethe; Sigurdson, Alice; Doody, Michele; Bhatti, Parveen; Alexander, Bruce H; Hooning, Maartje J; van den Ouweland, Ans M W; Oldenburg, Rogier A; Schutte, Mieke; Hall, Per; Czene, Kamila; Liu, Jianjun; Li, Yuqing; Cox, Angela; Elliott, Graeme; Brock, Ian; Reed, Malcolm W R; Shen, Chen-Yang; Yu, Jyh-Cherng; Hsu, Giu-Cheng; Chen, Shou-Tung; Anton-Culver, Hoda; Ziogas, Argyrios; Andrulis, Irene L; Knight, Julia A; kConFab; Beesley, Jonathan; Goode, Ellen L; Couch, Fergus; Chenevix-Trench, Georgia; Hoover, Robert N; Ponder, Bruce A J; Hunter, David J; Pharoah, Paul D P; Dunning, Alison M; Chanock, Stephen J; Easton, Douglas F

    2009-01-01

    Genome-wide association studies (GWAS) have identified seven breast cancer susceptibility loci, but these explain only a small fraction of the familial risk of the disease. Five of these loci were identified through a two-stage GWAS involving 390 familial cases and 364 controls in the first stage, and 3,990 cases and 3,916 controls in the second stage1. To identify additional loci, we tested over 800 promising associations from this GWAS in a further two stages involving 37,012 cases and 40,069 controls from 33 studies in the CGEMS collaboration and Breast Cancer Association Consortium. We found strong evidence for additional susceptibility loci on 3p (rs4973768: per-allele OR = 1.11, 95% CI = 1.08–1.13, P = 4.1 × 10−23) and 17q (rs6504950: per-allele OR = 0.95, 95% CI = 0.92–0.97, P = 1.4 × 10−8). Potential causative genes include SLC4A7 and NEK10 on 3p and COX11 on 17q. PMID:19330027

  1. Linkage results on 11q21-22 in Eastern Quebec pedigrees densely affected by schizophrenia

    SciTech Connect

    Maziade, M.; Raymond, V.; Cliche, D.

    1995-12-18

    The 11q21-22 region is of interest for schizophrenia because several candidate genes are located in this section of the genome. The 11q21-22 region, including DRD2, was surveyed by linkage analysis in a sample (N = 242) made of four large multigenerational pedigrees densely affected by schizophrenia (SZ) and eight others by bipolar disorder (BP). These pedigrees were ascertained in a large area of Eastern Quebec and Northern New Brunswick and are still being extended. Family members were administered a {open_quotes}consensus best-estimate diagnosis procedure{close_quotes} (DSM-III-R criteria) blind to probands and relatives` diagnosis and to pedigree assignment (SZ or BP). For linkage analysis, 11 microsatellite polymorphism (CA repeat) markers, located at 11q21-22, and comprising DRD2, were genotyped. Results show no evidence of a major gene for schizophrenia. However, a maximum lod score of 3.41 at the D11S35 locus was observed in an affected-only analysis of one large SZ family, pedigree 255. Whether or not the positive linkage trend in pedigree 255 reflects a true linkage for a small proportion of SZ needs to be confirmed through the extension of this kindred and through replication. 36 refs., 2 tabs.

  2. Inherited 1q21.1q21.2 duplication and 16p11.2 deletion: a two-hit case with more severe clinical manifestations.

    PubMed

    Brisset, Sophie; Capri, Yline; Briand-Suleau, Audrey; Tosca, Lucie; Gras, Domitille; Fauret-Amsellem, Anne-Laure; Pineau, Dominique; Saada, Julien; Ortonne, Valérie; Verloes, Alain; Goossens, Michel; Tachdjian, Gérard; Métay, Corinne

    2015-09-01

    We report paternally inherited duplication of 1q12q21.2 of 5.8 Mb associated with maternally inherited deletion of 16p11.2 of 545 Kb, this latter first identified in a fetus exhibiting an absent nasal bone detected during pregnancy. During the neonatal period, the young boy presented developmental delay, epilepsy, congenital anomalies and overweight. The clinical features of the proband with two rearrangements were more severe than in either of the parents carrying only one or the other mutation. Thus our data support a two-hit model in which the concomitant presence of these two copy-number variations exacerbates the neurodevelopmental phenotype. PMID:26162704

  3. [Familial translocation t(3;22) detected in a carrier child with mental retardation and other abnormalities].

    PubMed

    Gregori Romero, M; Gil Benso, R; López Ginés, C; Pellín Pérez, A; Barberá Guillem, E

    1984-10-31

    A case of familial translocation t(3;22) (q21;q13) detected through a boy carrier with various functional and phenotypical alterations is described. The caryotype study (G bands) showed that the mother, one maternal aunt, two maternal uncles, and the brother of the proband were likewise carriers of the same translocation. We discuss the type of segregation and the high familial incidence of the translocation. PMID:6524770

  4. A de novo microtriplication at 4q21.21-q21.22 in a patient with a vascular malignant hemangioma, elongated sigmoid colon, developmental delay, and absence of speech.

    PubMed

    Lebedev, Igor N; Nazarenko, Lyudmila P; Skryabin, Nikolay A; Babushkina, Nadezhda P; Kashevarova, Anna A

    2016-08-01

    The widespread application of array comparative genomic hybridization (aCGH) has provided new insights into the clinical significance of copy number variations (CNVs) in the human genome. Many microdeletion syndromes have recently been linked to corresponding reciprocal microduplication syndromes related to CNVs in the same chromosomal regions. However, the extent of CNVs may not be restricted to only microduplications but may also include microtriplications or even quadruplications. 4q21 microdeletion syndrome is one of these recently described syndromes. The phenotype includes growth restriction, neonatal hypotonia, severe developmental delay, absent or delayed speech, and distinct facial features. The minimal critical deleted region, which is 1.3 Mb in size, contains the PRKG2, RASGEF1B, HNRNPD, HNRPDL, and ENOPH1 genes. Here, we report a 5.4-year-old girl with developmental delay, absence of speech, muscular hypertension, macrocephaly, a broad forehead, frontal bossing, relatively elongated extremities, a vascular malignant hemangioma in anamnesis, and elongated sigmoid colon. aCGH revealed a microtriplication at 4q21.21-q21.22 that was 1.61 Mb in size. This de novo microtriplication included nine genes (BMP3, PRKG2, RASGEF1B, HNRNPD, HNRPDL, ENOPH1, TMEM150C, LINC00575, and SCD5) and overlapped with the minimal critical region for 4q21 microdeletion syndrome. Some clinical features of the patient were similar to those of 4q21 microdeletion (macrocephaly, frontal bossing, developmental delay, absence of speech, and anxiety), whereas others were mirrored (elongated extremities and muscular hypertension). The first identified case of a de novo microtriplication at 4q21.21-q21.22 emphasizes the clinical significance of CNVs at 4q21 for patients with developmental delay and absence of speech. © 2016 Wiley Periodicals, Inc. PMID:27288323

  5. Recurrent Rearrangements of Chromosome 1q21.1 and Variable Pediatric Phenotypes

    PubMed Central

    Mefford, Heather C.; Sharp, Andrew J.; Baker, Carl; Itsara, Andy; Jiang, Zhaoshi; Buysse, Karen; Huang, Shuwen; Maloney, Viv K.; Crolla, John A.; Baralle, Diana; Collins, Amanda; Mercer, Catherine; Norga, Koen; de Ravel, Thomy; Devriendt, Koen; Bongers, Ernie M.H.F.; de Leeuw, Nicole; Reardon, William; Gimelli, Stefania; Bena, Frederique; Hennekam, Raoul C.; Male, Alison; Gaunt, Lorraine; Clayton-Smith, Jill; Simonic, Ingrid; Park, Soo Mi; Mehta, Sarju G.; Nik-Zainal, Serena; Woods, C. Geoffrey; Firth, Helen V.; Parkin, Georgina; Fichera, Marco; Reitano, Santina; Giudice, Mariangela Lo; Li, Kelly E.; Casuga, Iris; Broomer, Adam; Conrad, Bernard; Schwerzmann, Markus; Räber, Lorenz; Gallati, Sabina; Striano, Pasquale; Coppola, Antonietta; Tolmie, John L.; Tobias, Edward S.; Lilley, Chris; Armengol, Lluis; Spysschaert, Yves; Verloo, Patrick; De Coene, Anja; Goossens, Linde; Mortier, Geert; Speleman, Frank; van Binsbergen, Ellen; Nelen, Marcel R.; Hochstenbach, Ron; Poot, Martin; Gallagher, Louise; Gill, Michael; McClellan, Jon; King, Mary-Claire; Regan, Regina; Skinner, Cindy; Stevenson, Roger E.; Antonarakis, Stylianos E.; Chen, Caifu; Estivill, Xavier; Menten, Björn; Gimelli, Giorgio; Gribble, Susan; Schwartz, Stuart; Sutcliffe, James S.; Walsh, Tom; Knight, Samantha J.L.; Sebat, Jonathan; Romano, Corrado; Schwartz, Charles E.; Veltman, Joris A.; de Vries, Bert B.A.; Vermeesch, Joris R.; Barber, John C.K.; Willatt, Lionel; Tassabehji, May; Eichler, Evan E.

    2009-01-01

    BACKGROUND Duplications and deletions in the human genome can cause disease or predispose persons to disease. Advances in technologies to detect these changes allow for the routine identification of submicroscopic imbalances in large numbers of patients. METHODS We tested for the presence of microdeletions and microduplications at a specific region of chromosome 1q21.1 in two groups of patients with unexplained mental retardation, autism, or congenital anomalies and in unaffected persons. RESULTS We identified 25 persons with a recurrent 1.35-Mb deletion within 1q21.1 from screening 5218 patients. The microdeletions had arisen de novo in eight patients, were inherited from a mildly affected parent in three patients, were inherited from an apparently unaffected parent in six patients, and were of unknown inheritance in eight patients. The deletion was absent in a series of 4737 control persons (P = 1.1×10−7). We found considerable variability in the level of phenotypic expression of the microdeletion; phenotypes included mild-to-moderate mental retardation, microcephaly, cardiac abnormalities, and cataracts. The reciprocal duplication was enriched in the nine children with mental retardation or autism spectrum disorder and other variable features (P = 0.02). We identified three deletions and three duplications of the 1q21.1 region in an independent sample of 788 patients with mental retardation and congenital anomalies. CONCLUSIONS We have identified recurrent molecular lesions that elude syndromic classification and whose disease manifestations must be considered in a broader context of development as opposed to being assigned to a specific disease. Clinical diagnosis in patients with these lesions may be most readily achieved on the basis of genotype rather than phenotype. PMID:18784092

  6. Fusion of FIG to the receptor tyrosine kinase ROS in a glioblastoma with an interstitial del(6)(q21q21).

    PubMed

    Charest, Alain; Lane, Keara; McMahon, Kevin; Park, Julie; Preisinger, Elizabeth; Conroy, Helen; Housman, David

    2003-05-01

    The transmembrane proto-oncogene receptor tyrosine kinase (RTK) ROS is an orphan receptor that is aberrantly expressed in neoplasms of the central nervous system. Here, we report the fusion of its carboxy-terminal kinase domain to the amino-terminal portion of a protein called FIG (Fused in Glioblastoma) in a human glioblastoma multiforme (GBM). By characterizing both FIG and ROS genes in normal and in U118MG GBM cells, we determined that an intra-chromosomal homozygous deletion of 240 kilobases on 6q21 is responsible for the formation of the FIG-ROS locus. The FIG-ROS transcript is encoded by 7 FIG exons and 9 ROS-derived exons. We also demonstrate that the FIG-ROS locus encodes for an in-frame fusion protein with a constitutively active kinase activity, suggesting that FIG-ROS may act as an oncogene. This is the first example of a fusion RTK protein that results from an intra-chromosomal deletion, and it represents the first fusion RTK protein isolated from a human astrocytoma. PMID:12661006

  7. Novel interstitial 2.6 Mb deletion on 9q21 associated with multiple congenital anomalies.

    PubMed

    Pua, Heather H; Krishnamurthi, Swetha; Farrell, Jessica; Margeta, Marta; Ursell, Philip C; Powers, Martin; Slavotinek, Anne M; Jeng, Linda J B

    2014-01-01

    Array comparative genomic hybridization (aCGH) is now commonly used to identify copy number changes in individuals with developmental delay, intellectual disabilities, autism spectrum disorders, and/or multiple congenital anomalies. We report on an infant with multiple congenital anomalies and a novel 2.6 Mb interstitial deletion within 9q21.32q21.33 detected by aCGH. Her clinical presentation included dysmorphic craniofacial features, cleft palate, atrial septal defect, bicornuate uterus, bilateral hip dislocation, hypotonia, and recurrent pneumonia. Parental aCGH studies were negative for copy loss in this region. To our knowledge, no similar deletions have been reported in available databases or published literature. This deletion encompasses 12 genes, and prediction algorithms as well as experimental data suggest that a subset is likely to be haploinsufficient. Included are a neurotrophin receptor (NKG2D), a gene implicated in cilia function (KIF27), an adaptor protein important for ubiquitin-dependent protein quality control (UBQLN1), a gene important for transcription and signaling (HNRNPK), and a gene involved in maintaining genomic stability (RMI1). Identifying additional patients with similar copy losses and further study of these genes will contribute to a better understanding of the pathophysiology of multiple congenital anomalies. PMID:24501764

  8. A Somatic Origin of Homologous Robertsonian Translocations and Isochromosomes

    PubMed Central

    Robinson, W. P.; Bernasconi, F.; Basaran, S.; Yüksel-Apak, M.; Neri, G.; Serville, F.; Balicek, P.; Haluza, R.; Farah, L. M. S.; Lüleci, G.; Schinzel, A. A.

    1994-01-01

    One t(14q14q), three t(15q15q), two t(21q21q), and two t(22q22q) nonmosaic, apparently balanced, de novo Robertsonian translocation cases were investigated with polymorphic markers to establish the origin of the translocated chromosomes. Four cases had results indicative of an isochromosome: one t(14q14q) case with mild mental retardation and maternal uniparental disomy (UPD) for chromosome 14, one t(15q15q) case with the Prader-Willi syndrome and UPD(15), a phenotypically normal carrier of t(22q22q) with maternal UPD(22), and a phenotypically normal t(21q21q) case of paternal UPD(21). All UPD cases showed complete homozygosity throughout the involved chromosome, which is supportive of a postmeiotic origin. In the remaining four cases, maternal and paternal inheritance of the involved chromosome was found, which unambiguously implies a somatic origin. One t(15q15q) female had a child with a ring chromosome 15, which was also of probable postmeiotic origin as recombination between grandparental haplotypes had occurred prior to ring formation. UPD might be expected to result from de novo Robertsonian translocations of meiotic origin; however, all de novo homologous translocation cases, so far reported, with UPD of chromosomes 14, 15, 21, or 22 have been isochromosomes. These data provide the first direct evidence that nonmosaic Robertsonian translocations, as well as isochromosomes, are commonly the result of a mitotic exchange. ImagesFigure 1 PMID:8304346

  9. A somatic origin of homologous Robertsonian translocations and isochromosomes

    SciTech Connect

    Robinson, W.P.; Bernasconi, F.; Schinzel, A.A. ); Basaran, S.; Yueksel-Apak, M. ); Neri, G. ); Serville, F. ); Balicek, P.; Haluza, R. ); Farah, L.M.S. )

    1994-02-01

    One t(14q 14q), three t(15q 15q), two t(21q21q), and two t(22q22q) nonmosaic, apparently balanced, de novo Robertsonian translocation cases were investigated with polymorphic markers to establish the origin of the translocated chromosomes. Four cases had results indicative of an isochromosome: one t(14q14q) case with mild mental retardation and maternal uniparental disomy (UPD) for chromosome 14, one t(15q15q) case with the Prader-Willi syndrome and UPD(15), a phenotypically normal carrier of t(22q22q) with maternal UPD(22), and a phenotypically normal t(21q21q) case of paternal UPD(21). All UPD cases showed complete homozygosity throughout the involved chromosome, which is supportive of a postmeiotic origin. In the remaining four cases, maternal and paternal inheritance of the involved chromosome was found, which unambiguously implies a somatic origin. One t(15q15q) female had a child with a ring chromosome 15, which was also of probable postmeiotic origin as recombination between grandparental haplotypes had occurred prior to ring formation. UPD might be expected to result from de novo Robertsonian translocations of meiotic origin; however, all de novo homologous translocation cases, so far reported, with UPD of chromosomes 14, 15, 21, or 22 have been isochromosomes. These data provide the first direct evidence that nonmosaic Robertsonian translocations, as well as isochromosomes, are commonly the result of a mitotic exchange. 75 refs., 1 fig., 4 tabs.

  10. Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities.

    PubMed

    Brunetti-Pierri, Nicola; Berg, Jonathan S; Scaglia, Fernando; Belmont, John; Bacino, Carlos A; Sahoo, Trilochan; Lalani, Seema R; Graham, Brett; Lee, Brendan; Shinawi, Marwan; Shen, Joseph; Kang, Sung-Hae L; Pursley, Amber; Lotze, Timothy; Kennedy, Gail; Lansky-Shafer, Susan; Weaver, Christine; Roeder, Elizabeth R; Grebe, Theresa A; Arnold, Georgianne L; Hutchison, Terry; Reimschisel, Tyler; Amato, Stephen; Geragthy, Michael T; Innis, Jeffrey W; Obersztyn, Ewa; Nowakowska, Beata; Rosengren, Sally S; Bader, Patricia I; Grange, Dorothy K; Naqvi, Sayed; Garnica, Adolfo D; Bernes, Saunder M; Fong, Chin-To; Summers, Anne; Walters, W David; Lupski, James R; Stankiewicz, Pawel; Cheung, Sau Wai; Patel, Ankita

    2008-12-01

    Chromosome region 1q21.1 contains extensive and complex low-copy repeats, and copy number variants (CNVs) in this region have recently been reported in association with congenital heart defects, developmental delay, schizophrenia and related psychoses. We describe 21 probands with the 1q21.1 microdeletion and 15 probands with the 1q21.1 microduplication. These CNVs were inherited in most of the cases in which parental studies were available. Consistent and statistically significant features of microcephaly and macrocephaly were found in individuals with microdeletion and microduplication, respectively. Notably, a paralog of the HYDIN gene located on 16q22.2 and implicated in autosomal recessive hydrocephalus was inserted into the 1q21.1 region during the evolution of Homo sapiens; we found this locus to be deleted or duplicated in the individuals we studied, making it a probable candidate for the head size abnormalities observed. We propose that recurrent reciprocal microdeletions and microduplications within 1q21.1 represent previously unknown genomic disorders characterized by abnormal head size along with a spectrum of developmental delay, neuropsychiatric abnormalities, dysmorphic features and congenital anomalies. These phenotypes are subject to incomplete penetrance and variable expressivity. PMID:19029900

  11. Cytogenetic and molecular characterization of eight new reciprocal translocations in the pig species. Estimation of their incidence in French populations

    PubMed Central

    Ducos, Alain; Pinton, Alain; Yerle, Martine; Séguéla, Anne; Berland, Hélène-Marie; Brun-Baronnat, Corinne; Bonnet, Nathalie; Darré, Roland

    2002-01-01

    Eight new cases of reciprocal translocation in the domestic pig are described. All the rearrangements were highlighted using GTG banding techniques. Chromosome painting experiments were also carried out to confirm the proposed hypotheses and to accurately locate the breakpoints. Three translocations, rcp(4;6)(q21;p14), rcp(2;6)(p17;q27) and rcp(5;17)(p12;q13) were found in boars siring small litters (8.3 and 7.4 piglets born alive per litter, on average, for translocations 2/6 and 5/17, respectively). The remaining five, rcp(5;8)(p12;q21), rcp(15;17)(q24;q21), rcp(7;8)(q24;p21), rcp(5;8)(p11;p23) and rcp(3;15)(q27;q13) were identified in young boars controlled before entering reproduction. A decrease in prolificacy of 22% was estimated for the 3/15 translocation after reproduction of the boar carrier. A parental origin by inheritance of the translocation was established for the (5;8)(p11;p23) translocation. The overall incidence of reciprocal translocations in the French pig populations over the 2000/2001 period was estimated (0.34%). PMID:12081804

  12. Challenging behaviour in a patient with schizophrenia and a 1q21.1 duplication

    PubMed Central

    Gulati, Gautam; Behrman, Sophie; Khosla, Vivek; Murphy, Valerie

    2014-01-01

    We report the case of a 42-year-old man with a 22-year history of schizophrenia, necessitating frequent detentions under the Mental Health Act for relapses in his mental state and challenging behaviour which has also brought him into contact with the law. His illness has proven resistant to treatment with conventional strategies and he developed serious priapism with clozapine. His challenging behaviour, some of which is not felt to be associated with schizophrenia, complicates any discharge planning from his current detention. Based on a history of childhood cardiac disease, and mildly atypical facies, a genetic screen was requested which showed a 1q21.1 duplication, likely causal in his schizophrenic illness. A review of proteins coded by the locus of the duplication did not reveal any specific targets for pharmacotherapy. PMID:24973346

  13. Localization of disinhibition-dementia-parkinsonism-amyotrophy complex to 17q21-22

    SciTech Connect

    Wilhelmsen, K.C.; Lynch, T.; Pavlou, E.; Higgins, M.; Nygaard, T.G.

    1994-12-01

    Disinhibition-dementia-parkinsonism-amyotrophy complex (DDPAC) is defined by familial adult-onset behavioral disturbance, followed by frontal lobe dementia, parkinsonism, and amyotrophy in variable proportions. A genetic etiology of DDPAC was suspected because of the familial clustering in family Mo, despite their wide geographic distribution. We have mapped the DDPAC locus to a 12-cM (sex averaged) region between D17S800 and D17S787 on chromosome 17q21-22. The basis for the variability of the clinical findings and pathology in DDPAC is unknown but suggests that the DDPAC locus should be screened as a candidate locus in family studies of conditions with behavioral abnormalities and neurological degeneration.

  14. Mapping a gene causing cerebral cavernous malformation to 7q11.2-q21.

    PubMed Central

    Günel, M; Awad, I A; Anson, J; Lifton, R P

    1995-01-01

    Cerebral cavernous malformation is a common disease of the brain vasculature of unknown cause characterized by dilated thin-walled sinusoidal vessels (caverns); these lesions cause varying clinical presentations which include headache, seizure, and hemorrhagic stroke. This disorder is frequently familial, with autosomal dominant inheritance. Using a general linkage approach in two extended cavernous malformation kindreds, we have identified linkage of this trait to chromosome 7q11.2-q21. Multipoint linkage analysis yields a peak logarithm of odds (lod) score of 6.88 with zero recombination with locus D7S669 and localizes the gene to a 7-cM region in the interval between loci ELN and D7S802. Images Fig. 1 Fig. 2 PMID:7604043

  15. Cutaneous features in 17q21.31 deletion syndrome: a differential diagnosis for cardio-facio-cutaneous syndrome

    PubMed Central

    Burkitt Wright, Emma; Donnai, Dian; Johnson, Diana; Clayton-Smith, Jill

    2010-01-01

    Microdeletion of 17q21.31 causes a recurrent recognisable dysmorphic syndrome. Four further patients with 17q21.31 microdeletions are reported here where previously the diagnosis of cardio-facio-cutaneous (CFC) syndrome was suggested. These patients have significant similarities of facial gestalt to previously reported 17q21.31 microdeletion patients, but a striking feature that has not been emphasised previously is the large number of naevi and other pigmentary skin abnormalities that may be present. These features, together with a coarse facial appearance, relative macrocephaly and significant learning disabilities, had led to the previous diagnostic suggestion of CFC syndrome in each of these four cases. PMID:21084979

  16. Clinical characterization of a male patient with the recently described 8q21.11 microdeletion syndrome.

    PubMed

    Quintela, Ines; Barros, Francisco; Castro-Gago, Manuel; Carracedo, Angel; Eiris, Jesus

    2015-06-01

    The 8q21.11 microdeletion syndrome (OMIM # 614230) has been recently described and is primarily characterized by intellectual disability and facial dysmorphism. We describe here a male patient of 9 years 9 months of age with moderate intellectual disability and dysmorphic facial features. A high resolution copy number variation analysis, performed with the Affymetrix Cytogenetics Whole-Genome 2.7 M SNP array, allowed the identification of a heterozygous 7.069 Mb microdeletion at chromosome 8q21.11-q21.13. Clinical comparison of our patient with literature shows many similarities. However, the whole facial appearance of our patient, especially the elongated rather than rounded face and the absence of a wide nasal bridge and epicanthal folds, confers him a phenotype similar only to a subset, but not to the majority, of the hitherto described patients. PMID:25898976

  17. Disruption of genes in the retinoid cascade may explain the microscopic neuroblastoma in a fetus with de novo unbalanced translocation

    SciTech Connect

    Goodman, A.B.

    1995-03-13

    The microscopic neuroblastoma in a fetus with de novo unbalanced translocation (3;10)(q21;q26) may be explained as the disruption of genes in the retinoid cascade, rather than simply a two-hit hypothesis for the development of tumor cells. 5 refs.

  18. Evidence for structural heterogeneity from molecular cytogenetic analysis of dicentric Robertsonian translocations.

    PubMed Central

    Sullivan, B. A.; Jenkins, L. S.; Karson, E. M.; Leana-Cox, J.; Schwartz, S.

    1996-01-01

    Most Robertsonian translocations are dicentric, suggesting that the location of chromosomal breaks leading to their formation occur in the acrocentric short arm. Previous cytogenetic and molecular cytogenetic studies have shown that few Robertsonian translocations retain ribosomal genes or beta-satellite DNA. Breakpoints in satellite III DNA, specifically between two chromosome 14-specific subfamilies, pTRS-47 and pTRS-63, have been indicated for most of the dicentric 14q21q and 13q14q translocations that have been studied. We have analyzed the structure of 36 dicentric translocations, using several repetitive DNA probes that localize to the acrocentric short arm. The majority of the translocations retained satellite III DNA, while others proved variable in structure. Of 10 14q21q translocations analyzed, satellite III DNA was undetected in 1; 6 retained one satellite III DNA subfamily, pTRS-47; and 3 appeared to contain two 14-specific satellite III DNA sub-families, pTRS-47 and pTRS-63. In 10/11 translocations involving chromosome 15, the presence of satellite III DNA was observed. Our results show that various regions of the acrocentric short arm, and, particularly, satellite III DNA sequences, are involved in the formation of Robertsonian translocations. Images Figure 1 Figure 2 Figure 4 Figure 5 Figure 6 PMID:8659523

  19. Del(18)(q12.2q21.1) syndrome: a case report and clinical review of the literature.

    PubMed

    Imataka, G; Ohwada, Y; Shimura, N; Yoshihara, S; Arisaka, O

    2015-09-01

    The terminal deletion of the long arm of chromosome 18 is relatively common among cytogenetic abnormalities, which occur incidentally in approximately 1 in 40,000 live births. Proximal interstitial deletions of the long arm of chromosome 18 are less frequent. The critical region on chromosome 18 of this syndrome is del(18)(q12.2q21.1) and has recently been recognized as a new clinical entity. We describe a 8-year-old boy with developmental delay, obesity, and epilepsy, with characteristic facial anomalies in whom G-banding chromosome analysis revealed a unique karyotype of 46, XY, del(18)(q12.2q21.1). The patient was diagnosed with interstitial deletion chromosome 18q-syndrome. He received weight control therapy from a medical dietitian. For his epilepsy, he was administered oral carbamazepine at 4 mg/kg/day. At age six, he entered a special needs elementary school. After entering school, he often showed hyperkinesis, and was diagnosed with attention deficit hyperactivity disorder with mild mental retardation. Because patients with only del(18)(q12.2q21.1) have no serious associated malformations, physicians should be aware that even adult patients may have 18q-syndrome. Therefore, if epilepsy occurs in patients with minor facial anomalies, psychomotor retardation, obesity, and the possibility of 18q-syndrome with del(18)(q12.2q21.1) should be kept in mind, and chromosome testing should be performed. PMID:26400529

  20. De novo der(X)t(X;10)(q26;q21) with features of distal trisomy 10q: case report of paternal origin identified by late replication with BrdU and the human androgen receptor assay (HAR).

    PubMed Central

    Garcia-Heras, J; Martin, J A; Witchel, S F; Scacheri, P

    1997-01-01

    We describe an 11 year old girl with a de novo unbalanced t(X;10) that resulted in a deletion of Xq26-->Xqter and a trisomy of 10q21-->10qter. Her clinical features were of distal trisomy 10q, but she lacked the cardiovascular and renal malformations observed in duplications of 10q24-->10qter and had only moderate mental retardation. X inactivation was assessed on peripheral blood lymphocytes by late replication with BrdU (LR) and the human androgen receptor assay (HAR). By LR the der(X) was inactive without spreading to 10q21-->10qter in all cells. The HAR assay showed skewed methylation of the paternal allele (90%). The correlation of HAR and LR suggests that the der(X) was paternally inherited and is consistent with data from other de novo balanced and unbalanced X;autosome translocations detected in females. This is the first report of parental origin of a de novo trisomy 10q. Images PMID:9132498

  1. Structural diversity and African origin of the 17q21.31 inversion polymorphism.

    PubMed

    Steinberg, Karyn Meltz; Antonacci, Francesca; Sudmant, Peter H; Kidd, Jeffrey M; Campbell, Catarina D; Vives, Laura; Malig, Maika; Scheinfeldt, Laura; Beggs, William; Ibrahim, Muntaser; Lema, Godfrey; Nyambo, Thomas B; Omar, Sabah A; Bodo, Jean-Marie; Froment, Alain; Donnelly, Michael P; Kidd, Kenneth K; Tishkoff, Sarah A; Eichler, Evan E

    2012-08-01

    The 17q21.31 inversion polymorphism exists either as direct (H1) or inverted (H2) haplotypes with differential predispositions to disease and selection. We investigated its genetic diversity in 2,700 individuals, with an emphasis on African populations. We characterize eight structural haplotypes due to complex rearrangements that vary in size from 1.08-1.49 Mb and provide evidence for a 30-kb H1-H2 double recombination event. We show that recurrent partial duplications of the KANSL1 gene have occurred on both the H1 and H2 haplotypes and have risen to high frequency in European populations. We identify a likely ancestral H2 haplotype (H2') lacking these duplications that is enriched among African hunter-gatherer groups yet essentially absent from West African populations. Whereas H1 and H2 segmental duplications arose independently and before human migration out of Africa, they have reached high frequencies recently among Europeans, either because of extraordinary genetic drift or selective sweeps. PMID:22751100

  2. A novel locus for a hereditary recurrent neuropathy on chromosome 21q21.

    PubMed

    Calpena, E; Martínez-Rubio, D; Arpa, J; García-Peñas, J J; Montaner, D; Dopazo, J; Palau, F; Espinós, C

    2014-08-01

    Hereditary recurrent neuropathies are uncommon. Disorders with a known molecular basis falling within this group include hereditary neuropathy with liability to pressure palsies (HNPP) due to the deletion of the PMP22 gene or to mutations in this same gene, and hereditary neuralgic amyotrophy (HNA) caused by mutations in the SEPT9 gene. We report a three-generation family presenting a hereditary recurrent neuropathy without pathological changes in either PMP22 or SEPT9 genes. We performed a genome-wide mapping, which yielded a locus of 12.4 Mb on chromosome 21q21. The constructed haplotype fully segregated with the disease and we found significant evidence of linkage. After mutational screening of genes located within this locus, encoding for proteins and microRNAs, as well as analysis of large deletions/insertions, we identified 71 benign polymorphisms. Our findings suggest a novel genetic locus for a recurrent hereditary neuropathy of which the molecular defect remains elusive. Our results further underscore the clinical and genetic heterogeneity of this group of neuropathies. PMID:24878226

  3. A radiation hybrid map of the BRCA1 region of chromosome 17q12-q21

    SciTech Connect

    Abel, K.J.; Boehnke, M.; Prahalad, M.; Flejter, W.L.; Watkins, M.; Chandrasekharappa, S.C.; Glover, T.W. Howard Hughes Medical Institute, Ann Arbor, MI ); Ho, P.; VanderStoep, J.; Weber, B.L. ); Collins, F.S. Michigan Human Genome Center, Ann Arbor, MI Howard Hughes Medical Institute, Ann Arbor, MI )

    1993-09-01

    The chromosomal region 17q12-q21 contains a gene (BRCA1) conferring susceptibility to early-onset familial breast and ovarian cancer. An 8000-rad radiation-reduced hybrid (RH) panel was constructed to provide a resource for long-range mapping of this region. A large fraction of the hybrids ([approximately]90%) retained detectable human chromosome 17 sequences. The complete panel of 76 hybrids was scored for the presence or absence of 22 markers from this chromosomal region, including 14 cloned genes, seven microsatellite repeats, and one anonymous DNA segment. Statistical analysis of the marker retention data employing multipoint methods provided both comprehensive and framework maps of this chromosomal region, including distance estimates between adjacent markers. The comprehensive RH map includes 17 loci and spans 179 cRays[sub (8000)]. Likelihood ratios of at least 1000:1 support the 10-locus framework order: cen-D17S250-ERBB2-(THRA1, TOP2A)-D17S855-PPY-D17S190-MTBT1-GP3A-BTR-D17S588-tel. The order obtained from RH mapping, when used in conjunction with other methods, will be useful in linkage analysis of breast cancer families and will facilitate the development of a physical map of this region. 42 refs., 3 figs., 2 tabs.

  4. Reassessing the Evolutionary History of the 17q21 Inversion Polymorphism.

    PubMed

    Alves, Joao M; Lima, Ana C; Pais, Isa A; Amir, Nadir; Celestino, Ricardo; Piras, Giovanna; Monne, Maria; Comas, David; Heutink, Peter; Chikhi, Lounès; Amorim, António; Lopes, Alexandra M

    2015-12-01

    A polymorphic inversion that lies on chromosome 17q21 comprises two major haplotype families (H1 and H2) that not only differ in orientation but also in copy-number. Although the processes driving the spread of the inversion-associated lineage (H2) in humans remain unclear, a selective advantage has been proposed for one of its subtypes. Here, we genotyped a large panel of individuals from previously overlooked populations using a custom array with a unique panel of H2-specific single nucleotide polymorphisms and found a patchy distribution of H2 haplotypes in Africa, with North Africans displaying a higher frequency of inverted subtypes, when compared with Sub-Saharan groups. Interestingly, North African H2s were found to be closer to "non-African" chromosomes further supporting that these populations may have diverged more recently from groups outside Africa. Our results uncovered higher diversity within the H2 family than previously described, weakening the hypothesis of a strong selective sweep on all inverted chromosomes and suggesting a rather complex evolutionary history at this locus. PMID:26560338

  5. The Distribution and Most Recent Common Ancestor of the 17q21 Inversion in Humans

    PubMed Central

    Donnelly, Michael P.; Paschou, Peristera; Grigorenko, Elena; Gurwitz, David; Mehdi, Syed Qasim; Kajuna, Sylvester L.B.; Barta, Csaba; Kungulilo, Selemani; Karoma, N.J.; Lu, Ru-Band; Zhukova, Olga V.; Kim, Jong-Jin; Comas, David; Siniscalco, Marcello; New, Maria; Li, Peining; Li, Hui; Manolopoulos, Vangelis G.; Speed, William C.; Rajeevan, Haseena; Pakstis, Andrew J.; Kidd, Judith R.; Kidd, Kenneth K.

    2010-01-01

    The polymorphic inversion on 17q21, sometimes called the microtubular associated protein tau (MAPT) inversion, is an ∼900 kb inversion found primarily in Europeans and Southwest Asians. We have identified 21 SNPs that act as markers of the inverted, i.e., H2, haplotype. The inversion is found at the highest frequencies in Southwest Asia and Southern Europe (frequencies of ∼30%); elsewhere in Europe, frequencies vary from < 5%, in Finns, to 28%, in Orcadians. The H2 inversion haplotype also occurs at low frequencies in Africa, Central Asia, East Asia, and the Americas, though the East Asian and Amerindian alleles may be due to recent gene flow from Europe. Molecular evolution analyses indicate that the H2 haplotype originally arose in Africa or Southwest Asia. Though the H2 inversion has many fixed differences across the ∼900 kb, short tandem repeat polymorphism data indicate a very recent date for the most recent common ancestor, with dates ranging from 13,600 to 108,400 years, depending on assumptions and estimation methods. This estimate range is much more recent than the 3 million year age estimated by Stefansson et al. in 2005.1 PMID:20116045

  6. Syndromal frontonasal dysostosis in a child with a complex translocation involving chromosomes 3, 7, and 11

    SciTech Connect

    Stevens, C.A.; Qumsiyeh, M.B. |

    1995-02-13

    We report on a 4-year-old boy with typical frontonasal dysostosis and an apparently balanced de novo translocation involving chromosomes 3, 7, and 11, and four breakpoints. The karyotype was 46,XY,t(7;3)(3;11) (7pter{r_arrow}7q21.3::3q27{r_arrow}3qter;3pter{r_arrow}3q23::11q21{r_arrow}11qter;11pter{r_arrow}11q21::3q23{r_arrow}3q27::7q21.3{r_arrow}7qter). In situ hybridization with a chromosome 3 painting probe confirmed the interpretation from GTG banding. The child had a widow`s peak, marked hypertelorism, absence of the nasal tip, and widely separated nares. He also had an atrial septal defect, micropenis, small testes, clubfeet, scoliosis, block C2-4, and structural brain abnormalities on MRI. In review we found two other cases of frontonasal dysostosis with chromosome abnormalities, neither of which was similar to our case. The presence of a de novo (apparently) balanced translocation in our patient may help to locate the gene(s) for frontonasal dysplasia and perhaps other midline craniofacial malformations. 16 refs., 4 figs.

  7. A cohort of balanced reciprocal translocations associated with dyslexia: identification of two putative candidate genes at DYX1.

    PubMed

    Buonincontri, Roberta; Bache, Iben; Silahtaroglu, Asli; Elbro, Carsten; Nielsen, Anne-Mette Veber; Ullmann, Reinhard; Arkesteijn, Ger; Tommerup, Niels

    2011-01-01

    Dyslexia is one of the most common neurodevelopmental disorders where likely many genes are involved in the pathogenesis. So far six candidate dyslexia genes have been proposed, and two of these were identified by rare chromosomal translocations in affected individuals. By systematic re-examination of all translocation carriers in Denmark, we have identified 16 different translocations associated with dyslexia. In four families, where the translocation co-segregated with the phenotype, one of the breakpoints concurred (at the cytogenetic level) with either a known dyslexia linkage region--at 15q21 (DYX1), 2p13 (DYX3) and 1p36 (DYX8)--or an unpublished linkage region at 19q13. As a first exploitation of this unique cohort, we identify three novel candidate dyslexia genes, ZNF280D and TCF12 at 15q21, and PDE7B at 6q23.3, by molecular mapping of the familial translocation with the 15q21 breakpoint. PMID:20798984

  8. Weill-Marchesani syndrome - possible linkage of the autosomal dominant form to 15q21.1

    SciTech Connect

    Wirtz, M.K.; Samples, J.R.; Rust, K.

    1996-10-02

    Weill-Marchesani syndrome comprises short stature, brachydactyly, microspherophakia, glaucoma, and ectopia lentis is regarded as an autosomal recessive trait. We present two families each with affected individuals in 3 generations demonstrating autosomal dominant inheritance of Weill-Marchesani syndrome. Linkage analysis in these 2 families suggests a gene for Weill-Marchesani syndrome maps to 15q21.1. The dislocated lenses and connective tissue disorder in these families suggests that fibrillin-1 and microfibril-associated protein 1, which both map to 15q21.1, are candidate genes for Weill-Marchesani syndrome. Immunohistochemistry staining of skin sections from family 1 showed an apparent decrease in fibrillin staining compared to control individuals. 28 refs., 3 figs., 2 tabs.

  9. A YAC-, P1, and cosmid-based physical map of the BRCA1 region on chromosome 17q21

    SciTech Connect

    Couch, F.J.; Castilla, L.H.; Brody, L.C.

    1995-01-01

    A familial early-onset breast cancer gene (BRCA1) has been localized to chromosome 17q21. To characterize this region and to aid in the identification of the BRCA1 gene, a physical map of a region of 1.0-1.5 Mb between the EDH17B1 and the PPY loci on chromosome 17q21 was generated. The physical map is composed of a yeast artificial chromosome (YAC) and P1 phage contig with one gap. The majority of the interval has also been converted to a cosmid contig. Twenty-three PCR-based sequence-tagged sites (STSs) were mapped to these contigs, thereby confirming the order and overlap of individual clones. This complex physical map of the BRCA1 region was used to isolate genes by a number of gene identification techniques and to generate transcript maps of the region. 32 refs., 4 figs.

  10. Interstitial deletion of 8q21{yields}22 associated with minor anomalies, congenital heart defect, and Dandy-Walker variant

    SciTech Connect

    Donahue, M.L.; Ryan, R.M.

    1995-03-13

    We describe an infant with a deletion of 8q21{yields}22 who had distinct clinical manifestations including minor facial anomalies, a congenital heart defect, a Dandy-Walker variant, and mild to moderate developmental delay. Her facial characteristics included small, wide-spaced eyes, asymmetric bilateral epicanthal folds, a broad nasal bridge, a {open_quotes}carp-shaped{close_quotes} mouth, micrognathia, and prominent, apparently low-set ears. Three other reports describe children with larger proximal deletions of 8q that include 8q21 and q22. These four children all have similar facial appearance. Of the others reported, one had a congenital heart defect and one had craniosynostosis. This case, in addition to the previously noted three cases, helps in delineating a recognizable syndrome. 12 refs., 3 figs., 1 tab.

  11. Regional assignment of the human homebox-containing gene EN1 to chromosome 2q13-q21

    SciTech Connect

    Koehler, A.; Muenke, M. ); Logan, C. ); Joyner, A.L. Samuel Lunenfeld Research Institute, Toronto )

    1993-01-01

    The human homeobox-containing genes EN1 and EN2 are closely related to the Drosophila pattern formation gene engrailed (en), which may be important in brain development, as shown by gene expression studies during mouse embryogenesis. Here, we have refined the localization of EN1 to human chromosome 2q13-q21 using a mapping panel of rodent/human cell hybrids containing different regions of chromosome 2 and a lymphoblastoid cell line with an interstitial deletion, del(2) (q21-q23.2). This regional assignment of EN1 increases to 22 the number of currently known genes on human chromosome 2q that have homologs on the proximal region of mouse chromosome 1. 15 refs., 2 figs.

  12. Robertsonian translocations

    SciTech Connect

    1993-12-31

    Chapter 27, describes the occurrence of Robertsonian translocations (RTs), which refer to the recombination of whole chromosome arms, in both monocentric and dicentric chromosomes. The nonrandom participation of acrocentric chromosomes in RTs is documented by various methods, including unbiased ascertainment and ascertainment through trisomy, infertility, unspecified mental retardation, and Prader-Willi syndrome. Causes of nonrandom participation of chromosomes in RTs is presented, as are the following topics: segregation in carriers of RTs and segregation in sperm cells of RT carriers, interchromosomal effects and conclusions. 48 refs., 3 figs., 2 tabs.

  13. Mild phenotype associated with Inv Dup 8 (q21.2-q22.3) of maternal origin

    SciTech Connect

    Tupler, R.; Pagliano, E.; Barbierato, L.

    1996-03-15

    We report on a girl with a de novo inverted duplication of chromosome 8 (q21.2-q22.3) associated with a mild phenotype. We were able to establish the maternal origin of the rearranged chromosome. We discuss the correlation between genotype and phenotype on the basis of a review of the findings from individuals with partial dup(8q). 6 refs., 4 figs.

  14. Loss of heterozygosis on chromosome 18q21-23 and muscle-invasive bladder cancer natural history

    PubMed Central

    CAI, TOMMASO; MONDAINI, NICOLA; TISCIONE, DANIELE; DAL CANTO, MAURIZIO; SANTI, RAFFAELLA; BARTOLETTI, RICCARDO; NESI, GABRIELLA

    2015-01-01

    Loss of heterozygosis (LOH) on chromosome (Chr) 18q21-23 was reported to be one of the most common genetic alterations identified in bladder cancer. The current study aimed to determine the prognostic role of LOH on Chr 18q21-23 in patients diagnosed with muscle-invasive urothelial bladder carcinoma (MIBC). A total of 34 consecutive patients were enrolled in the present prospective study. LOH on Chr 18 was assessed by performing multiplex polymerase chain reaction on paired blood and tumour tissue samples from each patient. The following primers were used in the present study: D18S51, MBP LW and MBP H. These data were then compared with follow-up information. The main outcome measure was patient status at the end of the follow-up. Cox regression was used to evaluate the impact of each parameter on cancer-specific survival and the Kaplan Meier test for disease-free survival was plotted in order to estimate survival. Out of 34 patients, 18 (52.9%) exhibited ≥1 alteration in one of the loci analysed on chromosome 18, while 16 (47.1%) revealed no alterations. No correlation was identified with stage (P=0.18) or grade (P=0.06); however, LOH on Chr 18q21-23 was significantly associated with a lower recurrence-free probability (P<0.0001). Kaplan-Meier curves demonstrated a significant association between patient status at follow-up and LOH on Chr 18 (P<0.001). In addition, multivariate analysis identified LOH on Chr 18 (P<0.001) and stage (P=0.01) as independent survival predictors. Furthermore, artificial neural network analysis was consistent with the results of the multivariate analysis. In conclusion, the present study highlighted the role of LOH on Chr 18q21-23 in predicting the clinical outcome of patients with MIBC. PMID:26622891

  15. Translocation 10;18 in a patient with juvenile neuronal ceroid-lipofuscinosis (Batten disease)

    SciTech Connect

    Tuck-Muller, C.M.; Li, S.; Chen, H.

    1995-06-05

    We report the first observation of a chromosome abnormality in a patient with typical juvenile ceroid-lipfuscinosis (NCL), who was found to have an apparently balanced translocation between chromosomes 10 and 18 (t(10;18)(q22;q21.1)). Since juvenile NCL was previously mapped to 16p12, this report raises the possibility of heterogeneity in this form of NCL. 22 refs., 2 figs.

  16. Prenatal diagnosis of a 7q21.13q22.1 deletion detected using high-resolution microarray

    PubMed Central

    Kim, Kyoung-Bo; Ha, Jung-Sook; Shin, So-Jin; Kim, Chun Soo

    2014-01-01

    We report a case of de novo 7q interstitial deletion detected by conventional karyotyping and by microarray of amniotic fluid sampled during the prenatal period. A 32-year-old pregnant woman was evaluated at our hospital following detection of increased nuchal translucency at 12 weeks and 5 days of gestation. Conventional karyotyping revealed 46,XX,del(7)(q21q22) in 20 interphase mitotic cells, and high-resolution microarray revealed 12.8 Mb (90,625,014-103,430,901) deletion in the region 7q21.13q22.1. Both parents had normal karyotypes. After birth, the neonate displayed several anomalies, including palatine cleft, upslanted and wide palpebral fissure, low-set ears, micrognathia, microcephaly, ventriculomegaly, subglottic tracheal stenosis, hearing loss, and hand/foot deformities, including brachydactyly, polydactyly, and cutaneous syndactyly. This case study helps explain the phenotype-genotype relationship in patients with 7q21.13q22.1 deletion. PMID:25105107

  17. Genome-Wide Association Study for Type 2 Diabetes in Indians Identifies a New Susceptibility Locus at 2q21

    PubMed Central

    Tabassum, Rubina; Chauhan, Ganesh; Dwivedi, Om Prakash; Mahajan, Anubha; Jaiswal, Alok; Kaur, Ismeet; Bandesh, Khushdeep; Singh, Tejbir; Mathai, Benan John; Pandey, Yogesh; Chidambaram, Manickam; Sharma, Amitabh; Chavali, Sreenivas; Sengupta, Shantanu; Ramakrishnan, Lakshmi; Venkatesh, Pradeep; Aggarwal, Sanjay K.; Ghosh, Saurabh; Prabhakaran, Dorairaj; Srinath, Reddy K.; Saxena, Madhukar; Banerjee, Monisha; Mathur, Sandeep; Bhansali, Anil; Shah, Viral N.; Madhu, Sri Venkata; Marwaha, Raman K.; Basu, Analabha; Scaria, Vinod; McCarthy, Mark I.; Venkatesan, Radha; Mohan, Viswanathan; Tandon, Nikhil; Bharadwaj, Dwaipayan

    2013-01-01

    Indians undergoing socioeconomic and lifestyle transitions will be maximally affected by epidemic of type 2 diabetes (T2D). We conducted a two-stage genome-wide association study of T2D in 12,535 Indians, a less explored but high-risk group. We identified a new type 2 diabetes–associated locus at 2q21, with the lead signal being rs6723108 (odds ratio 1.31; P = 3.32 × 10−9). Imputation analysis refined the signal to rs998451 (odds ratio 1.56; P = 6.3 × 10−12) within TMEM163 that encodes a probable vesicular transporter in nerve terminals. TMEM163 variants also showed association with decreased fasting plasma insulin and homeostatic model assessment of insulin resistance, indicating a plausible effect through impaired insulin secretion. The 2q21 region also harbors RAB3GAP1 and ACMSD; those are involved in neurologic disorders. Forty-nine of 56 previously reported signals showed consistency in direction with similar effect sizes in Indians and previous studies, and 25 of them were also associated (P < 0.05). Known loci and the newly identified 2q21 locus altogether explained 7.65% variance in the risk of T2D in Indians. Our study suggests that common susceptibility variants for T2D are largely the same across populations, but also reveals a population-specific locus and provides further insights into genetic architecture and etiology of T2D. PMID:23209189

  18. Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31.

    PubMed

    Permuth-Wey, Jennifer; Lawrenson, Kate; Shen, Howard C; Velkova, Aneliya; Tyrer, Jonathan P; Chen, Zhihua; Lin, Hui-Yi; Chen, Y Ann; Tsai, Ya-Yu; Qu, Xiaotao; Ramus, Susan J; Karevan, Rod; Lee, Janet; Lee, Nathan; Larson, Melissa C; Aben, Katja K; Anton-Culver, Hoda; Antonenkova, Natalia; Antoniou, Antonis C; Armasu, Sebastian M; Bacot, François; Baglietto, Laura; Bandera, Elisa V; Barnholtz-Sloan, Jill; Beckmann, Matthias W; Birrer, Michael J; Bloom, Greg; Bogdanova, Natalia; Brinton, Louise A; Brooks-Wilson, Angela; Brown, Robert; Butzow, Ralf; Cai, Qiuyin; Campbell, Ian; Chang-Claude, Jenny; Chanock, Stephen; Chenevix-Trench, Georgia; Cheng, Jin Q; Cicek, Mine S; Coetzee, Gerhard A; Cook, Linda S; Couch, Fergus J; Cramer, Daniel W; Cunningham, Julie M; Dansonka-Mieszkowska, Agnieszka; Despierre, Evelyn; Doherty, Jennifer A; Dörk, Thilo; du Bois, Andreas; Dürst, Matthias; Easton, Douglas F; Eccles, Diana; Edwards, Robert; Ekici, Arif B; Fasching, Peter A; Fenstermacher, David A; Flanagan, James M; Garcia-Closas, Montserrat; Gentry-Maharaj, Aleksandra; Giles, Graham G; Glasspool, Rosalind M; Gonzalez-Bosquet, Jesus; Goodman, Marc T; Gore, Martin; Górski, Bohdan; Gronwald, Jacek; Hall, Per; Halle, Mari K; Harter, Philipp; Heitz, Florian; Hillemanns, Peter; Hoatlin, Maureen; Høgdall, Claus K; Høgdall, Estrid; Hosono, Satoyo; Jakubowska, Anna; Jensen, Allan; Jim, Heather; Kalli, Kimberly R; Karlan, Beth Y; Kaye, Stanley B; Kelemen, Linda E; Kiemeney, Lambertus A; Kikkawa, Fumitaka; Konecny, Gottfried E; Krakstad, Camilla; Kjaer, Susanne Krüger; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Lancaster, Johnathan M; Le, Nhu D; Leminen, Arto; Levine, Douglas A; Liang, Dong; Lim, Boon Kiong; Lin, Jie; Lissowska, Jolanta; Lu, Karen H; Lubiński, Jan; Lurie, Galina; Massuger, Leon F A G; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R; Menon, Usha; Modugno, Francesmary; Moysich, Kirsten B; Nakanishi, Toru; Narod, Steven A; Nedergaard, Lotte; Ness, Roberta B; Nevanlinna, Heli; Nickels, Stefan; Noushmehr, Houtan; Odunsi, Kunle; Olson, Sara H; Orlow, Irene; Paul, James; Pearce, Celeste L; Pejovic, Tanja; Pelttari, Liisa M; Pike, Malcolm C; Poole, Elizabeth M; Raska, Paola; Renner, Stefan P; Risch, Harvey A; Rodriguez-Rodriguez, Lorna; Rossing, Mary Anne; Rudolph, Anja; Runnebaum, Ingo B; Rzepecka, Iwona K; Salvesen, Helga B; Schwaab, Ira; Severi, Gianluca; Shridhar, Viji; Shu, Xiao-Ou; Shvetsov, Yurii B; Sieh, Weiva; Song, Honglin; Southey, Melissa C; Spiewankiewicz, Beata; Stram, Daniel; Sutphen, Rebecca; Teo, Soo-Hwang; Terry, Kathryn L; Tessier, Daniel C; Thompson, Pamela J; Tworoger, Shelley S; van Altena, Anne M; Vergote, Ignace; Vierkant, Robert A; Vincent, Daniel; Vitonis, Allison F; Wang-Gohrke, Shan; Palmieri Weber, Rachel; Wentzensen, Nicolas; Whittemore, Alice S; Wik, Elisabeth; Wilkens, Lynne R; Winterhoff, Boris; Woo, Yin Ling; Wu, Anna H; Xiang, Yong-Bing; Yang, Hannah P; Zheng, Wei; Ziogas, Argyrios; Zulkifli, Famida; Phelan, Catherine M; Iversen, Edwin; Schildkraut, Joellen M; Berchuck, Andrew; Fridley, Brooke L; Goode, Ellen L; Pharoah, Paul D P; Monteiro, Alvaro N A; Sellers, Thomas A; Gayther, Simon A

    2013-01-01

    Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3' untranslated region at putative microRNA (miRNA)-binding sites represent functional targets that influence EOC susceptibility. Here, we evaluate the association between 767 miRNA-related single-nucleotide polymorphisms (miRSNPs) and EOC risk in 18,174 EOC cases and 26,134 controls from 43 studies genotyped through the Collaborative Oncological Gene-environment Study. We identify several miRSNPs associated with invasive serous EOC risk (odds ratio=1.12, P=10(-8)) mapping to an inversion polymorphism at 17q21.31. Additional genotyping of non-miRSNPs at 17q21.31 reveals stronger signals outside the inversion (P=10(-10)). Variation at 17q21.31 is associated with neurological diseases, and our collaboration is the first to report an association with EOC susceptibility. An integrated molecular analysis in this region provides evidence for ARHGAP27 and PLEKHM1 as candidate EOC susceptibility genes. PMID:23535648

  19. Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31

    PubMed Central

    Permuth-Wey, Jennifer; Lawrenson, Kate; Shen, Howard C.; Velkova, Aneliya; Tyrer, Jonathan P.; Chen, Zhihua; Lin, Hui-Yi; Chen, Y. Ann; Tsai, Ya-Yu; Qu, Xiaotao; Ramus, Susan J.; Karevan, Rod; Lee, Janet; Lee, Nathan; Larson, Melissa C.; Aben, Katja K.; Anton-Culver, Hoda; Antonenkova, Natalia; Antoniou, Antonis; Armasu, Sebastian M.; Bacot, François; Baglietto, Laura; Bandera, Elisa V.; Barnholtz-Sloan, Jill; Beckmann, Matthias W.; Birrer, Michael J.; Bloom, Greg; Bogdanova, Natalia; Brinton, Louise A.; Brooks-Wilson, Angela; Brown, Robert; Butzow, Ralf; Cai, Qiuyin; Campbell, Ian; Chang-Claude, Jenny; Chanock, Stephen; Chenevix-Trench, Georgia; Cheng, Jin Q.; Cicek, Mine S.; Coetzee, Gerhard A.; Cook, Linda S.; Couch, Fergus J.; Cramer, Daniel W.; Cunningham, Julie M.; Dansonka-Mieszkowska, Agnieszka; Despierre, Evelyn; Doherty, Jennifer A; Dörk, Thilo; du Bois, Andreas; Dürst, Matthias; Easton, Douglas F; Eccles, Diana; Edwards, Robert; Ekici, Arif B.; Fasching, Peter A.; Fenstermacher, David A.; Flanagan, James M.; Garcia-Closas, Montserrat; Gentry-Maharaj, Aleksandra; Giles, Graham G.; Glasspool, Rosalind M.; Gonzalez-Bosquet, Jesus; Goodman, Marc T.; Gore, Martin; Górski, Bohdan; Gronwald, Jacek; Hall, Per; Halle, Mari K.; Harter, Philipp; Heitz, Florian; Hillemanns, Peter; Hoatlin, Maureen; Høgdall, Claus K.; Høgdall, Estrid; Hosono, Satoyo; Jakubowska, Anna; Jensen, Allan; Jim, Heather; Kalli, Kimberly R.; Karlan, Beth Y.; Kaye, Stanley B.; Kelemen, Linda E.; Kiemeney, Lambertus A.; Kikkawa, Fumitaka; Konecny, Gottfried E.; Krakstad, Camilla; Kjaer, Susanne Krüger; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Lancaster, Johnathan M.; Le, Nhu D.; Leminen, Arto; Levine, Douglas A.; Liang, Dong; Lim, Boon Kiong; Lin, Jie; Lissowska, Jolanta; Lu, Karen H.; Lubiński, Jan; Lurie, Galina; Massuger, Leon F.A.G.; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R; Menon, Usha; Modugno, Francesmary; Moysich, Kirsten B.; Nakanishi, Toru; Narod, Steven A.; Nedergaard, Lotte; Ness, Roberta B.; Nevanlinna, Heli; Nickels, Stefan; Noushmehr, Houtan; Odunsi, Kunle; Olson, Sara H.; Orlow, Irene; Paul, James; Pearce, Celeste L; Pejovic, Tanja; Pelttari, Liisa M.; Pike, Malcolm C.; Poole, Elizabeth M.; Raska, Paola; Renner, Stefan P.; Risch, Harvey A.; Rodriguez-Rodriguez, Lorna; Rossing, Mary Anne; Rudolph, Anja; Runnebaum, Ingo B.; Rzepecka, Iwona K.; Salvesen, Helga B.; Schwaab, Ira; Severi, Gianluca; Shridhar, Vijayalakshmi; Shu, Xiao-Ou; Shvetsov, Yurii B.; Sieh, Weiva; Song, Honglin; Southey, Melissa C.; Spiewankiewicz, Beata; Stram, Daniel; Sutphen, Rebecca; Teo, Soo-Hwang; Terry, Kathryn L.; Tessier, Daniel C.; Thompson, Pamela J.; Tworoger, Shelley S.; van Altena, Anne M.; Vergote, Ignace; Vierkant, Robert A.; Vincent, Daniel; Vitonis, Allison F.; Wang-Gohrke, Shan; Weber, Rachel Palmieri; Wentzensen, Nicolas; Whittemore, Alice S.; Wik, Elisabeth; Wilkens, Lynne R.; Winterhoff, Boris; Woo, Yin Ling; Wu, Anna H.; Xiang, Yong-Bing; Yang, Hannah P.; Zheng, Wei; Ziogas, Argyrios; Zulkifli, Famida; Phelan, Catherine M.; Iversen, Edwin; Schildkraut, Joellen M.; Berchuck, Andrew; Fridley, Brooke L.; Goode, Ellen L.; Pharoah, Paul D. P.; Monteiro, Alvaro N.A.; Sellers, Thomas A.; Gayther, Simon A.

    2013-01-01

    Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3′ untranslated region at putative microRNA (miRNA) binding sites represent functional targets that influence EOC susceptibility. Here, we evaluate the association between 767 miRNA binding site single nucleotide polymorphisms (miRSNPs) and EOC risk in 18,174 EOC cases and 26,134 controls from 43 studies genotyped through the Collaborative Oncological Gene-environment Study. We identify several miRSNPs associated with invasive serous EOC risk (OR=1.12, P=10−8) mapping to an inversion polymorphism at 17q21.31. Additional genotyping of non-miRSNPs at 17q21.31 reveals stronger signals outside the inversion (P=10−10). Variation at 17q21.31 associates with neurological diseases, and our collaboration is the first to report an association with EOC susceptibility. An integrated molecular analysis in this region provides evidence for ARHGAP27 and PLEKHM1 as candidate EOC susceptibility genes. PMID:23535648

  20. Duplication of 5q21 in a mildly retarded male and his non-retarded mother

    SciTech Connect

    Stallard, R.; Zurcher, V.; Schwartz, S.

    1994-09-01

    Euchromatic autosomal additions to chromosomal complements are typically associated with global effects including mental retardation (MR) and dysmorphism. We report a familial duplication that does not appear to cause consistent, significant effects. A hyperactive male with mild MR was referred for fra(X) testing at 8 yrs. His karyotype was fra(X) negative and normal except for an addition in one 5q. The abnormal 5 was also in the maternal karyotype, but all other parental chromosomes were normal. The addition (=8.5% the length of a 5) was interpreted as a duplication of band 5q21. FISH with Coatasome 5 (Oncor) showed the addition was from 5. The proband`s karyotype was designated 46,XY,dup(5)(q15q22.1)mat; his mother`s, 46,XX,dup(5)(q15q22.1). Single copy probes are being used to test the cytogenetic interpretation. At 39 yrs, the non-retarded, somewhat inattentive mother, who has a high school diploma and subsequent secretarial courses, cares for the proband and his chromosomally normal, but learning disabled sister at home. The family situation is chaotic with reported paternal psychiatric illness and abuse of the proband and his sister. The mother`s father is dead, but her four younger siblings and mother are reportedly normal. Their chromosomes have not been available. The proband was born at 40 weeks following an uneventful pregnancy, with length and weight at the 5-10th centiles. He walked and talked at about one year. At 9 yrs, his ht/wt ratio was 10th centile. Foot length as <3rd centile; soft masses were present on the anterior ankles. He was otherwise physically normal. His estimated I.Q. was 75 and he was severely hyperactive despite Ritalin. This is the first report of a familial duplication in 5q; no identical, isolated case is known. Although additional family members need evaluation, the presence of the dup(5q) in the non-retarded mother suggests that it may not be associated with the proband`s MR.

  1. Inheritance of a Chromosome 3 and 21 Translocation in the Fetuses, with One also Having Trisomy 21, in Three Pregnancies in One Family.

    PubMed

    Pazarbasi, A; Demirhan, O; Alptekin, D; Ozgunen, Ft; Ozpak, L; Yilmaz, Mb; Nazlican, E; Tanriverdi, N; Luleyap, U; Gümürdülü, D

    2013-12-01

    The majority of chromosome rearrangements are balanced reciprocal and Robertsonian translocations. It is now known that such abnormalities cause no phenotypic effect on the carrier but lead to increased risk of producing unbalanced gametes. Here, we report the inheritance of a translocation between chromosomes 3 and 21 in a family with one of two fetuses with Down Syndrome carrying the same translocation and the other also carrying the same translocation without the additional chromosome 21. Chromosomal analysis from fetal amniotic fluid and peripheral blood lymphocytes from the family were performed at the Çukurova University Hospital at Adana, Turkey. We assessed a family in which the translocation between chromosomes 3 and 21 segregates: one of the three progenies carried the 47,XX,+21,t(3;21)(q21;q22) karyotype and presented with Down Syndrome; another of the three progenies carried the 46,XX,t(3;21) (q21;q22) karyotype and the third had the 46,XY karyotype. Their mother is phenotypically normal. Apparently this rearrangement occurred due to an unbalanced chromosome segregation of the mother [t(3;21)(q21;q22)mat]. This family will enable us to explain the behavior of segregation patterns and the mechanism for each type of translocation from carrier to carrier and their effects on reproduction and numerical aberrations. These findings can be used in clinical genetics and may be used as an effective tool for reproductive guidance and genetic counseling. PMID:24778571

  2. Chromosome 3 duplication q21 leads to qter deletion p25 leads to pter syndrome in children of carriers of a pericentric inversion inv(3) (p25q21).

    PubMed Central

    Allderdice, P W; Browne, N; Murphy, D P

    1975-01-01

    Close phenotypic similarity between two cases carrying a rec(3) dup q,inv(3) (p25q21), 12 additional infants from the same inv (3)(p25q21) kindred who lived less than 1 year, and eight cases studied in other medical centers has led us to postulate the existence of a distinct chromosome 3 duplication-deletion syndrome. In the presence of trisomy for (3)q21 leads to qter and monosomy for (3)p25 leads to pter, the facial dysmorphy is unique: a distorted head shape due to irregular cranial sutures, thick low eyebrows, long eyelashes, persistent lanugo, distended veins on the scalp, hypertelorism, oblique palpebral fissures, a very short nose with a broad depressed bridge and anteverted nares, protruding maxilla, thin upper lip, micrognathia, low-set ears, and a short webbed neck. Port-wine stains, congenital glaucoma, cloudy corneas, cleft palate and harelip also occur frequently. Each infant has difficulty sucking and swallowing. Congenital anomalies of the cardiovascular system, of midgut rotation, and of the urogenital system are noted for the infants who died neonatally. Most frequent is a ventricular septal defect, followed by atrial septal defect, patent ductus arteriosus, patent foramen ovale, and coarctation of the aorta. Omphalocele, umbilical hernia, hyperplastic kidneys, polycystic kidneys, double ureter, hydro-ureter, hydronephrosis, and undescended testes often occur. The extremities are short in proportion to the length of the trunk. Clinodactyly, coxa valga, talipes, and spina bifida are frequently observed. Images Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 7 Fig. 8 PMID:1200027

  3. Detection of a complex translocation using fluorescent in situ hybridization (FISH)

    SciTech Connect

    Rosen, B.A.; Abuelo, D.N.; Mark, H.F.

    1994-09-01

    The use of fluorescent in situ hybridization (FISH) allowed the detection of a complex 3-way translocation in a patient with multiple congenital malformations and mental retardation. The patient was a 10-year-old girl with mental retardation, seizures, repaired cleft palate, esotropia, epicanthal folds, broad nasal bridge, upward slanting palpebral fissures, single transverse palmar crease, brachydactyly, hypoplastic nails, ectrodactyly between the third and fourth right toes, and hypoplasia of the left third toe. Chromosome analysis performed at birth was reported as normal. We performed high resolution banding analysis which revealed an apparently balanced translocation between chromosomes 2 and 9. However, because of her multiple abnormalities, further studies were ordered. Fluorescent in situ hybridization (FISH) using chromosome painting probes revealed a karyotype of 46,XX,t(2;8;9) (2pter{yields}q31::8q21.2{yields}8qter; 8pter{yields}q21.2::2q31{yields}q34::9q34{yields}qter; 9pter{yields}q34::2q34{yields}qter). The 3-way translocation appears to be de novo, as neither parent is a translocation carrier. This case illustrates the importance of using FISH to further investigate cases of apparently balanced translocations in the presence of phenotypic abnormalities and/or mental retardation.

  4. Identification of ZCCHC8 as fusion partner of ROS1 in a case of congenital glioblastoma multiforme with a t(6;12)(q21;q24.3).

    PubMed

    Coccé, Mariela C; Mardin, Balca R; Bens, Susanne; Stütz, Adrian M; Lubieniecki, Fabiana; Vater, Inga; Korbel, Jan O; Siebert, Reiner; Alonso, Cristina N; Gallego, Marta S

    2016-09-01

    Congenital gliobastoma multiforme (GBM) is rare and little is known about the molecular defects underlying the initiation and progression of this tumor type. We present a case of congenital GBM analyzed by conventional cytogenetics, fluorescence in situ hybridization, array comparative genomic hybridization and next generation sequencing. On cytogenetic analysis we detected a reciprocal translocation t(6;12)(q21;q24.3). By sequencing, the translocation was shown to form a fusion between the 5' region of ZCCHC8 and the 3' region of ROS1. RT-PCR analyses confirmed the existence of an in-frame fusion transcript with ZCCHC8 exons 1-3 joined to ROS1 exons 36-43. In addition to the ZCCHC8-ROS1 fusion, we detected a deletion in the short arm of chromosome 9, including homozygous loss of the CDKN2A/2B locus in 9p21.3 and heterozygous deletion of the HAUS6 gene in 9p22.1. The latter encodes a protein involved in faithful chromosome segregation by regulating microtubule nucleation and its deletion might be associated with the marked subclonal changes of ploidy observed in the tumor. This report adds the ZCCHC8-ROS1 fusion as oncogenic driver in GBM and supports the role of ROS1 activation in the pathogenesis of a subset of GBM. © 2016 Wiley Periodicals, Inc. PMID:27121553

  5. Genome-wide association study for type 2 diabetes in Indians identifies a new susceptibility locus at 2q21.

    PubMed

    Tabassum, Rubina; Chauhan, Ganesh; Dwivedi, Om Prakash; Mahajan, Anubha; Jaiswal, Alok; Kaur, Ismeet; Bandesh, Khushdeep; Singh, Tejbir; Mathai, Benan John; Pandey, Yogesh; Chidambaram, Manickam; Sharma, Amitabh; Chavali, Sreenivas; Sengupta, Shantanu; Ramakrishnan, Lakshmi; Venkatesh, Pradeep; Aggarwal, Sanjay K; Ghosh, Saurabh; Prabhakaran, Dorairaj; Srinath, Reddy K; Saxena, Madhukar; Banerjee, Monisha; Mathur, Sandeep; Bhansali, Anil; Shah, Viral N; Madhu, Sri Venkata; Marwaha, Raman K; Basu, Analabha; Scaria, Vinod; McCarthy, Mark I; Venkatesan, Radha; Mohan, Viswanathan; Tandon, Nikhil; Bharadwaj, Dwaipayan

    2013-03-01

    Indians undergoing socioeconomic and lifestyle transitions will be maximally affected by epidemic of type 2 diabetes (T2D). We conducted a two-stage genome-wide association study of T2D in 12,535 Indians, a less explored but high-risk group. We identified a new type 2 diabetes-associated locus at 2q21, with the lead signal being rs6723108 (odds ratio 1.31; P = 3.32 × 10⁻⁹). Imputation analysis refined the signal to rs998451 (odds ratio 1.56; P = 6.3 × 10⁻¹²) within TMEM163 that encodes a probable vesicular transporter in nerve terminals. TMEM163 variants also showed association with decreased fasting plasma insulin and homeostatic model assessment of insulin resistance, indicating a plausible effect through impaired insulin secretion. The 2q21 region also harbors RAB3GAP1 and ACMSD; those are involved in neurologic disorders. Forty-nine of 56 previously reported signals showed consistency in direction with similar effect sizes in Indians and previous studies, and 25 of them were also associated (P < 0.05). Known loci and the newly identified 2q21 locus altogether explained 7.65% variance in the risk of T2D in Indians. Our study suggests that common susceptibility variants for T2D are largely the same across populations, but also reveals a population-specific locus and provides further insights into genetic architecture and etiology of T2D. PMID:23209189

  6. Molecular characterization of a novel amplicon at 1q21-q22 frequently observed in human sarcomas.

    PubMed Central

    Forus, A.; Berner, J. M.; Meza-Zepeda, L. A.; Saeter, G.; Mischke, D.; Fodstad, O.; Myklebost, O.

    1998-01-01

    In a recent comparative genomic hybridization (CGH) study of a panel of sarcomas, we detected recurrent amplification of 1q21-q22 in soft tissue and bone tumours. Amplification of this region had not previously been associated with sarcoma development, but occasional amplification of CACY/S100A6 and MUC1 in 1q21 had been reported for melanoma and breast carcinoma respectively. Initial screening by Southern blot analysis showed amplification of S100A6, FLG and SPRR3 in several sarcomas and, in a first attempt to characterize the 1q21-q22 amplicon in more detail, we have now investigated the amplification status of these and 11 other markers in the region in 35 sarcoma samples. FLG was the most frequently amplified gene, and the markers located in the same 4.5-Mb region as FLG showed a higher incidence of amplification than the more distal ones. However, for most of the 14 markers, amplification levels were low, and only APOA2 and the anonymous marker D1S3620 showed high-level amplifications (> tenfold increases) in one sample each. We used fluorescence in situ hybridization (FISH) to determine the amplification patterns of two overlapping yeast artificial chromosomes (YACs) covering the region between D1S3620 and FLG (789f2 and 764a1), as well as two more distally located YACs in nine selected samples. Six samples had amplification of the YAC containing D1S3620 and, in three, 764a1 was also included. Five of these tumours showed normal copies of the more distal YACs; thus, it seems likely that an important gene may be located within 789f2, or very close. Two samples had high copy numbers of the most distal YACs. Taken together, FISH and molecular analyses indicate complex amplification patterns in 1q21-q22 with at least two amplicons: one located near D1S3620/789f2 and one more distal. Images Figure 1 Figure 2 Figure 3 PMID:9716033

  7. Disseminated Gastric MALT Lymphoma with Monoclonal Gammopathy, t(11;18)(q21;q21), and Subsequent Development of T-Large Granular Lymphocytic Leukemia: A Case Report and Review of the Literature

    PubMed Central

    Akoum, Riad; Serhal, Wassim; Farhat, Hussein

    2015-01-01

    Background. Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) is a well-characterized entity that may share clinical and morphological findings with other low-grade non-Hodgkin's lymphomas. Dissemination of MALT-type lymphoma to bone marrow and peripheral blood simultaneously with the presence of T-large granular cell leukemia (T-LGL) has rarely been reported. Case Presentation. This is the case of a 42-year-old male who presented with a gastric MALT-type lymphoma, disseminated to the bone marrow and the peripheral blood with high serum IgM levels and t(11;18)(q21;q21). The morphological, immunophenotypical and, immunohistochemical studies of the successive bone marrow and peripheral blood samples had revealed the coexistence of two distinct lymphoma cell populations: a B-cell, marginal zone type population expressing CD19, CD20, CD22, CD79b, IgM, and kappa light chain, and a T-large granular cell population, developed after treatment with rituximab expressing CD3, CD8, CD5, CD7, and CD45. Conclusion. Based on the analysis of this unusual case we performed an extensive review of the literature to elucidate the relationship between T-LGL and B-cell lymphomas and to emphasize the importance of paraprotein analysis at diagnosis of gastric MALT lymphoma. PMID:26064133

  8. Disseminated Gastric MALT Lymphoma with Monoclonal Gammopathy, t(11;18)(q21;q21), and Subsequent Development of T-Large Granular Lymphocytic Leukemia: A Case Report and Review of the Literature.

    PubMed

    Akoum, Riad; Serhal, Wassim; Farhat, Hussein

    2015-01-01

    Background. Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) is a well-characterized entity that may share clinical and morphological findings with other low-grade non-Hodgkin's lymphomas. Dissemination of MALT-type lymphoma to bone marrow and peripheral blood simultaneously with the presence of T-large granular cell leukemia (T-LGL) has rarely been reported. Case Presentation. This is the case of a 42-year-old male who presented with a gastric MALT-type lymphoma, disseminated to the bone marrow and the peripheral blood with high serum IgM levels and t(11;18)(q21;q21). The morphological, immunophenotypical and, immunohistochemical studies of the successive bone marrow and peripheral blood samples had revealed the coexistence of two distinct lymphoma cell populations: a B-cell, marginal zone type population expressing CD19, CD20, CD22, CD79b, IgM, and kappa light chain, and a T-large granular cell population, developed after treatment with rituximab expressing CD3, CD8, CD5, CD7, and CD45. Conclusion. Based on the analysis of this unusual case we performed an extensive review of the literature to elucidate the relationship between T-LGL and B-cell lymphomas and to emphasize the importance of paraprotein analysis at diagnosis of gastric MALT lymphoma. PMID:26064133

  9. Using the neanderthal and denisova genetic data to understand the common MAPT 17q21 inversion in modern humans.

    PubMed

    Setó-Salvia, Núria; Sánchez-Quinto, Federico; Carbonell, Eudald; Lorenzo, Carlos; Comas, David; Clarimón, Jordi

    2012-12-01

    The polymorphic inversion on 17q21, that includes the MAPT gene, represents a unique locus in the human genome characterized by a large region with strong linkage disequilibrium. Two distinct haplotypes, H1 and H2, exist in modern humans, and H1 has been unequivocally related to several neurodegenerative disorders. Recent data indicate that recurrent inversions of this genomic region have occurred through primate evolution, with the H2 haplotype being the ancestral state. Neandertals harbored the H1 haplotype; however, until now, no data were available for the Denisova hominin. Neandertals and Denisovans are sister groups that share a common ancestor with modern humans. We analyzed the MAPT sequence and assessed the differences between modern humans, Neandertals, Denisovans, and great apes. Our analysis indicated that the Denisova hominin carried the H1 haplotype, and the Neandertal and Denisova common ancestor probably shared the same subhaplotype (H1j). We also found 68 intronic variants within the MAPT gene, 23 exclusive to Denisova hominin, 6 limited to Neandertals, and 24 exclusive to present-day humans. Our results reinforce previous data; this suggests that the 17q21 inversion arose within the modern human lineage. The data also indicate that archaic hominins that coexisted in Eurasia probably shared the same MAPT subhaplotype, and this can be found in almost 2% of chromosomes from European ancestry. PMID:23959642

  10. Effects of a 17q21 chromosome gene variant, tobacco smoke and furred pets on infant wheeze.

    PubMed

    Bräuner, E V; Loft, S; Raaschou-Nielsen, O; Vogel, U; Andersen, P S; Sørensen, M

    2012-01-01

    The first common genetic factor identified for pediatric asthma by genome-wide association is the chromosome 17q21 locus, harbouring the ORMDL3 gene. ORMDL3 is involved in facilitation of endoplasmic reticulum-mediated inflammatory responses, believed to underlie its asthma association. We investigated associations between the rs7216389 polymorphism in the 17q21 locus affecting ORMDL3 expression and the risk for recurrent wheeze and interactions with exposure to tobacco smoke and furred pets during pregnancy and infancy using a birth cohort of 101,042 infants. Rs7216389 was significantly associated with recurrent wheeze risk among 18-month-old infants. There was a 1.35-fold higher risk of recurrent wheeze among homozygous variant allele carriers compared with homozygous wild-type allele carriers. There was significant interaction between rs7216389 and domestic furred pets, with a positive association between pets and wheeze among homozygous wild-type carriers and a negative association among homozygous variant allele carriers. There was no interaction between rs7216389 and tobacco smoke exposure. PMID:21796154

  11. Novel Association of Odontogenic Myxoma with Constitutional Chromosomal 1q21 Microduplication: Case Report and Review of the Literature.

    PubMed

    Best-Rocha, Alejandro; Patel, Kalyani; Hicks, John; Edmonds, Joseph L; Paldino, Michael J; Wu, Hao

    2016-01-01

    Odontogenic myxoma (OM) is a rare, benign, and locally aggressive tumor. It tends to occur in the posterior maxilla and mandible and is often associated with root resorption and perforation of cortex. Histopathologically, there is a proliferation of spindle, bipolar, and stellate cells, with bland nuclei within a myxoid to infrequently fibromyxoid extracellular matrix. Long, thin residual bony trabeculae are often seen floating within the spindle cell proliferation because of the infiltrating nature of this tumor, and these trabeculae impart a "soap bubble" or "tennis-racket" radiologic appearance. No syndromic association of OM has been reported. Although similar histopathologic features are shared with cardiac myxoma and soft tissue myxoma, mutations in the GNAS gene have not been identified in OM to date, and only 2 of 17 OMs showed mutations in the PRKAR1A gene. In this report, we describe a case of OM in a patient with constitutional 1q21 microduplication, a locus that harbors genes encoding certain proteins in the cAMP-dependent protein kinase A (PKA) signaling pathway, including G-protein-coupled receptors and 1 phosphodiesterase interacting protein. Review of the literature describes the key clinical features and molecular pathogenesis of 1q21 microduplication, as well as highlighting the role of PKA signaling pathway in the pathogenesis of myxomas in general. PMID:26230961

  12. Exclusion of chromosome 1q21-q31 from linkage to three pedigrees affected by the pigment-dispersion syndrome

    SciTech Connect

    Paglinauan, C.; Haines, J.L.; Del Bono, E.A.; Schuman, J.; Stawski, S.; Wiggs, J.L.

    1995-05-01

    The pigment-dispersion syndrome is a form of open-angle glaucoma that usually affects individuals in the first 3 decades of life. In addition to the typical optic-nerve degeneration seen in all types of glaucoma, the pigment-dispersion syndrome is characterized by distinctive clinical features including the deposition of pigment granules from the iris epithelium on a variety of ocular structures including the trabecular meshwork. Frequently this disorder affects young myopic individuals. In the early stages of the disease, affected individuals may have clinical evidence of dispersed pigment without an associated elevation of intraocular pressure and optic-nerve degeneration. However, as the disease process progresses, many affected individuals ({approximately}50%) will develop elevated intraocular pressure and degeneration of the optic nerve, causing a permanent loss of sight. The pigment-dispersion syndrome shares several clinical features with the form of autosomal dominant juvenile open-angle glaucoma that recently has been mapped to the 1q21-q31 region of chromosome 1. Our results indicate that the pigment-dispersion syndrome, a form of glaucoma that may also affect the juvenile population, is genetically unrelated to the autosomal dominant form of juvenile glaucoma caused by a defect in a gene located in the 1q21-q31 region of chromosome 1. 15 refs., 2 figs., 1 tab.

  13. Genomic Anatomy of a Premier Major Histocompatibility Complex Paralogous Region on Chromosome 1q21–q22

    PubMed Central

    Shiina, Takashi; Ando, Asako; Suto, Yumiko; Kasai, Fumio; Shigenari, Atsuko; Takishima, Nobusada; Kikkawa, Eri; Iwata, Kyoko; Kuwano, Yuko; Kitamura, Yuka; Matsuzawa, Yumiko; Sano, Kazumi; Nogami, Masahiro; Kawata, Hisako; Li, Suyun; Fukuzumi, Yasuhito; Yamazaki, Masaaki; Tashiro, Hiroyuki; Tamiya, Gen; Kohda, Atsushi; Okumura, Katsuzumi; Ikemura, Toshimichi; Soeda, Eiichi; Mizuki, Nobuhisa; Kimura, Minoru; Bahram, Seiamak; Inoko, Hidetoshi

    2001-01-01

    Human chromosomes 1q21–q25, 6p21.3–22.2, 9q33–q34, and 19p13.1–p13.4 carry clusters of paralogous loci, to date best defined by the flagship 6p MHC region. They have presumably been created by two rounds of large-scale genomic duplications around the time of vertebrate emergence. Phylogenetically, the 1q21–25 region seems most closely related to the 6p21.3 MHC region, as it is only the MHC paralogous region that includes bona fide MHC class I genes, the CD1 and MR1 loci. Here, to clarify the genomic structure of this model MHC paralogous region as well as to gain insight into the evolutionary dynamics of the entire quadriplication process, a detailed analysis of a critical 1.7 megabase (Mb) region was performed. To this end, a composite, deep, YAC, BAC, and PAC contig encompassing all five CD1 genes and linking the centromeric +P5 locus to the telomeric KRTC7 locus was constructed. Within this contig a 1.1-Mb BAC and PAC core segment joining CD1D to FCER1A was fully sequenced and thoroughly analyzed. This led to the mapping of a total of 41 genes (12 expressed genes, 12 possibly expressed genes, and 17 pseudogenes), among which 31 were novel. The latter include 20 olfactory receptor (OR) genes, 9 of which are potentially expressed. Importantly, CD1, SPTA1, OR, and FCERIA belong to multigene families, which have paralogues in the other three regions. Furthermore, it is noteworthy that 12 of the 13 expressed genes in the 1q21–q22 region around the CD1 loci are immunologically relevant. In addition to CD1A-E, these include SPTA1, MNDA, IFI-16, AIM2, BL1A, FY and FCERIA. This functional convergence of structurally unrelated genes is reminiscent of the 6p MHC region, and perhaps represents the emergence of yet another antigen presentation gene cluster, in this case dedicated to lipid/glycolipid antigens rather than antigen-derived peptides. [The nucleotide sequence data reported in this paper have been submitted to the DDBJ, EMBL, and GenBank databases under

  14. Immunoglobulin gene translocations in chronic lymphocytic leukemia: A report of 35 patients and review of the literature

    PubMed Central

    DE BRAEKELEER, MARC; TOUS, CORINE; GUÉGANIC, NADIA; LE BRIS, MARIE-JOSÉE; BASINKO, AUDREY; MOREL, FRÉDÉRIC; DOUET-GUILBERT, NATHALIE

    2016-01-01

    Chronic lymphocytic leukemia (CLL) represents the most common hematological malignancy in Western countries, with a highly heterogeneous clinical course and prognosis. Translocations involving the immunoglobulin (IG) genes are regularly identified. From 2000 to 2014, we identified an IG gene translocation in 18 of the 396 patients investigated at diagnosis (4.6%) and in 17 of the 275 analyzed during follow-up (6.2%). A total of 4 patients in whom the IG translocation was identified at follow-up did not carry the translocation at diagnosis. The IG heavy locus (IGH) was involved in 27 translocations (77.1%), the IG κ locus (IGK) in 1 (2.9%) and the IG λ locus (IGL) in 7 (20.0%). The chromosome band partners of the IG translocations were 18q21 in 16 cases (45.7%), 11q13 and 19q13 in 4 cases each (11.4% each), 8q24 in 3 cases (8.6%), 7q21 in 2 cases (5.7%), whereas 6 other bands were involved once (2.9% each). At present, 35 partner chromosomal bands have been described, but the partner gene has solely been identified in 10 translocations. CLL associated with IG gene translocations is characterized by atypical cell morphology, including plasmacytoid characteristics, and the propensity of being enriched in prolymphocytes. The IG heavy chain variable region (IGHV) mutational status varies between translocations, those with unmutated IGHV presumably involving cells at an earlier stage of B-cell lineage. All the partner genes thus far identified are involved in the control of cell proliferation and/or apoptosis. The translocated partner gene becomes transcriptionally deregulated as a consequence of its transposition into the IG locus. With the exception of t(14;18)(q32;q21) and its variants, prognosis appears to be poor for the other translocations. Therefore, searching for translocations involving not only IGH, but also IGL and IGK, by banding and molecular cytogenetics is required. Furthermore, it is important to identify the partner gene to ensure the patients receive

  15. 47,XX,+der(18),t(9;18)(p24;q21) mat: a distinct partial trisomy 18q--syndrome?

    PubMed Central

    Bass, H N; Weber-Parisi, F; Sparkes, R S

    1978-01-01

    A moderately retarded girl had a 47,XX,+der(18),t(9;18)(p24;q21)mat abnormality that was inherited from her mother, who had a 46,XX,t(9;18)(p24;q21) karyotype in most cells, and a minor cell line of 47,XX,+der(18),-t(9;18)(p24;q21). Her dysmorphic features--bilateral epicanthic folds, low-set, abnormal ears, low posterior hairline, clinodactyly of the 5th fingers, and broad great toes--were similar to those of other patients with an additional number 18 chromosome in which all or most of the long arm was missing, thus raising the possibility of a distinct syndrome. Images PMID:739531

  16. Copy number variation analysis of the 17q21.31 region and its role in neurodegenerative diseases.

    PubMed

    Cervera-Carles, Laura; Pagonabarraga, Javier; Pascual-Sedano, Berta; Pastor, Pau; Campolongo, Antonia; Fortea, Juan; Blesa, Rafael; Alcolea, Daniel; Morenas-Rodríguez, Estrella; Sala, Isabel; Lleó, Alberto; Kulisevsky, Jaime; Clarimón, Jordi

    2016-03-01

    The H1 haplotype of the 17q21.31 inversion polymorphism has been consistently associated with progressive supranuclear palsy, corticobasal degeneration, and Parkinson's disease in Caucasians. Recently, large polymorphic segmental duplications resulting into complex rearrangements at this locus with a high diversity range in human populations have been revealed. We sought to explore whether the two multi-allelic copy number variants that are present in the H1 clade (with segmental duplications of 300 and 218 kilobases in length) could be responsible for the known H1-related risk of developing these neurodegenerative disorders. A total of 857 Spanish subjects including 330 patients with Parkinson's disease, 96 with progressive supranuclear palsy, 55 with corticobasal degeneration, 51 dementia with Lewy bodies, and 325 neurologically healthy controls, were genotyped for the H1/H2 haplotype. Subsequently, the two copy number variants that are characteristic of the H1 haplotype were evaluated through a high-resolution approach based on droplet digital polymerase chain reaction, in all H1 homozygous subjects. The H1 allele was significantly overrepresented in all diagnostic groups compared with controls (Parkinson's disease, P = 0.0001; progressive supranuclear palsy, P = 1.22 × 10(-6) ; corticobasal degeneration, P = 0.0002; and dementia with Lewy bodies, P = 0.032). However, no dosage differences were found for any of the two copy number variants analyzed. The H1 haplotype is associated with the risk of several neurodegenerative disorders, including dementia with Lewy bodies. However, common structural diversity within the 17q21.31-H1 clade does not explain this genetic association. © 2015 Wiley Periodicals, Inc. PMID:26453547

  17. The interferon-inducible, double-stranded RNA-specific adenosine deaminase gene (DSRAD) maps to human chromosome 1q21.1-21.2

    SciTech Connect

    Weier, H.U.G.; Greulich, K.M.; George, C.X.; Samuel, C.E.

    1995-11-20

    The interferon-inducible double-stranded RNA-specific adenosine deaminase is an RNA-modifying enzyme implicated in the generation of biased hypermutations of viral RNAs and the site-selective editing of mammalian mRNAs of neural origin. The gene for the dsRNA-specific adenosine deaminase has been mapped by fluorescence in situ hybridization (FISH) of genomic clones to a single locus on human chromosome 1 bands q21.1-21.2. Simultaneous multicolor FISH including X clones and yeast artificial chromosomes showed a localization of the gene in band 1q21 centromeric of D1S1705. 22 refs., 1 fig.

  18. Human and mouse chromosomal mapping of the myeloid cell leukemia-1 gene: MCL1 maps to human chromosome 1q21, a region that is frequently altered in preneoplastic and neoplastic disease

    SciTech Connect

    Craig, R.W.; Zhou, P.; Kozopas, K.M.

    1994-09-15

    The MCL1 gene, recently identified in a myeloid leukemia cell line, has sequence similarity to BCL2, the gene at the t(14;18) translocation in follicular lymphoma. The chromosomal location of MCL1 has now been determined. The human locus (MCL1) was mapped to the long arm of human chromosome 1q21, using the methods of in situ hybridization and somatic cell hybrid analysis. In the mouse, MCL1-related sequences were mapped to positions on two mouse chromosomes (chromosomes 3 and 5), using haplotype analysis of an interspecific cross. The location of the locus on mouse chromosome 3 (Mcl1) was homologous to that of MCL1 on human chromosome 1; the second locus (Mcl-rs on mouse chromosome 5) may represent a pseudogene. The proximal long arm of human chromosome 1, where MCL1 is located, is duplicated and/or rearranged in a variety of preneoplastic and neoplastic diseases including hematologic diseases and solid tumors. MCL1 is thus a candidate gene for involvement in cancer. 46 refs., 2 figs., 3 tabs.

  19. The Koolen-de Vries syndrome: a phenotypic comparison of patients with a 17q21.31 microdeletion versus a KANSL1 sequence variant.

    PubMed

    Koolen, David A; Pfundt, Rolph; Linda, Katrin; Beunders, Gea; Veenstra-Knol, Hermine E; Conta, Jessie H; Fortuna, Ana Maria; Gillessen-Kaesbach, Gabriele; Dugan, Sarah; Halbach, Sara; Abdul-Rahman, Omar A; Winesett, Heather M; Chung, Wendy K; Dalton, Marguerite; Dimova, Petia S; Mattina, Teresa; Prescott, Katrina; Zhang, Hui Z; Saal, Howard M; Hehir-Kwa, Jayne Y; Willemsen, Marjolein H; Ockeloen, Charlotte W; Jongmans, Marjolijn C; Van der Aa, Nathalie; Failla, Pinella; Barone, Concetta; Avola, Emanuela; Brooks, Alice S; Kant, Sarina G; Gerkes, Erica H; Firth, Helen V; Õunap, Katrin; Bird, Lynne M; Masser-Frye, Diane; Friedman, Jennifer R; Sokunbi, Modupe A; Dixit, Abhijit; Splitt, Miranda; Kukolich, Mary K; McGaughran, Julie; Coe, Bradley P; Flórez, Jesús; Nadif Kasri, Nael; Brunner, Han G; Thompson, Elizabeth M; Gecz, Jozef; Romano, Corrado; Eichler, Evan E; de Vries, Bert Ba

    2016-05-01

    The Koolen-de Vries syndrome (KdVS; OMIM #610443), also known as the 17q21.31 microdeletion syndrome, is a clinically heterogeneous disorder characterised by (neonatal) hypotonia, developmental delay, moderate intellectual disability, and characteristic facial dysmorphism. Expressive language development is particularly impaired compared with receptive language or motor skills. Other frequently reported features include social and friendly behaviour, epilepsy, musculoskeletal anomalies, congenital heart defects, urogenital malformations, and ectodermal anomalies. The syndrome is caused by a truncating variant in the KAT8 regulatory NSL complex unit 1 (KANSL1) gene or by a 17q21.31 microdeletion encompassing KANSL1. Herein we describe a novel cohort of 45 individuals with KdVS of whom 33 have a 17q21.31 microdeletion and 12 a single-nucleotide variant (SNV) in KANSL1 (19 males, 26 females; age range 7 months to 50 years). We provide guidance about the potential pitfalls in the laboratory testing and emphasise the challenges of KANSL1 variant calling and DNA copy number analysis in the complex 17q21.31 region. Moreover, we present detailed phenotypic information, including neuropsychological features, that contribute to the broad phenotypic spectrum of the syndrome. Comparison of the phenotype of both the microdeletion and SNV patients does not show differences of clinical importance, stressing that haploinsufficiency of KANSL1 is sufficient to cause the full KdVS phenotype. PMID:26306646

  20. Activation of a novel gene in 3q21 and identification of intergenic fusion transcripts with ecotropic viral insertion site I in leukemia.

    PubMed

    Pekarsky, Y; Rynditch, A; Wieser, R; Fonatsch, C; Gardiner, K

    1997-09-15

    We have identified a novel gene, GR6, located within the leukemia breakpoint region of 3q21, that is normally expressed in early fetal development but not in adult peripheral blood. GR6 is activated in the UCSD-AML1 cell line and in a leukemic sample, both of which carry a t(3;3)(q21;q26). In UCSD-AML1, we have also identified fusion transcripts between the ecotropic viral insertion site I (EVI1) gene in 3q26 and GR6 and between EVI1 and Ribophorin I that maps 30 kb telomeric to GR6 in 3q21. All fusions splice the 5' ends of the 3q21 genes into exon 2 of the EVI1 gene, an event that is similar to the normal intergenic splicing of MDS1-EVI1 and to those previously documented in leukemias with t(3;21) and t(3;12), in which acute myelogenous leukemia 1-EVI1 fusions and ETV6-EVI1 fusions, respectively, occur. The Ribophorin I-EVI1 fusion in particular may be a common occurrence in t(3;3). PMID:9307271

  1. BRCA1 maps proximal to D17S579 on chromosome 17q21 by genetic analysis

    PubMed Central

    Chamberlain, Jeffrey S.; Boehnke, Michael; Frank, Thomas S.; Kiousis, Sam; Xu, Junxhe; Guo, Sun-Wei; Hauser, Elizabeth R.; Norum, Robert A.; Helmbold, Elizabeth A.; Markel, Dorene S.; Keshavarzi, Sima M.; Jackson, C. Eugene; Calzone, Kathleen; Garber, Judy; Collins, Francis S.; Weber, Barbara L.

    1993-01-01

    Previous studies have demonstrated linkage between early-onset breast cancer and ovarian cancer and genetic markers on chromosome 17q21. These markers define the location of a gene (BRCA1) which appears to be inherited as an autosomal dominant susceptibility allele. We analyzed five families with multiple affected individuals for evidence of linkage to the BRCA1 region. Two of the five families appear to be linked to BRCA1. One apparently linked family contains critical recombinants, suggesting that the gene is proximal to the marker D17S579 (Mfd188). These findings are consistent with the maximum-likelihood position estimated by the Breast Cancer Linkage Consortium and with recombination events detected in other linked families. Linkage analysis was greatly aided by PCR-based analysis of paraffin-embedded normal breast tissue from deceased family members, demonstrating the feasibility and importance of this approach. One of the two families with evidence of linkage between breast cancer and genetic markers flanking BRCA1 represents the first such family of African-American descent to be reported in detail. ImagesFigure 4 PMID:8460646

  2. Family based genome-wide copy number scan identifies complex rearrangements at 17q21.31 in dyslexics.

    PubMed

    Veerappa, Avinash M; Saldanha, Marita; Padakannaya, Prakash; Ramachandra, Nallur B

    2014-10-01

    Developmental dyslexia (DD) is a complex heritable disorder with unexpected difficulty in learning to read and spell despite adequate intelligence, education, environment, and normal senses. We performed genome-wide screening for copy number variations (CNVs) in 10 large Indian dyslexic families using Affymetrix Genome-Wide Human SNP Array 6.0. Results revealed the complex genomic rearrangements due to one non-contiguous deletion and five contiguous micro duplications and micro deletions at 17q21.31 region in three dyslexic families. CNVs in this region harbor the genes KIAA1267, LRRC37A, ARL17A/B, NSFP1, and NSF. The CNVs in case 1 and case 2 at this locus were found to be in homozygous state and case 3 was a de novo CNV. These CNVs were found with at least one CNV having a common break and end points in the parents. This cluster of genes containing NSF is implicated in learning, cognition, and memory, though not formally associated with dyslexia. Molecular network analysis of these and other dyslexia related module genes suggests NSF and other genes to be associated with cellular/vesicular membrane fusion and synaptic transmission. Thus, we suggest that NSF in this cluster would be the nearest gene responsible for the learning disability phenotype. PMID:25139666

  3. A new form of childhood onset, autosomal recessive spinocerebellar ataxia and epilepsy is localized at 16q21-q23.

    PubMed

    Gribaa, M; Salih, M; Anheim, M; Lagier-Tourenne, C; H'mida, D; Drouot, N; Mohamed, A; Elmalik, S; Kabiraj, M; Al-Rayess, M; Almubarak, M; Bétard, C; Goebel, H; Koenig, M

    2007-07-01

    Childhood ataxias are a complex set of inherited disorders. Ataxias associated with generalized tonic-clonic epilepsy are usually included with the progressive myoclonus epilepsies (PME). Five disease entities, Unverricht-Lundborg disease, Lafora's disease, neuronal ceroid lipofuscinoses, myoclonic epilepsy with ragged red fibres and sialidoses, account for the majority of PME cases. Two rare forms of ataxia plus epilepsy, sensory ataxic neuropathy, dysarthria and ophthalmoparesis, and infantile onset spinocerebellar ataxia were described recently and found to be caused by defective mitochondrial proteins. We report here a large consanguineous family from Saudi Arabia with four affected children presenting with generalized tonic-clonic epilepsy, ataxia and mental retardation, but neither myoclonus nor mental deterioration. MRI and muscle biopsy of one patient revealed, respectively, posterior white matter hyperintensities and vacuolization of the sarcotubular system. We localized the defective gene by homozygosity mapping to a 19 Mb interval in 16q21-q23 between markers D16S3091 and D16S3050. Linkage studies in this region will allow testing for homogeneity of this novel ataxia-epilepsy entity. PMID:17470496

  4. The human myosin light chain kinase (MLCK) from hippocampus: Cloning, sequencing, expression, and localization to 3qcen-q21

    SciTech Connect

    Potier, M.C.; Rossier, J.; Turnell, W.G.; Pekarsky, Y.; Gardiner, K.

    1995-10-10

    Myosin light chain kinase (MLCK), a key enzyme in muscle contraction, has been shown by immunohistology to be present in neurons and glia. We describe here the cloning of the cDNA for human MLCK from hippocampus, encoding a protein sequence 95% similar to smooth muscle MLCKs but less than 60% similar to skeletal muscle MLCKs. The cDNA clone detected two RNA transcripts in human frontal and entorhinal cortex, in hippocampus, and in jejunum, one corresponding to MLCK and the other probably to telokin, the carboxy-terminal 154 codons of MLCK expressed as an independent protein in smooth muscle. Levels of expression were lower in brain compared to smooth muscle. We show that within the protein sequence, a motif of 28 or 24 residues is repeated five times, the second repeat ending with the putative methionine start codon. These repeats overlap with a second previously reported module of 12 residues repeated five times in the human sequence. In addition, the acidic C-terminus of all MLCKs from both brain and smooth muscle resembles the C-terminus of tubulins. The chromosomal localization of the gene for human MLCK is shown to be at 3qcen-q21, as determined by PCR and Southern blotting using two somatic cell hybrid panels. 33 refs., 8 figs.

  5. A human homologue of the Drosophila polarity gene frizzled has been identified and mapped to 17q21.1

    SciTech Connect

    Zhao, Z.; Lee, C.C.; Baldini, A.

    1995-05-20

    The frizzled (fz) locus in Drosophila is required for the transmission of polarity signals across the plasma membrane in epidermal cells, as well as to their neighboring cells in the developing wing. The identification of a tissue polarity gene from the fz locus in Drosophila melanogaster has been reported. The fz gene encodes a protein (Fz) with seven putative transmembrane domains, which was suggested to function as a G-protein-coupled receptor. Here the authors report the identification of a human homologue for the fz gene (FZD2). The FZD2 gene was isolated from a human ovarian cDNA library and mapped to 17q21.1 by fluorescent in situ hybridization (FISH) with a corresponding cosmid. The full-length cDNA of human FZD2 encodes a protein (FZD-2) of 565 amino acids that shares 56% sequence identity with Drosophila Fz. The expression of the FZD2 gene seems to be developmentally regulated, with high levels of expression in fetal kidney and lung and in adult colon and ovary. The structure of FZD-2 suggests that it has a role in transmembrane signal transmission, although its precise physiological function and associated pathways are yet to be determined. 9 refs., 2 figs.

  6. Compositions and methods for detecting gene rearrangements and translocations

    DOEpatents

    Rowley, Janet D.; Diaz, Manuel O.

    2000-01-01

    Disclosed is a series of nucleic acid probes for use in diagnosing and monitoring certain types of leukemia using, e.g., Southern and Northern blot analyses and fluorescence in situ hybridization (FISH). These probes detect rearrangements, such as translocations involving chromosome band 11q23 with other chromosomes bands, including 4q21, 6q27, 9p22, 19p13.3, in both dividing leukemic cells and interphase nuclei. The breakpoints in all such translocations are clustered within an 8.3 kb BamHI genomic region of the MLL gene. A novel 0.7 kb BamH1 cDNA fragment derived from this gene detects rearrangements on Southern blot analysis with a single BamHI restriction digest in all patients with the common 11q23 translocations and in patients with other 11q23 anomalies. Northern blot analyses are presented demonstrating that the MLL gene has multiple transcripts and that transcript size differentiates leukemic cells from normal cells. Also disclosed are MLL fusion proteins, MLL protein domains and anti-MLL antibodies.

  7. Familial translocation involving chromosomes 1 and 9 in a patient with Philadelphia-positive CML

    SciTech Connect

    Rehman, K.; Rosner, F.; Shanske, A.

    1994-09-01

    CML has provided a model for understanding the genetic basis of neoplasia. Approximately 5% of Philadelphia-positive patients have a variant chromosome rearrangement. We recently evaluated a patient with a previously unreported simple variant translocation that is part of a familial rearrangement. He had a constitutional translocation, t(1;9)(p21;p22), which was initially identified after his wife had a routine amniocentesis. Case report: K.H. was a 54-year-old male with CML for 4 years. He had been treated until recently with hydroxyurea. An abnormal male karyotype, 46,XY,t(1;9)(q21;p22),t(9;22)(q34;q11) was recorded from an unstimulated blood sample soon after diagnosis. Both translocations involved the same number 9 homologue resulting in a derivative 9(1pter{r_arrow}1q21::9p22{r_arrow}9q34::22q11{r_arrow}22qter). A recent CT scan of the chest showed a lytic lesion of a rib with associated soft tissue mass in the right costo-vertebral angle. He was hospitalized for progressive pain in the right lower chest and fever, treated for a UTI, required multiple transfusions for declining hemoglobin and platelets and died shortly thereafter. Autopsy revealed widespread chloromas as part of terminal CML. At least 13 complex rearrangements involving chromosomes 1, 9 and 22 are known. Our case represents a unique rearrangement with a familial component and also unique breakpoints for a Philadelphia variant. In line with the current view of cancer as a clonal disorder, perhaps the constitutional translocation contributed to the multi-step nature of the malignant transformation. In fact, a number of cancer-specific breakpoints in both regions of 1p and 9p are involved in the familial translocation.

  8. Physiology in conservation translocations

    PubMed Central

    Tarszisz, Esther; Dickman, Christopher R.; Munn, Adam J.

    2014-01-01

    Conservation translocations aim to restore species to their indigenous ranges, protect populations from threats and/or reinstate ecosystem functions. They are particularly important for the conservation and management of rare and threatened species. Despite tremendous efforts and advancement in recent years, animal conservation translocations generally have variable success, and the reasons for this are often uncertain. We suggest that when little is known about the physiology and wellbeing of individuals either before or after release, it will be difficult to determine their likelihood of survival, and this could limit advancements in the science of translocations for conservation. In this regard, we argue that physiology offers novel approaches that could substantially improve translocations and associated practices. As a discipline, it is apparent that physiology may be undervalued, perhaps because of the invasive nature of some physiological measurement techniques (e.g. sampling body fluids, surgical implantation). We examined 232 publications that dealt with translocations of terrestrial vertebrates and aquatic mammals and, defining ‘success’ as high or low, determined how many of these studies explicitly incorporated physiological aspects into their protocols and monitoring. From this review, it is apparent that physiological evaluation before and after animal releases could progress and improve translocation/reintroduction successes. We propose a suite of physiological measures, in addition to animal health indices, for assisting conservation translocations over the short term and also for longer term post-release monitoring. Perhaps most importantly, we argue that the incorporation of physiological assessments of animals at all stages of translocation can have important welfare implications by helping to reduce the total number of animals used. Physiological indicators can also help to refine conservation translocation methods. These approaches fall

  9. Hereditary Hyperparathyroidism–Jaw Tumor Syndrome: The Endocrine Tumor Gene HRPT2 Maps to Chromosome 1q21-q31

    PubMed Central

    Szabó, József; Heath, Brett; Hill, Virginia M.; Jackson, Charles E.; Zarbo, Richard J.; Mallette, Lawrence E.; Chew, Shern L.; Besser, Gordon M.; Thakker, Rajesh V.; Huff, Vicki; Leppert, Mark F.; Heath, Hunter

    1995-01-01

    The syndrome of hereditary hyperparathyroidism and jaw tumors (HPT-JT) is characterized by inheritance, in an autosomal dominant pattern, of recurrent parathyroid adenomas, fibro-osseous tumors of the mandible and/or maxilla, Wilms tumor, and parathyroid carcinoma. This syndrome is clinically and genetically distinct from other endocrine neoplasia syndromes and appears to result from mutation of an endocrine tumor gene designated “HRPT2.” We studied five HPT-JT families (59 persons, 20 affected); using PCR-based markers, we instituted a genomewide linkage search after excluding several candidate genes. Lod scores were calculated at various recombination fractions (θ), penetrance 90%. We mapped HRPT2 to the long arm of chromosome 1 (1q21-q31). The maximal lod score was 6.10 at θ = .0 with marker D1S212, or >106 odds in favor of linkage. In six hereditary Wilms tumor families (96 persons, 29 affected), we found no linkage to 1q markers closely linked with HRPT2 (lod scores −15.6 [D1S191] and −17.8 [D1S196], θ = .001). Nine parathyroid adenomas and one Wilms tumor from nine members of three HPT-JT families were examined for loss of heterozygosity at linked loci. The parathyroid adenomas and Wilms tumor showed no loss of heterozygosity for these DNA markers. Our data establish that HRPT2, an endocrine tumor gene on the long arm of chromosome 1, is responsible for the HPT-JT syndrome but not for the classical hereditary Wilms tumor syndrome. ImagesFigure 1 PMID:7717405

  10. High-density genetic map of the BRCA1 region of chromosome 17q12-q21

    SciTech Connect

    Anderson, L.A.; Friedman, L.; Lynch, E.; King, M.C. ); Osborne-Lawrence, S.; Bowcock, A. ); Weissenbach, J. )

    1993-09-01

    To facilitate the positional cloning of the breast-ovarian cancer gene BRCA1, the authors constructed a high-density genetic map of the 8.3-cM interval between D17S250 and GIP on chromosome 17q12-q21. Markers were mapped by linkage in the CEPH and in extended kindreds in the breast cancer series. The map comprises 33 ordered polymorphisms, including 12 genes and 21 anonymous markers, yielding an average of one polymorphism every 250 kb. Twenty-five of the markers are PCR-based systems. The order of polymorphic genes and markers is cen-D17S250-D17S518-HER2-THRA1-RARA-D17S80-KRT10-[D17S800-D17S857]-GAS-D17S856-EDH17B-D17S855-D17S859-D17S858-[PPY-D17S78]-D17S183-EPB3-D17S579-D17S509-[D17S508-D17S190 = D17S810]-D17S791-[D17S181 = D17S806]-D17S797-HOX2B-GP3A-[D17S507 = GIP]-qter. BRCA1 lies in the middle of the interval, between THRA1 and D17S183. Markers from this map can be used to determine whether cancer is linked to BRCA1 in families, to evaluate whether tumors have lost heterozygosity at loci in the region, and to identify probes for characterizing chromosomal rearrangements from patients and from tumors. 21 refs., 1 fig., 3 tabs.

  11. Hereditary hyperparathyroidism-jaw tumor syndrome: the endocrine tumor gene HRPT2 maps to chromosome 1q21-q31

    SciTech Connect

    Szabo, J.; Heath, B.; Hill, V.M.; Heath, H. III; Leppert, M.F.; Jackson, C.E.; Zarbo, R.J.; Mallette, L.E.; Huff, V.; Chew, S.L.

    1995-04-01

    The syndrome of hereditary hyperparathyroidism and jaw tumors (HPT-JT) is characterized by inheritance, in an autosomal dominant pattern, of recurrent parathyroid adenomas, fibro-osseous tumors of the mandible and/or maxilla, Wilms tumor, and parathyroid carcinoma. This syndrome is clinically and genetically distinct from other endocrine neoplasia syndromes and appears to result from mutation of an endocrine tumor gene designated {open_quotes}HRPT2{close_quotes}. We studied five HPT-JT families (59 persons, 20 affected); using PCR-based markers, we instituted a genome-wide linkage search after excluding several candidate genes. Lod scores were calculated at various recombination fractions ({theta}), penetrance 90%. We mapped HRPT2 to the long arm of chromosome 1 (1q21-q31). The maximal lod score was 6.10 at {theta} = .0 with marker D1S212, or >10{sup 6} odds in favor of linkage. In six hereditary Wilms tumor families (96 persons, 29 affected), we found no linkage to 1q markers closely linked with HRPT2 (lod scores -15.6 [D1S191] and -17.8 [D1S196], {theta} = .001). Nine parathyroid adenomas and one Wilms tumor from nine members of three HPT-JT families were examined for loss of heterozygosity at linked loci. The parathyroid adenomas and Wilms tumor showed no loss of heterozygosity for these DNA markers. Our data establish that HRPT2, an endocrine tumor gene on the long arm of chromosome 1, is responsible for the HPT-JT syndrome but not for the classical hereditary Wilms tumor syndrome. 32 refs., 2 figs., 2 tabs.

  12. Physical and transcription map of a 25 Mb region on human chromosome 7 (region q21-q22)

    SciTech Connect

    Scherer, S. |; Little, S.; Vandenberg, A.

    1994-09-01

    We are interested in the q21-q22 region of chromosome 7 because of its implication in a number of diseases. This region of about 25 Mb appears to be involved in ectrodactyly/ectodermal dysplasia/cleft plate (EEC) and split hand/split foot deformity (SHFD1), as well as myelodysplastic syndrome and acute non-lymphocyte leukemia. In order to identify the genes responsible for these and other diseases, we have constructed a physical map of this region. The proximal and distal boundaries of the region were operationally defined by the microsatellite markers D7S660 and D7S692, which are about 35 cM apart. This region between these two markers could be divided into 13 intervals on the basis of chromosome breakpoints contained in somatic cell hybrids. The map positions for 43 additional microsatellite markers and 25 cloned genes were determined with respect to these intervals. A physical map based on contigs of over 250 YACs has also been assembled. While the contigs encompass all of the known genetic markers mapped to the region and almost cover the entire 25-Mb region, there are 3 gaps on the map. One of these gaps spans a set of DNA markers for which no corresponding YAC clones could be identified. To connect the two adjacent contigs we have initiated cosmid walking with a chromosome 7-specific library (Lawrence Livermore Laboratory). A tiling path of 60 contiguous YAC clones has been assembled and used for direct cDNA selection. Over 300 cDNA clones have been isolated and characterized. They are being grouped into transcription units by Northern blot analysis and screening of full-length cDNA libraries. Further, exon amplification and direct cDNA library screening with evolutionarily conserved sequences are being performed for a 1-Mb region spanning the SHFD1 locus to ensure detection of all transcribed sequences.

  13. Mechanism of the t(14; 18) chromosomal translocation: structural analysis of both derivative 14 and 18 reciprocal partners

    SciTech Connect

    Bakhshi, A.; Wright, J.J.; Graninger, W.; Seto, M.; Owens, J.; Cossman, J.; Jensen, J.P.; Goldman, P.; Korsmeyer, S.J.

    1987-04-01

    To elucidate the mechanism of the t(14;18)(q32;q21) chromosomal translocation found in follicular lymphoma, the authors examined the structure of both derivative (der) chromosomal breakpoints as well as their germ-line predecessors. They noted that chromosome segment 18q21 was juxtaposed with immunoglobulin heavy (H) chain gene diversity (D/sub H/) regions on all five der(18) chromosomes they examined, and they confirmed the juncture with immunoglobulin H-chain gene joining (J/sub H/) regions on the der(14) chromosome. However, the t(14;18) was not fully reciprocal in that chromosome 14 DNA between the D/sub H/ and J/sub H/ regions was deleted. Furthermore, extra nucleotides, reminiscent of N segments, were present at the der(14) and possibly der(18) junctions. This indicates that despite the mature B-cell phenotype of follicular lymphoma, the t(14;18) occurs during attempted D/sub H/-J/sub H/ joining, the earliest event in immunoglobulin rearrangement in a pre-B-cell. The detailed analysis of the germ-line 18q21 region indicated that most breakpoints clustered within a 150-base-pair major breakpoint region. A direct repeat duplication of chromosome 18 sequences was discovered at both chromosomal junctures, typical of the repair of a naturally occurring staggered double-stranded DNA break. These results prompt a translocation model with illegitimate pairing of a staggered double-stranded DNA break at 18q21 and an immunoglobulin endonuclease-mediated break at 14q32 and with N-segment addition, repair, and ligation to generate der(14) and der(18) chromosomes.

  14. PTPN13, a Fas-associated protein tyrosine phosphatase, is located on the long arm of chromosome 4 at band q21.3

    SciTech Connect

    Inazawa, Johji; Ariyama, Takeshi; Abe, Tatsuo

    1996-01-15

    PTPN13 is a protein tyrosine phosphatase that associates with the C-terminal negative regulatory domain in the Fas (APO-1/CD95) receptor. The PTPN13 protein contains six GLGF repeats that have been found in the rat postsynaptic density protein (PSD-95) and the Drosophila tumor suppressor protein, lethal-(1)-disclarge-1 (dlg-1). The localization of the PTPN13 gene to human chromosome 4q21.3 was determined by both FISH and PCR analysis of somatic cell hybrids. This 4q21.3 chromosomal region contains a gene for autosomal dominant polycystic kidney disease as well as the region frequently deleted in liver and ovarian cancers, suggesting that PTPN13 is a candidate for one of the putative tumor suppressor genes on the long arm of chromosome 4. 21 refs., 1 fig.

  15. Localization of the gene encoding peptidylglycine [alpha]-amidating monooxygenase (PAM) to human chromosome 5q14-5q21

    SciTech Connect

    Ouafik, L.H.; Giraud, P.; Oliver, C. ); Mattei, M.G. ); Eipper, B.A.; Mains, R.E. )

    1993-11-01

    Peptidylglycine [alpha]-amidating monooxygenase (PAM; EC 1.14.17.3) is a multifunctional protein containing two enzymes that act sequentially to catalyze the [alpha]-amidation of neuroendocrine peptides. Southern blot analysis of human placental DNA demonstrated that PAM is encoded by a single gene. The chromosomal localization of the PAM gene was established using in situ hybridization. A 2.2-kb human PAM cDNA hybridized to human metaphase chromosomes revealed a significant clustering of silver grains over chromosome 5 bands q14-q21. The gene encoding another enzyme important in the post-translational processing of neuroendocrine precursors, prohormone convertase 1 (PC1), is localized in the same region (5q15-q21). 14 refs., 2 figs.

  16. Gene structure and chromosome localization to 7q21.3 of the human rod photoreceptor transducin {gamma}-subunit gene (GNGT1)

    SciTech Connect

    Scherer, S.W.; Tsui, Lap-Chee |; Feinstein, D.S.

    1996-07-01

    The transducin {gamma}-subunit gene (GNGT1) encodes a member ({gamma}{sub 1}) of the family of heterotrimeric G-protein {gamma}-subunits that is specific to rod photoreceptors. In this report we have determined the complete structure of the GNGT1 gene and have localized it to human chromosome 7q21.3 using somatic cell hybrid and yeast artificial chromosome analysis. 16 refs., 2 figs.

  17. The gene encoding myeloid alpha-3-fucosyl-transferase (FUT4) is located between D1 1S388 and D11S919 on 11q21.

    PubMed

    Reguigne, I; James, M R; Richard, C W; Mollicone, R; Seawright, A; Lowe, J B; Oriol, R; Couillin, P

    1994-01-01

    The last step in the biosynthesis of Le(x) antigen, the addition of a fucose to precursor polysaccharides, can be catalyzed by different alpha-3-fucosyltransferases. We localized the gene (FUT4) encoding myeloid alpha-3-fucosyltransferase by PCR assay using panels of somatic cell and radiation hybrids which retain different rearrangements of chromosome 11. FUT4 was assigned to chromosome band 11q21 between D11S388 and D11S919. PMID:8287679

  18. 17q21.31 microdeletion syndrome: Description of a case further contributing to the delineation of Koolen-de Vries syndrome.

    PubMed

    Bernardo, Pia; Madia, Francesca; Santulli, Lia; Del Gaudio, Luigi; Caccavale, Carmela; Zara, Federico; Traverso, Monica; Cirillo, Mario; Striano, Salvatore; Coppola, Antonietta

    2016-08-01

    The widespread use of Array Comparative Genomic Hybridization (aCGH) technology has enabled the identification of several syndromes associated with copy number variants (CNVs) including the 17q21.31 microdeletion. The 17q21.31 microdeletion syndrome, also known as Koolen-de Vries syndrome, was first described in 2006 in individuals with intellectual disabilities and organ abnormalities. We report the clinical, instrumental, cytogenetic and molecular investigations of a boy admitted for epilepsy and intellectual disabilities. We carried out detailed analysis of the clinical phenotype of this patient and investigated the genetic basis by using aCGH. We identified a de novo microdeletion on chromosome 17q21.31, compatible with Koolen-de Vries syndrome. Our case shares some of the typical characteristics of the syndrome already described by other authors: delayed psychomotor development, primarily affecting the expressive language, dysmorphic facial features, and epilepsy. However the clinical outcome was not severe as the intellectual disabilities were moderate with good adaptive and functional behaviour. Epilepsy was easily controlled by a single drug, and he never needed surgery for organ abnormalities. PMID:26897099

  19. Mapping of the human dentin matrix acidic phosphoprotein gene (DMP1) to the dentinogenesis imperfecta type II critical region at chromosome 4q21

    SciTech Connect

    Aplin, H.M.; Hirst, K.L.; Crosby, A.H.; Dixon, M.J.

    1995-11-20

    Dentinogenesis imperfecta type II (DGI1) is an autosomal dominant disorder of dentin formation, which has been mapped to human chromosome 4q12-q21. The region most likely to contain the DGI1 locus is a 3.2-cM region surrounding the osteopontin (SPP1) locus. Recently, a novel dentin-specific acidic phosphoprotein (dmp1) has been cloned in the rat and mapped to mouse chromosome 5q21. In the current investigation, we have isolated a cosmid containing the human DMP1 gene. The isolation of a short tandem repeat polymorphism at this locus has allowed us to map the DMP1 locus to human chromosome 4q21 and demonstrate that it is tightly linked to DGI1 in two families (Z{sub max} = 11.01, {theta} = 0.001). The creation of a yeast artificial chromosome contig around SPP1 has further allowed us to demonstrate that DMP1 is located within 150 kb of the bone sialoprotein and 490 kb of the SPP1 loci, respectively. DMP1 is therefore a strong candidate for the DGI1 locus. 12 refs., 2 figs., 1 tab.

  20. Clinical relevance of 8q23, 15q13 and 18q21 SNP genotyping to evaluate colorectal cancer risk

    PubMed Central

    Baert-Desurmont, Stéphanie; Charbonnier, Françoise; Houivet, Estelle; Ippolito, Lorena; Mauillon, Jacques; Bougeard, Marion; Abadie, Caroline; Malka, David; Duffour, Jacqueline; Desseigne, Françoise; Colas, Chrystelle; Pujol, Pascal; Lejeune, Sophie; Dugast, Catherine; Buecher, Bruno; Faivre, Laurence; Leroux, Dominique; Gesta, Paul; Coupier, Isabelle; Guimbaud, Rosine; Berthet, Pascaline; Manouvrier, Sylvie; Cauchin, Estelle; Prieur, Fabienne; Laurent-Puig, Pierre; Lebrun, Marine; Jonveaux, Philippe; Chiesa, Jean; Caron, Olivier; Morin-Meschin, Marie-Emmanuelle; Polycarpe-Osaer, Florence; Giraud, Sophie; Zaanan, Aziz; Bonnet, Delphine; Mansuy, Ludovic; Bonadona, Valérie; El Chehadeh, Salima; Duhoux, François; Gauthier-Villars, Marion; Saurin, Jean-Christophe; Collonge-Rame, Marie- Agnès; Brugières, Laurence; Wang, Qing; Bressac-de Paillerets, Brigitte; Rey, Jean-Marc; Toulas, Christine; Buisine, Marie-Pierre; Bronner, Myriam; Sokolowska, Joanna; Hardouin, Agnès; Cailleux, Anne-Françoise; Sebaoui, Hakim; Blot, Julien; Tinat, Julie; Benichou, Jacques; Frebourg, Thierry

    2016-01-01

    To determine if the at-risk single-nucleotide polymorphism (SNP) alleles for colorectal cancer (CRC) could contribute to clinical situations suggestive of an increased genetic risk for CRC, we performed a prospective national case–control study based on highly selected patients (CRC in two first-degree relatives, one before 61 years of age; or CRC diagnosed before 51 years of age; or multiple primary CRCs, the first before 61 years of age; exclusion of Lynch syndrome and polyposes) and controls without personal or familial history of CRC. SNPs were genotyped using SNaPshot, and statistical analyses were performed using Pearson's χ2 test, Cochran–Armitage test of trend and logistic regression. We included 1029 patients and 350 controls. We confirmed the association of CRC risk with four SNPs, with odds ratio (OR) higher than previously reported: rs16892766 on 8q23.3 (OR: 1.88, 95% confidence interval (CI): 1.30–2.72; P=0.0007); rs4779584 on 15q13.3 (OR: 1.42, CI: 1.11–1.83; P=0.0061) and rs4939827 and rs58920878/Novel 1 on 18q21.1 (OR: 1.49, CI: 1.13–1.98; P=0.007 and OR: 1.49, CI: 1.14–1.95; P=0.0035). We found a significant (P<0.0001) cumulative effect of the at-risk alleles or genotypes with OR at 1.62 (CI: 1.10–2.37), 2.09 (CI: 1.43–3.07), 2.87 (CI: 1.76–4.70) and 3.88 (CI: 1.72–8.76) for 1, 2, 3 and at least 4 at-risk alleles, respectively, and OR at 1.71 (CI: 1.18–2.46), 2.29 (CI: 1.55–3.38) and 6.21 (CI: 2.67–14.42) for 1, 2 and 3 at-risk genotypes, respectively. Combination of SNPs may therefore explain a fraction of clinical situations suggestive of an increased risk for CRC. PMID:25873010

  1. Clinical relevance of 8q23, 15q13 and 18q21 SNP genotyping to evaluate colorectal cancer risk.

    PubMed

    Baert-Desurmont, Stéphanie; Charbonnier, Françoise; Houivet, Estelle; Ippolito, Lorena; Mauillon, Jacques; Bougeard, Marion; Abadie, Caroline; Malka, David; Duffour, Jacqueline; Desseigne, Françoise; Colas, Chrystelle; Pujol, Pascal; Lejeune, Sophie; Dugast, Catherine; Buecher, Bruno; Faivre, Laurence; Leroux, Dominique; Gesta, Paul; Coupier, Isabelle; Guimbaud, Rosine; Berthet, Pascaline; Manouvrier, Sylvie; Cauchin, Estelle; Prieur, Fabienne; Laurent-Puig, Pierre; Lebrun, Marine; Jonveaux, Philippe; Chiesa, Jean; Caron, Olivier; Morin-Meschin, Marie-Emmanuelle; Polycarpe-Osaer, Florence; Giraud, Sophie; Zaanan, Aziz; Bonnet, Delphine; Mansuy, Ludovic; Bonadona, Valérie; El Chehadeh, Salima; Duhoux, François; Gauthier-Villars, Marion; Saurin, Jean-Christophe; Collonge-Rame, Marie-Agnès; Brugières, Laurence; Wang, Qing; Bressac-de Paillerets, Brigitte; Rey, Jean-Marc; Toulas, Christine; Buisine, Marie-Pierre; Bronner, Myriam; Sokolowska, Joanna; Hardouin, Agnès; Cailleux, Anne-Françoise; Sebaoui, Hakim; Blot, Julien; Tinat, Julie; Benichou, Jacques; Frebourg, Thierry

    2016-01-01

    To determine if the at-risk single-nucleotide polymorphism (SNP) alleles for colorectal cancer (CRC) could contribute to clinical situations suggestive of an increased genetic risk for CRC, we performed a prospective national case-control study based on highly selected patients (CRC in two first-degree relatives, one before 61 years of age; or CRC diagnosed before 51 years of age; or multiple primary CRCs, the first before 61 years of age; exclusion of Lynch syndrome and polyposes) and controls without personal or familial history of CRC. SNPs were genotyped using SNaPshot, and statistical analyses were performed using Pearson's χ(2) test, Cochran-Armitage test of trend and logistic regression. We included 1029 patients and 350 controls. We confirmed the association of CRC risk with four SNPs, with odds ratio (OR) higher than previously reported: rs16892766 on 8q23.3 (OR: 1.88, 95% confidence interval (CI): 1.30-2.72; P=0.0007); rs4779584 on 15q13.3 (OR: 1.42, CI: 1.11-1.83; P=0.0061) and rs4939827 and rs58920878/Novel 1 on 18q21.1 (OR: 1.49, CI: 1.13-1.98; P=0.007 and OR: 1.49, CI: 1.14-1.95; P=0.0035). We found a significant (P<0.0001) cumulative effect of the at-risk alleles or genotypes with OR at 1.62 (CI: 1.10-2.37), 2.09 (CI: 1.43-3.07), 2.87 (CI: 1.76-4.70) and 3.88 (CI: 1.72-8.76) for 1, 2, 3 and at least 4 at-risk alleles, respectively, and OR at 1.71 (CI: 1.18-2.46), 2.29 (CI: 1.55-3.38) and 6.21 (CI: 2.67-14.42) for 1, 2 and 3 at-risk genotypes, respectively. Combination of SNPs may therefore explain a fraction of clinical situations suggestive of an increased risk for CRC. PMID:25873010

  2. Polymorphisms in a Putative Enhancer at the 10q21.2 Breast Cancer Risk Locus Regulate NRBF2 Expression.

    PubMed

    Darabi, Hatef; McCue, Karen; Beesley, Jonathan; Michailidou, Kyriaki; Nord, Silje; Kar, Siddhartha; Humphreys, Keith; Thompson, Deborah; Ghoussaini, Maya; Bolla, Manjeet K; Dennis, Joe; Wang, Qin; Canisius, Sander; Scott, Christopher G; Apicella, Carmel; Hopper, John L; Southey, Melissa C; Stone, Jennifer; Broeks, Annegien; Schmidt, Marjanka K; Scott, Rodney J; Lophatananon, Artitaya; Muir, Kenneth; Beckmann, Matthias W; Ekici, Arif B; Fasching, Peter A; Heusinger, Katharina; Dos-Santos-Silva, Isabel; Peto, Julian; Tomlinson, Ian; Sawyer, Elinor J; Burwinkel, Barbara; Marme, Frederik; Guénel, Pascal; Truong, Thérèse; Bojesen, Stig E; Flyger, Henrik; Benitez, Javier; González-Neira, Anna; Anton-Culver, Hoda; Neuhausen, Susan L; Arndt, Volker; Brenner, Hermann; Engel, Christoph; Meindl, Alfons; Schmutzler, Rita K; Arnold, Norbert; Brauch, Hiltrud; Hamann, Ute; Chang-Claude, Jenny; Khan, Sofia; Nevanlinna, Heli; Ito, Hidemi; Matsuo, Keitaro; Bogdanova, Natalia V; Dörk, Thilo; Lindblom, Annika; Margolin, Sara; Kosma, Veli-Matti; Mannermaa, Arto; Tseng, Chiu-Chen; Wu, Anna H; Floris, Giuseppe; Lambrechts, Diether; Rudolph, Anja; Peterlongo, Paolo; Radice, Paolo; Couch, Fergus J; Vachon, Celine; Giles, Graham G; McLean, Catriona; Milne, Roger L; Dugué, Pierre-Antoine; Haiman, Christopher A; Maskarinec, Gertraud; Woolcott, Christy; Henderson, Brian E; Goldberg, Mark S; Simard, Jacques; Teo, Soo H; Mariapun, Shivaani; Helland, Åslaug; Haakensen, Vilde; Zheng, Wei; Beeghly-Fadiel, Alicia; Tamimi, Rulla; Jukkola-Vuorinen, Arja; Winqvist, Robert; Andrulis, Irene L; Knight, Julia A; Devilee, Peter; Tollenaar, Robert A E M; Figueroa, Jonine; García-Closas, Montserrat; Czene, Kamila; Hooning, Maartje J; Tilanus-Linthorst, Madeleine; Li, Jingmei; Gao, Yu-Tang; Shu, Xiao-Ou; Cox, Angela; Cross, Simon S; Luben, Robert; Khaw, Kay-Tee; Choi, Ji-Yeob; Kang, Daehee; Hartman, Mikael; Lim, Wei Yen; Kabisch, Maria; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; McKay, James; Sangrajrang, Suleeporn; Toland, Amanda E; Yannoukakos, Drakoulis; Shen, Chen-Yang; Yu, Jyh-Cherng; Ziogas, Argyrios; Schoemaker, Minouk J; Swerdlow, Anthony; Borresen-Dale, Anne-Lise; Kristensen, Vessela; French, Juliet D; Edwards, Stacey L; Dunning, Alison M; Easton, Douglas F; Hall, Per; Chenevix-Trench, Georgia

    2015-07-01

    Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 [0.82-0.88]) and ER-negative (OR = 0.87 [0.82-0.91]) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:D) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 [0.91-0.95] and OR = 1.06 [1.03-1.09]) and ER-negative (OR = 0.95 [0.91-0.98] and OR = 1.08 [1.04-1.13]) disease. There was weaker evidence for iCHAV4, located 5' of ADO, associated only with ER-positive breast cancer (OR = 0.93 [0.90-0.96]). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1-4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer. PMID:26073781

  3. Polymorphisms in a Putative Enhancer at the 10q21.2 Breast Cancer Risk Locus Regulate NRBF2 Expression

    PubMed Central

    Darabi, Hatef; McCue, Karen; Beesley, Jonathan; Michailidou, Kyriaki; Nord, Silje; Kar, Siddhartha; Humphreys, Keith; Thompson, Deborah; Ghoussaini, Maya; Bolla, Manjeet K.; Dennis, Joe; Wang, Qin; Canisius, Sander; Scott, Christopher G.; Apicella, Carmel; Hopper, John L.; Southey, Melissa C.; Stone, Jennifer; Broeks, Annegien; Schmidt, Marjanka K.; Scott, Rodney J.; Lophatananon, Artitaya; Muir, Kenneth; Beckmann, Matthias W.; Ekici, Arif B.; Fasching, Peter A.; Heusinger, Katharina; dos-Santos-Silva, Isabel; Peto, Julian; Tomlinson, Ian; Sawyer, Elinor J.; Burwinkel, Barbara; Marme, Frederik; Guénel, Pascal; Truong, Thérèse; Bojesen, Stig E.; Flyger, Henrik; Benitez, Javier; González-Neira, Anna; Anton-Culver, Hoda; Neuhausen, Susan L.; Arndt, Volker; Brenner, Hermann; Engel, Christoph; Meindl, Alfons; Schmutzler, Rita K.; Arnold, Norbert; Brauch, Hiltrud; Hamann, Ute; Chang-Claude, Jenny; Khan, Sofia; Nevanlinna, Heli; Ito, Hidemi; Matsuo, Keitaro; Bogdanova, Natalia V.; Dörk, Thilo; Lindblom, Annika; Margolin, Sara; Kosma, Veli-Matti; Mannermaa, Arto; Tseng, Chiu-chen; Wu, Anna H.; Floris, Giuseppe; Lambrechts, Diether; Rudolph, Anja; Peterlongo, Paolo; Radice, Paolo; Couch, Fergus J.; Vachon, Celine; Giles, Graham G.; McLean, Catriona; Milne, Roger L.; Dugué, Pierre-Antoine; Haiman, Christopher A.; Maskarinec, Gertraud; Woolcott, Christy; Henderson, Brian E.; Goldberg, Mark S.; Simard, Jacques; Teo, Soo H.; Mariapun, Shivaani; Helland, Åslaug; Haakensen, Vilde; Zheng, Wei; Beeghly-Fadiel, Alicia; Tamimi, Rulla; Jukkola-Vuorinen, Arja; Winqvist, Robert; Andrulis, Irene L.; Knight, Julia A.; Devilee, Peter; Tollenaar, Robert A.E.M.; Figueroa, Jonine; García-Closas, Montserrat; Czene, Kamila; Hooning, Maartje J.; Tilanus-Linthorst, Madeleine; Li, Jingmei; Gao, Yu-Tang; Shu, Xiao-Ou; Cox, Angela; Cross, Simon S.; Luben, Robert; Khaw, Kay-Tee; Choi, Ji-Yeob; Kang, Daehee; Hartman, Mikael; Lim, Wei Yen; Kabisch, Maria; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; McKay, James; Sangrajrang, Suleeporn; Toland, Amanda E.; Yannoukakos, Drakoulis; Shen, Chen-Yang; Yu, Jyh-Cherng; Ziogas, Argyrios; Schoemaker, Minouk J.; Swerdlow, Anthony; Borresen-Dale, Anne-Lise; Kristensen, Vessela; French, Juliet D.; Edwards, Stacey L.; Dunning, Alison M.; Easton, Douglas F.; Hall, Per; Chenevix-Trench, Georgia

    2015-01-01

    Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 [0.82–0.88]) and ER-negative (OR = 0.87 [0.82–0.91]) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:D) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 [0.91–0.95] and OR = 1.06 [1.03–1.09]) and ER-negative (OR = 0.95 [0.91–0.98] and OR = 1.08 [1.04–1.13]) disease. There was weaker evidence for iCHAV4, located 5′ of ADO, associated only with ER-positive breast cancer (OR = 0.93 [0.90–0.96]). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1–4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer. PMID:26073781

  4. Unbalanced interchromosomal insertion diagnosed prenatally by FISH, with carrier mother, previously misdiagnosed as having a balanced reciprocal translocation

    SciTech Connect

    Yu, M.T.; Leiber, E.; Qazi, Q.

    1994-09-01

    Insertion translocations are rare. A carrier with a balanced insertion translocation is most likely to be detected through offspring with an unbalanced translocation. We with to report a case where a correct diagnosis, made prenatally with FISH, corrected the initial misdiagnosis of the mother in another institute. PDL received an amniotic fluid sample from a 28 y.o. woman (G5P2Sab1TOP1) at 19 wks gestation. The indications were a reported balanced translocation, t(6;13), in the mother and a previous daughter with an unbalanced translocation. Chromosome analysis of the amniocytes showed a female karyotype with an abnormal chr. 13. Since the mother was diagnosed as having t(6;13)(q21;q34), the der(13) in the amniocytes was initially assumed to result from an adjacent segregation of the t(6;13). However, the banding patterns of this abnormal chr. 13 did not fit into the above defined translocation. With FISH and a chr. 13 painting probe, this der(13) was painted in the proximal and the distal thirds, but NOT in the middle region. This indicates that the middle section of the der(13) must have originated from 6q. The banding pattern is compatible with a direct insertion of 6q15 to 6q23.3 into 13q21.2. Thus, the fetus has partial trisomy 6q. After counseling, the mother elected to terminate the pregnancy but later changed her mind. An 8 lb 12 oz baby girl was born at 36 wks. (mother diabetic). Chromosome analysis of the newborn blood confirmed the dx. The mother was studied, using multicolor painting probes for chromosomes 13 and 6, a balanced direct insertion of 6q15 to 6q23.3 into chr. 13q21.2 was clearly shown. The previous affected daughter with a 13q+ is now 4 y.o. (a restudy is planned). She has microcephaly, severe developmental delay and other dysmorphic features. This case illustrates the advantage of using FISH to arrive at a definitive diagnosis of an insertion translocation.

  5. Acute promyelocytic leukemia with isochromosome 17q and cryptic PML-RARA successfully treated with all-trans retinoic acid and arsenic trioxide.

    PubMed

    Shepshelovich, Daniel; Oniashvili, Nino; Parnes, Doris; Klein, Alina; Muchtar, Eli; Yeshaya, Josepha; Aviram, Adina; Rabizadeh, Esther; Raanani, Pia

    2015-11-01

    Acute promyelocytic leukemia (APL) is a subtype of acute leukemia that is characterized by typical morphology, bleeding events and distinct chromosomal aberrations, usually the t(15;17)(q22;q21) translocation. Approximately 9% of APL patients harbor other translocations involving chromosome 17, such as the t(11;17)(q23;q21), t(5;17)(q35;q12-21), t(11;17)(q13;q21), and der(17). All-trans retinoic acid (ATRA) and arsenic trioxide (ATO) have specific targeted activities against the PML-RARA fusion protein. The combination of ATRA and ATO is reportedly superior to chemotherapy and ATRA as induction therapy for APL. The clinical significance of non-t(15:17) APL-related aberrations is controversial, with conflicting reports regarding sensitivity to modern, targeted therapy. Isochromosome 17q (iso(17q)) is rarely associated with APL and usually occurs concurrently with the t(15:17) translocation. No published data is available regarding the efficacy of ATO-based therapy for APL patients who harbor iso(17q). We report on an APL patient with iso(17q) as the sole cytogenetic aberration and a cryptic PML-RARA transcript, who was treated with ATRA and ATO after failure of chemotherapy and achieved complete remission. To our knowledge, this is the first published report of APL associated with iso(17q) as the sole cytogenetic aberration, which was successfully treated with an ATO containing regimen. PMID:26471811

  6. Obligate short-arm exchange in de novo Robertsonian translocation formation influences placement of crossovers in chromosome 21 nondisjunction.

    PubMed

    Berend, Sue Ann; Page, Scott L; Atkinson, William; McCaskill, Christopher; Lamb, Neil E; Sherman, Stephanie L; Shaffer, Lisa G

    2003-02-01

    Robertsonian translocations (ROBs) involving chromosome 21 are found in approximately 5% of patients with Down syndrome (DS). The most common nonhomologous ROB in DS is rob(14q21q). Aberrant recombination is associated with nondisjunction (NDJ) leading to trisomy 21. Haplotype analysis of 23 patients with DS and de novo rob(14q21q) showed that all translocations and all nondisjoined chromosomes 21 were maternally derived. Meiosis II NDJ occurred in 21 of 23 families. For these, a ROB DS chromosome 21 genetic map was constructed and compared to a normal female map and a published trisomy 21 map derived from meiosis II NDJ. The location of exchanges differed significantly from both maps, with a significant shift to a more distal interval in the ROB DS map. The shift may perturb segregation, leading to the meiosis II NDJ in this study, and is further evidence for crossover interference. More importantly, because the event in the short arms that forms the de novo ROB influences the placement of chiasmata in the long arm, it is most likely that the translocation formation occurs through a recombination pathway in meiosis. Additionally, we have demonstrated that events that occur in meiosis I can influence events, such as chromatid segregation in meiosis II, many decades later. PMID:12506337

  7. A homozygous balanced reciprocal translocation suggests LINC00237 as a candidate gene for MOMO (macrosomia, obesity, macrocephaly, and ocular abnormalities) syndrome.

    PubMed

    Vu, Phi Yen; Toutain, Jérôme; Cappellen, David; Delrue, Marie-Ange; Daoud, Hussein; El Moneim, Azza Abd; Barat, Pascal; Montaubin, Orianne; Bonnet, Françoise; Dai, Zong Qi; Philippe, Christophe; Tran, Cong Toai; Rooryck, Caroline; Arveiler, Benoît; Saura, Robert; Briault, Sylvain; Lacombe, Didier; Taine, Laurence

    2012-11-01

    Macrosomia, obesity, macrocephaly, and ocular abnormalities syndrome (MOMO syndrome) has been reported in only four patients to date. In these sporadic cases, no chromosomal or molecular abnormality has been identified thus far. Here, we report on the clinical, cytogenetic, and molecular findings in a child of healthy consanguineous parents suffering from MOMO syndrome. Conventional karyotyping revealed an inherited homozygous balanced reciprocal translocation (16;20)(q21;p11.2). Uniparental disomy testing showed bi-parental inheritance for both derivative chromosomes 16 and 20. The patient's oligonucleotide array-comparative genomic hybridization profile revealed no abnormality. From the homozygous balanced reciprocal translocation (16;20)(q21;p11.2), a positional cloning strategy, designed to narrow 16q21 and 20p11.2 breakpoints, revealed the disruption of a novel gene located at 20p11.23. This gene is now named LINC00237, according to the HUGO (Human Genome Organization) nomenclature. The gene apparently leads to the production of a non-coding RNA. We established that LINC00237 was expressed in lymphocytes of control individuals while normal transcripts were absent in lymphocytes of our MOMO patient. LINC00237 was not ubiquitously expressed in control tissues, but it was notably highly expressed in the brain. Our results suggested autosomal recessive inheritance of MOMO syndrome. LINC00237 could play a role in the pathogenesis of this syndrome and could provide new insights into hyperphagia-related obesity and intellectual disability. PMID:23034868

  8. Segregation of a paternal insertional translocation results in partial 4q monosomy or 4q trisomy in two siblings

    SciTech Connect

    Hegmann, K.M.; Spikes, A.S.; Orr-Urtreger, A.; Shaffer, L.G.

    1996-01-02

    A genetics evaluation was requested for a 6-week-old infant with multiple congenital malformations including mild craniofacial anomalies, truncal hypotonia, hypospadias, and a ventriculoseptal defect. Blood obtained for chromosome analysis revealed an abnormal chromosome 4. Paternal chromosome analysis showed a 46,XY, inv ins (3;4)(p21.32;q25q21.2), inv(4)(p15.3q21.2) karyotype. Therefore, the proband`s chromosome 4 was the unbalanced product of this insertional translocation from the father resulting in partial monosomy 4q. Additionally, the derivative 4 had a pericentric inversion which was also seen in the father`s chromosome 4. During genetic counseling, the proband`s 2-year-old brother was evaluated. He was not felt to be abnormal in appearance, but was described as having impulsive behavior. Chromosome analysis on this child revealed 46, XY, der(3) inv ins(3;4)(p21.32;q25q21.2)pat. This karyotype results in partial trisomy 4q. FISH using two-color {open_quotes}painting{close_quotes} probes for chromosomes 3 and 4 confirmed the G-banded interpretation in this family. The segregation seen in this family resulted in both reciprocal products being observed in the two children, with partial 4q monosomy showing multiple congenital anomalies, and partial 4q trisomy showing very few phenotypic abnormalities. 13 refs., 5 figs.

  9. Multiple independent variants in 6q21-22 associated with susceptibility to celiac disease in the Dutch, Finnish and Hungarian populations.

    PubMed

    Einarsdottir, Elisabet; Bevova, Marianna R; Zhernakova, Alexandra; Monsuur, Alienke; Koskinen, Lotta L E; van't Slot, Ruben; Mulder, Chris; Mearin, M Luisa; Korponay-Szabo, Ilma R; Kaukinen, Katri; Kurppa, Kalle; Kere, Juha; Mäki, Markku; Wijmenga, Cisca; Saavalainen, Päivi

    2011-06-01

    Celiac disease is an inflammatory enteropathy caused by intolerance to gluten. Previous linkage studies in the Dutch, Finnish and Hungarian populations have revealed a locus on chromosome 6q21-22 conferring susceptibility to celiac disease. This locus has previously been implicated in susceptibility to other autoimmune diseases such as Crohn's disease and type 1 diabetes. We performed fine mapping on 446 independent individuals with celiac disease and 641 controls of Dutch origin, testing 872 tagging SNPs in a 22 Mb region of chromosome 6. The 12 most promising SNPs were followed up in 2071 individuals from 284 Finnish and 357 Hungarian celiac disease families to identify risk variants in this region. Multiple markers in the region were significantly associated with celiac disease in the Dutch material. Two SNPs, rs9391227 and rs4946111, were significantly associated with celiac disease in the Finnish population. The association to rs9391227 represents the strongest association signal found in the Finnish (P = 0.003, OR 0.66) as well as the combined Dutch, Finnish and Hungarian populations (P = 3.6 × 10(-5), OR 0.76). The rs9391227 is situated downstream of the HECT domain and ankyrin repeat containing, E3 ubiquitin protein ligase 1 (HACE1) gene and is contained within a region of strong linkage disequilibrium enclosing HACE1. Two additional, independent, susceptibility variants in the 6q21-22 region were also found in a meta-analysis of the three populations. The 6q21-22 region was confirmed as a celiac disease susceptibility locus and harbors multiple independent associations, some of which may implicate ubiquitin-pathways in celiac disease susceptibility. PMID:21326284

  10. Expansion of a 12-kb VNTR containing the REXO1L1 gene cluster underlies the microscopically visible euchromatic variant of 8q21.2

    PubMed Central

    Tyson, Christine; Sharp, Andrew J; Hrynchak, Monica; Yong, Siu L; Hollox, Edward J; Warburton, Peter; Barber, John CK

    2014-01-01

    Copy number variants visible with the light microscope have been described as euchromatic variants (EVs) and EVs with extra G-light material at 8q21.2 have been reported only once before. We report four further patients with EVs of 8q21.2 ascertained for clinical (3) or reproductive reasons (1). Enhanced signal strength from two overlapping bacterial artificial chromosomes (BACs) and microarray analysis mapped the EV to a 284-kb interval in the reference genome. This interval consists of a sequence gap flanked by segmental duplications that contain the 12-kb components of one of the largest Variable Number Tandem Repeat arrays in the human genome. Using digital NanoString technology with a custom probe for the RNA exonuclease 1 homologue (S. cerevisiae)-like 1 (REXO1L1) gene within each 12-kb repeat, significantly enhanced diploid copy numbers of 270 and 265 were found in an EV family and a median diploid copy number of 166 copies in 216 controls. These 8q21.2 EVs are not thought to have clinical consequences as the phenotypes of the probands were inconsistent, those referred for reproductive reasons were otherwise phenotypically normal and the REXO1L1 gene has no known disease association. This EV was found in 4/3078 (1 in 770) consecutive referrals for chromosome analysis and needs to be distinguished from pathogenic imbalances of medial 8q. The REXO1L1 gene product is a marker of hepatitis C virus (HCV) infection and a possible association between REXO1L1 copy number and susceptibility to HCV infection, progression or response to treatment has not yet been excluded. PMID:24045839

  11. Multivariate analysis of anxiety disorders yields further evidence of linkage to chromosomes 4q21 and 7p in panic disorder families.

    PubMed

    Logue, Mark W; Bauver, Sarah R; Knowles, James A; Gameroff, Marc J; Weissman, Myrna M; Crowe, Raymond R; Fyer, Abby J; Hamilton, Steven P

    2012-04-01

    Replication has been difficult to achieve in linkage studies of psychiatric disease. Linkage studies of panic disorder have indicated regions of interest on chromosomes 1q, 2p, 2q, 3, 7, 9, 11, 12q13, 12q23, and 15. Few regions have been implicated in more than one study. We examine two samples, the Iowa (IA) and the Columba panic disorder families. We use the fuzzy-clustering method presented by Kaabi et al. [Kaabi et al. (2006); Am J Hum Genet 78: 543-553] to summarize liability to panic disorder, agoraphobia, simple phobia, and social phobia. Kaabi et al. applied this method to the Yale panic disorder linkage families and found evidence of linkage to chromosomes 4q21, 4q32, 7p, and 8. When we apply the same method to the IA families, we obtain overlapping evidence of linkage to chromosomes 4q21 and 7p. Additionally, we find evidence of linkage on chromosomes 1, 5, 6, 16, and 22. The Columbia (CO) data does not indicate linkage to any of the Kaabi et al. peaks, instead implicating chromosomes 2 and 22q11 (2 Mb from COMT). There is some evidence of overlapping linkage between the IA and CO datasets on chromosomes 1 and 14. While use of fuzzy clustering has not produced complete concordance across datasets, it has produced more than previously seen in analyses of panic disorder proper. We conclude that chromosomes 4q21 and 7p should be considered strong candidate regions for panic and fear-associated anxiety disorder loci. More generally, this suggests that analyses including multiple aspects of psychopathology may lead to greater consistency across datasets. PMID:22253211

  12. The 4q25, 1q21, and 16q22 polymorphisms and recurrence of atrial fibrillation after pulmonary vein isolation

    PubMed Central

    Kozluk, Edward; Franaszczyk, Maria; Lodzinski, Piotr; Piatkowska, Agnieszka; Ploski, Rafal; Opolski, Grzegorz

    2016-01-01

    Introduction The efficacy of pulmonary vein isolation (PVI) in atrial fibrillation (AF) is well documented. Several single nucleotide polymorphisms (SNPs) are associated with AF, mainly in the 4q25 locus, but also in 16q22 and 1q21. The aim of our study was to test the association between those SNPs and short- and long-term results of PVI. Material and methods Patients with AF who underwent PVI between 2006 and 2009 were included in the study. Pulmonary vein isolation was performed using a 4-mm non-irrigated ablation catheter, circular mapping catheter, and the LocaLisa system. All patients were genotyped for the 4q25, 16q22, and 1q21 SNPs. Results Two-hundred and thirty-eight patients were included. The median follow-up was 45 months. Six-month efficacy was 59.7%. None of the polymorphisms was linked with the risk of AF recurrence after 6 months in univariate analysis. In multivariate analysis rs2200733 in the recessive model was linked significantly with AF recurrence (odds ratio 1.87, p = 0.008). None of the polymorphisms predicted AF recurrence in long-term follow-up. Conclusions There is a trend in the relationship between TT genotype of the rs2200733 polymorphism and increased rate of AF recurrence after PVI in short-term (6 months) follow-up. None of the tested SNPs 4q25, 16q22, and 1q21 correlated with the results of a single AF ablation in long-term follow-up. PMID:26925117

  13. Multiple independent variants in 6q21-22 associated with susceptibility to celiac disease in the Dutch, Finnish and Hungarian populations

    PubMed Central

    Einarsdottir, Elisabet; Bevova, Marianna R; Zhernakova, Alexandra; Monsuur, Alienke; Koskinen, Lotta LE; Slot, Ruben van't; Mulder, Chris; Mearin, M Luisa; Korponay-Szabo, Ilma R; Kaukinen, Katri; Kurppa, Kalle; Kere, Juha; Mäki, Markku; Wijmenga, Cisca; Saavalainen, Päivi

    2011-01-01

    Celiac disease is an inflammatory enteropathy caused by intolerance to gluten. Previous linkage studies in the Dutch, Finnish and Hungarian populations have revealed a locus on chromosome 6q21-22 conferring susceptibility to celiac disease. This locus has previously been implicated in susceptibility to other autoimmune diseases such as Crohn's disease and type 1 diabetes. We performed fine mapping on 446 independent individuals with celiac disease and 641 controls of Dutch origin, testing 872 tagging SNPs in a 22 Mb region of chromosome 6. The 12 most promising SNPs were followed up in 2071 individuals from 284 Finnish and 357 Hungarian celiac disease families to identify risk variants in this region. Multiple markers in the region were significantly associated with celiac disease in the Dutch material. Two SNPs, rs9391227 and rs4946111, were significantly associated with celiac disease in the Finnish population. The association to rs9391227 represents the strongest association signal found in the Finnish (P=0.003, OR 0.66) as well as the combined Dutch, Finnish and Hungarian populations (P=3.6 × 10−5, OR 0.76). The rs9391227 is situated downstream of the HECT domain and ankyrin repeat containing, E3 ubiquitin protein ligase 1 (HACE1) gene and is contained within a region of strong linkage disequilibrium enclosing HACE1. Two additional, independent, susceptibility variants in the 6q21-22 region were also found in a meta-analysis of the three populations. The 6q21-22 region was confirmed as a celiac disease susceptibility locus and harbors multiple independent associations, some of which may implicate ubiquitin-pathways in celiac disease susceptibility. PMID:21326284

  14. Tetralogy of Fallot associated with pulmonary atresia and major aortopulmonary collateral arteries in a patient with interstitial deletion of 16q21-q22.1.

    PubMed

    Yamamoto, Toshiyuki; Dowa, Yuri; Ueda, Hideaki; Kawataki, Motoyoshi; Asou, Toshihide; Sasaki, Yuki; Harada, Naoki; Matsumoto, Naomichi; Matsuoka, Rumiko; Kurosawa, Kenji

    2008-06-15

    A newborn male had an interstitial deletion of 16q21-q22.1 accompanying tetralogy of Fallot associated with pulmonary atresia and major aortopulmonary collateral arteries (MAPCA), dysmorphic craniofacial features, failure to thrive, and severe psychomotor developmental delay. When the deletion in this patient and other reported patients are compared, the 16q22 region appears to be the smallest region for 16q deletion syndrome. Since over 50% of patients with the deletion of 16q22 region have congenital heart disease, there may be a responsible gene in this region. PMID:18470894

  15. Identification of four novel human genes amplified and overexpressed in breast carcinoma and localized to the q11-q21.3 region of chromosome 17

    SciTech Connect

    Tomasetto, C.; Regnier, C.; Basset, P.

    1995-08-10

    We have performed differential screening of a human metastatic lymph node cDNA library to identify genes possibly involved during breast cancer progression. We have identified four novel genes overexpressed in malignant tissues. They were all located between q11 and q21.3, a region known to contain the c-erbB-2 oncogene and the BRCA1 breast carcinomas, and overexpression of three of them was dependent on gene amplification in breast cancer cell lines. These findings further support the concept that human chromosome 17 specifically carries genes possibly involved in breast cancer progression. 61 refs., 3 figs., 4 tabs.

  16. TCFL4: a gene at 17q21.1 encoding a putative basic helix-loop-helix leucine-zipper transcription factor.

    PubMed

    Bjerknes, M; Cheng, H

    1996-11-28

    TCFL4 (transcription factor like 4) is the HGMW-approved symbol for the gene of a widely expressed putative basic helix-loop-helix leucine-zipper (bHLH-zip) transcription factor which is located 3' to HSD17B1 (17-beta-hydroxysteroid dehydrogenase gene) at 17q21.1, centromeric to the BRCA1 (a gene implicated in familial breast cancer) locus. We report the human gene structure and the murine cDNA sequence of two variants, about 1.5 and 2.2 kb in size. The deduced protein is highly conserved between mouse and man. PMID:8973301

  17. Interstitial deletions 4q21.1q25 and 4q25q27: Phenotypic variability and relation to Rieger anomaly

    SciTech Connect

    Kulharya, A.S.; Schneider, N.R.; Tonk, V.

    1995-01-16

    We describe clinical and chromosomal findings in two patients with del(4q). Patient 1, with interstitial deletion (4)(q21.1q25), had craniofacial and skeletal anomalies and died at 8 months hydrocephalus. Patient 2, with interstitial deletion (4)(q25q27), had craniofacial and skeletal anomalies with congenital hypotonia and developmental delay. These patients shared certain manifestations with other del(4q) patients but did not have Rieger anomaly. Clinical variability among patients with interstitial deletions of 4q may be related to variable expression, variable deletion, or imprinting of genes within the 4q region. 15 refs., 4 figs., 1 tab.

  18. Exclusion of one pedigree affected by adult onset primary open angle glaucoma from linkage to the juvenile glaucoma locus on chromosome 1q21-q31.

    PubMed Central

    Avramopoulos, D; Kitsos, G; Economou-Petersen, E; Grigoriadou, M; Vassilopoulos, D; Papageorgiou, C; Psilas, K; Petersen, M B

    1996-01-01

    A locus for autosomal dominant juvenile onset primary open angle glaucoma (POAG) was recently assigned to chromosome region 1q21-q31. In the present study, a large Greek family with autosomal dominant adult onset POAG was investigated using microsatellite markers. Exclusion of linkage of the adult onset POAG gene to the region D1S194-D1S191 was obtained in this pedigree. Therefore, the data provide evidence that juvenile and adult onset POAG are genetically distinct disease entities. PMID:9004141

  19. The IgG Fc receptor, FcγRIIB, is a target for deregulation by chromosomal translocation in malignant lymphoma

    PubMed Central

    Callanan, Mary B.; Le Baccon, Patricia; Mossuz, Pascal; Duley, Samuel; Bastard, Christian; Hamoudi, Rifat; Dyer, Martin J.; Klobeck, Gustav; Rimokh, Ruth; Sotto, Jean Jacques; Leroux, Dominique

    2000-01-01

    Rearrangement of chromosomal bands 1q21–23 is one of the most frequent chromosomal aberrations observed in hematological malignancy. The genes affected by these rearrangements remain poorly characterized. Typically, 1q21–23 rearrangements arise during tumor evolution and accompany disease-specific chromosomal rearrangements such as t(14;18) (BCL2) and t(8;14) (MYC), where they are thus thought to play an important role in tumor progression. The pathogenetic basis of this 1q21–23-associated disease progression is currently unknown. In this setting, we surveyed our series of follicular lymphoma for evidence of recurring 1q21–23 breaks and identified three cases in which a t(14;18)(q32;q21) was accompanied by a novel balanced t(1;22)(q22;q11). Molecular cloning of the t(1;22) in a cell line (B593) derived from one of these cases and detailed fluorescent in situ hybridization mapping in the two remaining cases identified the FCGR2B gene, which encodes the immunoreceptor tyrosine-based inhibition motif-bearing IgG Fc receptor, FcγRIIB, as the target gene of the t(1;22)(q22;q11). We demonstrate deregulation of FCGR2B leading to hyperexpression of FcγRIIb2 as the principal consequence of the t(1;22). This is evidence that IgG Fc receptors can be targets for deregulation through chromosomal translocation in lymphoma. It suggests that dysregulation of FCGR2B may play a role in tumor progression in follicular lymphoma. PMID:10618414

  20. Translocation of reptating chains

    NASA Astrophysics Data System (ADS)

    Żurek, S.; Drzewiński, A.; van Leeuwen, J. M. J.

    2011-05-01

    Voltage-driven translocation is modeled with the Rubinstein-Duke rules for hopping reptons in one- and two-dimensional lattices. The chain is driven through the pore by a bias potential promoting the transition of stored length in one direction. Coupling states give a semi-periodicity of the process that enables us to relate the properties to the stationary state of the master equation. The exact solution for short chains and Monte Carlo simulations for longer chains are used to calculate displacements, velocities and the translocation time.

  1. Problem-Elephant Translocation: Translocating the Problem and the Elephant?

    PubMed Central

    Fernando, Prithiviraj; Leimgruber, Peter; Prasad, Tharaka; Pastorini, Jennifer

    2012-01-01

    Human-elephant conflict (HEC) threatens the survival of endangered Asian elephants (Elephas maximus). Translocating “problem-elephants” is an important HEC mitigation and elephant conservation strategy across elephant range, with hundreds translocated annually. In the first comprehensive assessment of elephant translocation, we monitored 16 translocations in Sri Lanka with GPS collars. All translocated elephants were released into national parks. Two were killed within the parks where they were released, while all the others left those parks. Translocated elephants showed variable responses: “homers” returned to the capture site, “wanderers” ranged widely, and “settlers” established home ranges in new areas soon after release. Translocation caused wider propagation and intensification of HEC, and increased elephant mortality. We conclude that translocation defeats both HEC mitigation and elephant conservation goals. PMID:23236404

  2. Simulations of Polymer Translocation

    NASA Astrophysics Data System (ADS)

    Vocks, H.

    2008-07-01

    Transport of molecules across membranes is an essential mechanism for life processes. These molecules are often long, and the pores in the membranes are too narrow for the molecules to pass through as a single unit. In such circumstances, the molecules have to squeeze -- i.e., translocate -- themselves through the pores. DNA, RNA and proteins are such naturally occuring long molecules in a variety of biological processes. Understandably, the process of translocation has been an active topic of current research: not only because it is a cornerstone of many biological processes, but also due to its relevance for practical applications. Translocation is a complicated process in living organisms -- the presence of chaperone molecules, pH, chemical potential gradients, and assisting molecular motors strongly influence its dynamics. Consequently, the translocation process has been empirically studied in great variety in biological literature. Study of translocation as a biophysical process is more recent. Herein, the polymer is simplified to a sequentially connected string of N monomers as it passes through a narrow pore on a membrane. The quantities of interest are the typical time scale for the polymer to leave a confining cell (the ``escape of a polymer from a vesicle'' time scale), and the typical time scale the polymer spends in the pore (the ``dwell'' time scale) as a function of N and other parameters like membrane thickness, membrane adsorption, electrochemical potential gradient, etc. Our research is focused on computer simulations of translocation. Since our main interest is in the scaling properties, we use a highly simplified description of the translocation process. The polymer is described as a self-avoiding walk on a lattice, and its dynamics consists of single-monomer jumps from one lattice site to another neighboring one. Since we have a very efficient program to simulate such polymer dynamics, which we decribe in Chapter 2, we can perform long

  3. A Novel de novo Balanced Reciprocal Translocation t(18;22) Associated with Recurrent Miscarriages: A Case Report

    PubMed Central

    Dutta, Usha R.; Ponnala, Rajitha; Dalal, Ashwin

    2014-01-01

    Background Recurrent miscarriage is a major concern in the couples with reproductive problems. The chromosomal abnormalities, mainly balanced rearrangements are reported in variable phenotypes and the prevalence of them is 2-8% in such couples. Case Presentation In this study, the clinical, cytogenetic and molecular cytogenetic evaluations were performed on a couple with RM. The cytogenetic analysis of the husband revealed a balanced reciprocal translocation of t(18;22)(q21.1;q12) whereas wife had a normal karyotype of 46,XX. Further spectral karyotyping was performed to rule out the involvement of any other chromosomal aberrations present in the genome. Additional whole chromosome paint FISH (Fluorescence in situ hybridization) with paint probes 18 and 22 confirmed the translocation. Conclusion To our knowledge, this is the first report of a novel (18;22) translocation with unique breakpoints and their association with RM. The reciprocal translocations provide a good opportunity for the identification of disease associated genes. However, in recurrent miscarriages, most of them do not disrupt any gene at the breakpoint but can lead to unbalanced gametes and hence poor reproductive outcome like RM or birth of a child with malformations and intellectual disability. The translocation breakpoints might be risk factors for RM. Moreover, the impact of the balanced translocations in association with RM is discussed in this report. PMID:24918085

  4. Oncogene Translocations and NHL

    Cancer.gov

    A colloboration with several large population-based cohorts to determine whether the prevalence or level of t14;18 is associated with risk of NHL and to investigate the clonal relationship between translocation-bearing cells and subsequent tumors

  5. Cutaneous Borreliosis With a T-Cell-Rich Infiltrate and Simultaneous Involvement by B-Cell Chronic Lymphocytic Leukemia With t(14;18)(q32;q21).

    PubMed

    Kempf, Werner; Kazakov, Dmitry V; Hübscher, Eugen; Tinguely, Marianne

    2015-09-01

    Pseudolymphomatous infiltrates in Borrelia infection of the skin most commonly manifest with dense B-cell infiltrates and plasma cells. Cutaneous infiltrates of B-cell chronic lymphocytic leukemia (B-CLL) may accumulate at sites of infection, including Borrelia infection. We report an unusual constellation in a patient with synchronously diagnosed B-CLL and Borrelia infection of skin presenting with a dense dermal T-cell-rich infiltrate masking specific leukemic infiltrates of neoplastic B cells in the context of B-CLL harboring t(14;18)(q32;q21). Specific cutaneous involvement by B-CLL was confirmed by the detection of t(14;18)(q32;q21) (BCL2-IGH) using FISH in neoplastic B cells within the skin infiltrates. Borrelia burgdorferi (sensu lato) DNA detected by nested polymerase chain reaction in the skin biopsy and serological findings proved Borrelia infection. Complete resolution of the cutaneous infiltrates was observed after antibiotic treatment. This case demonstrates that Borrelia infection of the skin may present with dense T-cell-rich infiltrates mimicking cutaneous T-cell lymphoma and masking the synchronous presence of neoplastic B cells in the context of B-CLL. PMID:25171429

  6. Dissection of the genetics of Parkinson's disease identifies an additional association 5′ of SNCA and multiple associated haplotypes at 17q21

    PubMed Central

    Spencer, Chris C.A.; Plagnol, Vincent; Strange, Amy; Gardner, Michelle; Paisan-Ruiz, Coro; Band, Gavin; Barker, Roger A.; Bellenguez, Celine; Bhatia, Kailash; Blackburn, Hannah; Blackwell, Jennie M.; Bramon, Elvira; Brown, Martin A.; Brown, Matthew A.; Burn, David; Casas, Juan-Pablo; Chinnery, Patrick F.; Clarke, Carl E.; Corvin, Aiden; Craddock, Nicholas; Deloukas, Panos; Edkins, Sarah; Evans, Jonathan; Freeman, Colin; Gray, Emma; Hardy, John; Hudson, Gavin; Hunt, Sarah; Jankowski, Janusz; Langford, Cordelia; Lees, Andrew J.; Markus, Hugh S.; Mathew, Christopher G.; McCarthy, Mark I.; Morrison, Karen E.; Palmer, Colin N.A.; Pearson, Justin P.; Peltonen, Leena; Pirinen, Matti; Plomin, Robert; Potter, Simon; Rautanen, Anna; Sawcer, Stephen J.; Su, Zhan; Trembath, Richard C.; Viswanathan, Ananth C.; Williams, Nigel W.; Morris, Huw R.; Donnelly, Peter; Wood, Nicholas W.

    2011-01-01

    We performed a genome-wide association study (GWAS) in 1705 Parkinson's disease (PD) UK patients and 5175 UK controls, the largest sample size so far for a PD GWAS. Replication was attempted in an additional cohort of 1039 French PD cases and 1984 controls for the 27 regions showing the strongest evidence of association (P< 10−4). We replicated published associations in the 4q22/SNCA and 17q21/MAPT chromosome regions (P< 10−10) and found evidence for an additional independent association in 4q22/SNCA. A detailed analysis of the haplotype structure at 17q21 showed that there are three separate risk groups within this region. We found weak but consistent evidence of association for common variants located in three previously published associated regions (4p15/BST1, 4p16/GAK and 1q32/PARK16). We found no support for the previously reported SNP association in 12q12/LRRK2. We also found an association of the two SNPs in 4q22/SNCA with the age of onset of the disease. PMID:21044948

  7. Identification of a common microdeletion cluster in 7q21.3 subband among patients with myeloid leukemia and myelodysplastic syndrome

    SciTech Connect

    Asou, Hiroya; Matsui, Hirotaka; Ozaki, Yuko; Nagamachi, Akiko; Nakamura, Megumi; Aki, Daisuke; Inaba, Toshiya

    2009-05-29

    Monosomy 7 and interstitial deletions in the long arm of chromosome 7 (-7/7q-) is a common nonrandom chromosomal abnormality found frequently in myeloid disorders including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and juvenile myelomonocytic leukemia (JMML). Using a short probe-based microarray comparative genomic hybridization (mCGH) technology, we identified a common microdeletion cluster in 7q21.3 subband, which is adjacent to 'hot deletion region' thus far identified by conventional methods. This common microdeletion cluster contains three poorly characterized genes; Samd9, Samd9L, and a putative gene LOC253012, which we named Miki. Gene copy number assessment of three genes by real-time PCR revealed heterozygous deletion of these three genes in adult patients with AML and MDS at high frequency, in addition to JMML patients. Miki locates to mitotic spindles and centrosomes and downregulation of Miki by RNA interference induced abnormalities in mitosis and nuclear morphology, similar to myelodysplasia. In addition, a recent report indicated Samd9 as a tumor suppressor. These findings indicate the usefulness of the short probe-based CGH to detect microdeletions. The three genes located to 7q21.3 would be candidates for myeloid tumor-suppressor genes on 7q.

  8. Pericentric inversion of chromosome 11 (p14.3q21) associated with developmental delays, hypopigmented skin lesions and abnormal brain MRI findings - a new case report

    SciTech Connect

    Zachor, D.A.; Lofton, M.

    1994-09-01

    We report 3 year old male, referred for evaluation of developmental delays. Pregnancy was complicated by oligohydramnios, proteinuria and prematurity. Medical history revealed: bilateral inguinal hernia, small scrotal sac, undescended testes, developmental delays and behavioral problems. The child had: microcephaly, facial dysmorphic features, single palmar creases, hypopigmented skin lesions of variable size, intermittent exotropia and small retracted testes. Neurological examination was normal. Cognitive level was at the average range with mild delay in his adaptive behavior. Expressive language delays and severe articulation disorder were noted, as well as clumsiness, poor control and precision of gross and fine motor skills. Chromosomal analysis of peripheral leukocytes indicated that one of the number 11 chromosomes had undergone a pericentric inversion with breakpoints on the short (p) arm at band p14.3 and the long (q) arm at band q21. An MRI of the brain showed mild delay in myelinization pattern of white matter. Chromosome 11 inversion in other sites was associated with Beckwith-Wiedemann syndrome and several malignancies. To our knowledge this is the first description of inv(11)(p14.3q21) that is associated with microcephaly, dysmorphic features, hypopigmented skin lesions and speech delay. This inversion may disrupt the expression of the involved genes. However, additional cases with the same cytogenetic anomaly are needed to explore the phenotypic significance of this disorder.

  9. 7q21-rs6964587 and breast cancer risk: an extended case–control study by the Breast Cancer Association Consortium

    PubMed Central

    Milne, Roger L; Lorenzo-Bermejo, Justo; Burwinkel, Barbara; Malats, Núria; Arias, Jose Ignacio; Zamora, M Pilar; Benítez, Javier; Humphreys, Manjeet K; García-Closas, Montserrat; Chanock, Stephen J; Lissowska, Jolanta; Sherman, Mark E; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Nevanlinna, Heli; Heikkinen, Tuomas; Aittomäki, Kristiina; Blomqvist, Carl; Anton-Culver, Hoda; Ziogas, Argyrios; Devilee, Peter; van Asperen, Christie J; Tollenaar, Rob A E M; Seynaeve, Caroline; Hall, Per; Czene, Kamila; Liu, Jianjun; Irwanto, Astrid K; Kang, Daehee; Yoo, Keun-Young; Noh, Dong-Young; Couch, Fergus J; Olson, Janet E; Wang, Xianshu; Fredericksen, Zachary; Nordestgaard, Børge G; Bojesen, Stig E; Flyger, Henrik; Margolin, Sara; Lindblom, Annika; Fasching, Peter A; Schulz-Wendtland, Ruediger; Ekici, Arif B; Beckmann, Matthias W; Wang-Gohrke, Shan; Shen, Chen-Yang; Yu, Jyh-Cherng; Hsu, Huan-Ming; Wu, Pei-Ei; Giles, Graham G; Severi, Gianluca; Baglietto, Laura; English, Dallas R; Cox, Angela; Brock, Ian; Elliott, Graeme; Reed, Malcolm W R; Beesley, Jonathan; Chen, Xiaoqing; Fletcher, Olivia; Gibson, Lorna; Silva, Isabel dos Santos; Peto, Julian; Frank, Bernd; Heil, Joerg; Meindl, Alfons; Chang-Claude, Jenny; Hein, Rebecca; Vrieling, Alina; Flesch-Janys, Dieter; Southey, Melissa C; Smith, Letitia; Apicella, Carmel; Hopper, John L; Dunning, Alison M; Pooley, Karen A; Pharoah, Paul D P; Hamann, Ute; Pesch, Beate; Ko, Yon-Dschun; Easton, Douglas F; Chenevix-Trench, Georgia

    2012-01-01

    Background Using the Breast Cancer Association Consortium, the authors previously reported that the single nucleotide polymorphism 7q21-rs6964587 (AKAP9-M463I) is associated with breast cancer risk. The authors have now assessed this association more comprehensively using 16 independent case–control studies. Methods The authors genotyped 14 843 invasive case patients and 19 852 control subjects with white European ancestry and 2595 invasive case patients and 2192 control subjects with Asian ancestry. ORs were estimated by logistic regression, adjusted for study. Heterogeneity in ORs was assessed by fitting interaction terms or by subclassifying case patients and applying polytomous logistic regression. Results For white European women, the minor T allele of 7q21-rs6964587 was associated with breast cancer risk under a recessive model (OR 1.07, 95% CI 1.00 to 1.13, p = 0.04). Results were inconclusive for Asian women. From a combined analysis of 24 154 case patients and 33 376 control subjects of white European ancestry from the present and previous series, the best-fitting model was recessive, with an estimated OR of 1.08 (95% CI 1.03 to 1.13, p = 0.001). The OR was greater at younger ages (p trend = 0.01). Conclusion This may be the first common susceptibility allele for breast cancer to be identified with a recessive mode of inheritance. PMID:21931171

  10. Inherited Xq13.2-q21.31 duplication in a boy with recurrent seizures and pubertal gynecomastia: Clinical, chromosomal and aCGH characterization.

    PubMed

    Linhares, Natália D; Valadares, Eugênia R; da Costa, Silvia S; Arantes, Rodrigo R; de Oliveira, Luiz Roberto; Rosenberg, Carla; Vianna-Morgante, Angela M; Svartman, Marta

    2016-09-01

    We report on a 16-year-old boy with a maternally inherited ~ 18.3 Mb Xq13.2-q21.31 duplication delimited by aCGH. As previously described in patients with similar duplications, his clinical features included intellectual disability, developmental delay, speech delay, generalized hypotonia, infantile feeding difficulties, self-injurious behavior, short stature and endocrine problems. As additional findings, he presented recurrent seizures and pubertal gynecomastia. His mother was phenotypically normal and had completely skewed inactivation of the duplicated X chromosome, as most female carriers of such duplications. Five previously reported patients with partial Xq duplications presented duplication breakpoints similar to those of our patient. One of them, a fetus with multiple congenital abnormalities, had the same cytogenetic duplication breakpoint. Three of the reported patients shared many features with our proband but the other had some clinical features of the Prader-Willi syndrome. It was suggested that ATRX overexpression could be involved in the major clinical features of patients with partial Xq duplications. We propose that this gene could also be involved with the obesity of the patient with the Prader-Willi-like phenotype. Additionally, we suggest that the PCDH11X gene could be a candidate for our patient's recurrent seizures. In males, the Xq13-q21 duplication should be considered in the differential diagnosis of Prader-Willi syndrome, as previously suggested, and neuromuscular diseases, particularly mitochondriopathies. PMID:27617217

  11. Loci on 7p12.2, 10q21.2 and 14q11.2 are associated with risk of childhood acute lymphoblastic leukemia

    PubMed Central

    Papaemmanuil, Elli; Hosking, Fay J; Vijayakrishnan, Jayaram; Price, Amy; Olver, Bianca; Sheridan, Eammon; Kinsey, Sally E; Lightfoot, Tracy; Roman, Eve; Irving, Julie A E; Allan, James M.; Tomlinson, Ian P; Taylor, Malcolm; Greaves, Mel; Houlston, Richard S

    2016-01-01

    To identify risk variants for childhood acute lymphoblastic leukemia (ALL) we conducted a genome-wide association study of 2 case-control series, analyzing the genotypes of 291,423 tagging SNP genotypes in a total of 907 ALL cases and 2,398 controls. We identified risk loci for ALL at 7p12.2 (IKZF1, rs4132601; OR = 1.69, P = 1.20 x 10-19), 10q21.2 (ARIDB5, rs7089424; OR = 1.65, P = 6.69 x 10-19) and 14q11.2 (CEBPE, rs2239633; OR = 1.34, P = 2.88 x 10-7). The 10q21.2 (ARIDB5) risk association appears to be selective for the subset of B-cell precursor ALL with hyperdiploidy. These data show that common low-penetrance susceptibility alleles contribute to the risk of developing childhood ALL and provide novel insight into disease causation of this hematological cancer; notably all 3 risk variants map to genes involved in transcriptional regulation and differentiation of B-cell progenitors. PMID:19684604

  12. Genome-wide association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic dissections spanning FBN1 at 15q21.1

    PubMed Central

    LeMaire, Scott A; McDonald, Merry-Lynn N; Guo, Dong-chuan; Russell, Ludivine; Miller, Charles C; Johnson, Ralph J; Bekheirnia, Mir Reza; Franco, Luis M; Nguyen, Mary; Pyeritz, Reed E; Bavaria, Joseph E; Devereux, Richard; Maslen, Cheryl; Holmes, Kathryn W; Eagle, Kim; Body, Simon C; Seidman, Christine; Seidman, J G; Isselbacher, Eric M; Bray, Molly; Coselli, Joseph S; Estrera, Anthony L; Safi, Hazim J; Belmont, John W; Leal, Suzanne M; Milewicz, Dianna M

    2011-01-01

    Although thoracic aortic aneurysms and dissections (TAAD) can be inherited as a single-gene disorder, the genetic predisposition in the majority of affected people is poorly understood. In a multistage genome-wide association study (GWAS), we compared 765 individuals who had sporadic TAAD (STAAD) with 874 controls and identified common SNPs at a 15q21.1 locus that were associated with STAAD, with odds ratios of 1.6–1.8 that achieved genome-wide significance. We followed up 107 SNPs associated with STAAD with P < 1 × 10−5 in the region, in two separate STAAD cohorts. The associated SNPs fall into a large region of linkage disequilibrium encompassing FBN1, which encodes fibrillin-1. FBN1 mutations cause Marfan syndrome, whose major cardiovascular complication is TAAD. This study shows that common genetic variants at 15q21.1 that probably act via FBN1 are associated with STAAD, suggesting a common pathogenesis of aortic disease in Marfan syndrome and STAAD. PMID:21909107

  13. Identification and characterization of a novel gene disrupted by a pericentric inversion inv(4)(p13.1q21.1) in a family with cleft lip.

    PubMed

    Beiraghi, Soraya; Zhou, Ming; Talmadge, Catherine B; Went-Sumegi, Nils; Davis, Jack R; Huang, Dali; Saal, Howard; Seemayer, Thomas A; Sumegi, Janos

    2003-04-24

    Cleft lip with or without cleft palate is a common birth defect affecting 1 in every 700 live births. Several genetic loci are believed to be involved in the pathogenesis of syndromic and non-syndromic clefting. We identified a pericentric inversion of chromosome 4, inv(4)(p13q21) that segregates with cleft lip in a two-generation family. By using a combination of fluorescence in situ hybridization, yeast artificial chromosome, bacterial artificial chromosome contig mapping, and database searching we mapped and sequenced the inversion breakpoint region. The pericentric inversion disrupts a gene (ACOD4) on chromosome 4q21 that codes for a novel acyl-CoA desaturase enzyme. The 3.0 kb human ACOD4 cDNA spans approximately 170 kb and is composed of five exons of ACOD4. The inversion breakpoint is located in the second exon. The 3.0 kb mRNA is expressed at high level in fetal brain; a lower expression level was found in fetal kidney. No expression of ACOD4 was detected in fetal lung or liver or in adult tissues. The five exons code for a protein of 330 amino acids, with a predicted molecular weight of 37.5 kDa. The protein is highly similar to acyl-CoA desaturases from Drosophila melanogaster to Homo sapiens. The catalytically essential histidine clusters and the potential transmembrane domains are well conserved. PMID:12727354

  14. Atypical Down syndrome phenotype in a girl with 21;21 translocation trisomy.

    PubMed

    Tuysuz, B; Yavuz, A; Ozdil, M; Caferler, J; Ozon, H

    2010-01-01

    We describe a girl with microcephaly, short stature, coarse face, severe growth and developmental delay, seizures, hypertonia, bilateral flexion contractures of the knees, and a de novo 21;21 translocation trisomy 21 in peripheral blood lymphocytes. Fluorescence in situ hybridization (FISH) analysis confirmed the trisomy 21 translocation using whole chromosome painting probe 21 (WCP21). Chromosome analysis which was also performed on skin fibroblasts and revealed mosaicism for a translocation trisomy 21 cell line (22.3%) as well as a second cell line consisting of one normal chromosome 21 and a small ring chromosome 21 derived from the translocation 21q21q (61%) and a third line consisting of monosomy 21 (16.7%). FISH analyses by LS121 probe for the critical (21q22.2-22.3) region of Down syndrome (DS) on interphase blood cells resulted with 30% two signals and 70% three signals, skin fibroblasts showed 84% single signal, 9% two signals and 7% three signals. The size of ring chromosome 21 in skin fibroblasts was very small and probably there was a large, more proximally located deletion including chromosome 21q22 band. We consider that the atypical DS phenotype of the patient originated from the small ring chromosome 21 and the monosomy 21 in the skin fibroblasts and other tissues not available for analysis. Therefore, the clinical findings of the patient were most similar to monosomy 21 mosaicism syndrome. PMID:20420031

  15. Genetic counselling in carriers of reciprocal chromosomal translocations involving short arm of chromosome X.

    PubMed

    Panasiuk, Barbara; Usinskiené, Ruta; Kostyk, Ewa; Rybałko, Alicja; Stasiewicz-Jarocka, Beata; Krzykwa, Bogustawa; Pieńkowska-Grela, Barbara; Kucinskas, Vaidutis; Michalova, Kyra; Midro, Alina T

    2004-01-01

    A central concept in genetic counselling is the estimation of the probability of occurrence of unbalanced progeny at birth and other unfavourable outcomes of pregnancy (miscarriages, stillbirths and early death). The estimation of the occurrence probability for individual carriers of four different X-autosome translocations with breakpoints at Xp, namely t(X;5)(p22.2;q32), t(X;6)(p11.2;q21), t(X;7)(p22.2;p11.1), and t(X;22)(p22.1;p11.1), is presented. The breakpoint positions of chromosomal translocations were interpreted using GTG, RBG and FISH-wcp. Most of these translocations were detected in women with normal phenotype, karyotyped because of repeated miscarriages and/or malformed progeny. A girl with very rare pure trisomy Xp22.1-->pter and a functional Xp disomy was ascertained in one family and her clinical picture has been described in details. It has been suggested that not fully skewed X chromosome inactivation of X-autosome translocation with breakpoint positions at Xp22 (critical segment) could influence the phenotype and risk value. Therefore, the X inactivation status was additionally evaluated by analysis of replication banding patterns using RBG technique after incorporation of BrdU. In two carriers of translocations: t(X;5)(p22.2;q32) and t(X;7)(p22.2;p11.1), late replication state of der(X) was observed in 5/100 and 10/180 analysed cells, respectively. In these both cases the breakpoint positions were clustered at the critical segment Xp22.2. In two other cases, one with the breakpoint position within [t(X;22)(p22.1;p11.1)] and one outside the critical region [t(X;6)(p11.2;q21)], fully skewed inactivation was seen. Therefore, we suggest that neither the distribution of the breakpoint positions nor fully skewed inactivation influenced the phenotype of observed t(X;A) carriers. The occurrence probabilities of the unbalanced progeny were calculated according to Stene and Stengel-Rutkowski along with application of updated available empirical data. In

  16. Association of ADHD and the Protogenin gene in the chromosome 15q21.3 reading disabilities linkage region.

    PubMed

    Wigg, K G; Feng, Y; Crosbie, J; Tannock, R; Kennedy, J L; Ickowicz, A; Malone, M; Schachar, R; Barr, C L

    2008-11-01

    Twin studies indicate genetic overlap between symptoms of attention deficit hyperactivity disorder (ADHD) and reading disabilities (RD), and linkage studies identify several chromosomal regions possibly containing common susceptibility genes, including the 15q region. Based on a translocation finding and association to two specific alleles, the candidate gene, DYX1C1, has been proposed as the susceptibility gene for RD in 15q. Previously, we tested markers in DYX1C1 for association with ADHD. Although we identified association for haplotypes across the gene, we were unable to replicate the association to the specific alleles reported. Thus, the risk alleles for ADHD are yet to be identified. The susceptibility alleles may be in a remote regulatory element, or DYX1C1 may not be the risk gene. To continue study of 15q, we tested a coding region change in DYX1C1, followed by markers across the gene Protogenin (PRTG) in 253 ADHD nuclear families. PRTG was chosen based on its location and because it is closely related to DCC and Neogenin, two genes known to guide migratory cells and axons during development. The markers in DYX1C1 were not associated to ADHD when analyzed individually; however, six markers in PRTG showed significant association with ADHD as a categorical trait (P = 0.025-0.005). Haplotypes in both genes showed evidence for association. We identified association with ADHD symptoms measured as quantitative traits in PRTG, but no evidence for association with two key components of reading, word identification and decoding was observed. These findings, while preliminary, identify association of ADHD to a gene that potentially plays a role in cell migration and axon growth. PMID:19076634

  17. Coarctation of the aorta and mild to moderate developmental delay in a child with a de novo deletion of chromosome 15(q21.1q22.2)

    PubMed Central

    Lalani, Seema R; Sahoo, Trilochan; Sanders, Merideth E; Peters, Sarika U; Bejjani, Bassem A

    2006-01-01

    Background Deletion of 15q21q22 is a rare chromosomal anomaly. To date, there have been nine reports describing ten individuals with different segmental losses involving 15q21 and 15q22. Many of these individuals have common features of growth retardation, hypotonia and moderate to severe mental retardation. Congenital heart disease has been described in three individuals with interstitial deletion involving this region of chromosome 15. Case presentation We report a child with coarctation of the aorta, partial agenesis of corpus callosum and mild to moderate developmental delay, with a de novo deletion of 15q21.1q22.2, detected by the array Comparative Genomic Hybridization (CGH). We utilized chromosome 15-specific microarray-based CGH to define the chromosomal breakpoints in this patient. Conclusion This is the first description of mapping of an interstitial deletion involving the chromosome 15q21q22 segment using the chromosome 15-specific array-CGH. The report also expands the spectrum of clinical phenotype associated with 15q21q22 deletion. PMID:16472378

  18. Molecular and cytogenetic studies of an X; autosome translocation in a patient with premature ovarian failure and review of the literature

    SciTech Connect

    Powell, C.M.; Wangsa, D.; Nelson, L.M.; White, B.J.

    1994-08-01

    We have identified a patient with premature ovarian failure (POF) and a balanced X;autosome translocation: 46,X,t(X;6)(q13.3 or q21;p12) using high-resolution cytogenetic analysis and FISH. BrdU analysis showed that her normal X was late-replicating and translocated X earlier-replicating which is typical of balanced X;autosome rearrangements. Molecular studies were done to characterize the breakpoint on Xq and to determine the parental origin. PCR probes of tetranucleotide and dinucleotide repeat polymorphisms, and genomic probes were used to study DNA from the patient, her chromosomally normal parents and brother, and somatic cell hybrids containing each translocation chromosome. The translocation is paternally derived and is localized to Xq13.3-proximal Xq21.1, between PGK1 and DXS447 loci, a distance of 0.1 centimorgans. A {open_quotes}critical region{open_quotes} for normal ovarian function has been proposed for Xq13-q26 based on cytogenetic and clinical studies of patients with X;autosome translocations. Few cases have had molecular characterization of the breakpoints to further define the region. While translocations in the region may lead to ovarian dysfunction by disrupting normal meiosis or by a position effect, two recent reports of patients with premature ovarian failure and Xq deletions suggest that there is a gene (POF1) localized to Xq21.3-q27 or within Xq26.1-q27 responsible for POF. We now propose that there may be a second gene for POF (POF2) located at Xq13.3-q21.1. 52 refs., 5 figs., 2 tabs.

  19. Cryptic genomic imbalances in patients with de novo or familial apparently balanced translocations and abnormal phenotype

    PubMed Central

    Sismani, Carolina; Kitsiou-Tzeli, Sofia; Ioannides, Marios; Christodoulou, Christodoulos; Anastasiadou, Violetta; Stylianidou, Goula; Papadopoulou, Eleftheria; Kanavakis, Emanuel; Kosmaidou-Aravidou, Zoe; Patsalis, Philippos C

    2008-01-01

    Background Carriers of apparently balanced translocations are usually phenotypically normal; however in about 6% of de novo cases, an abnormal phenotype is present. In the current study we investigated 12 patients, six de novo and six familial, with apparently balanced translocations and mental retardation and/or congenital malformations by applying 1 Mb resolution array-CGH. In all de novo cases, only the patient was a carrier of the translocation and had abnormal phenotype. In five out of the six familial cases, the phenotype of the patient was abnormal, although the karyotype appeared identical to other phenotypically normal carriers of the family. In the sixth familial case, all carriers of the translocations had an abnormal phenotype. Results Chromosomal and FISH analyses suggested that the rearrangements were "truly balanced" in all patients. However, array-CGH, revealed cryptic imbalances in three cases (3/12, 25%), two de novo (2/12, 33.3%) and one familial (1/12, 16.6%). The nature and type of abnormalities differed among the cases. In the first case, what was identified as a de novo t(9;15)(q31;q26.1), a complex rearrangement was revealed involving a ~6.1 Mb duplication on the long arm of chromosome 9, an ~10 Mb deletion and an inversion both on the long arm of chromosome 15. These imbalances were located near the translocation breakpoints. In the second case of a de novo t(4;9)(q25;q21.2), an ~6.6 Mb deletion was identified on the short arm of chromosome 7 which is unrelated to the translocation. In the third case, of a familial, t(4;7)(q13.3;p15.3), two deletions of ~4.3 Mb and ~2.3 Mb were found, each at one of the two translocation breakpoints. In the remaining cases the translocations appeared balanced at 1 Mb resolution. Conclusion This study investigated both de novo and familial apparently balanced translocations unlike other relatively large studies which are mainly focused on de novo cases. This study provides additional evidence that cryptic

  20. An epigenetic signature in peripheral blood associated with the haplotype on 17q21.31, a risk factor for neurodegenerative tauopathy.

    PubMed

    Li, Yun; Chen, Jason A; Sears, Renee L; Gao, Fuying; Klein, Eric D; Karydas, Anna; Geschwind, Michael D; Rosen, Howard J; Boxer, Adam L; Guo, Weilong; Pellegrini, Matteo; Horvath, Steve; Miller, Bruce L; Geschwind, Daniel H; Coppola, Giovanni

    2014-03-01

    Little is known about how changes in DNA methylation mediate risk for human diseases including dementia. Analysis of genome-wide methylation patterns in patients with two forms of tau-related dementia--progressive supranuclear palsy (PSP) and frontotemporal dementia (FTD)--revealed significant differentially methylated probes (DMPs) in patients versus unaffected controls. Remarkably, DMPs in PSP were clustered within the 17q21.31 region, previously known to harbor the major genetic risk factor for PSP. We identified and replicated a dose-dependent effect of the risk-associated H1 haplotype on methylation levels within the region in blood and brain. These data reveal that the H1 haplotype increases risk for tauopathy via differential methylation at that locus, indicating a mediating role for methylation in dementia pathophysiology. PMID:24603599

  1. Meta-Analysis of 13 Genome Scans Reveals Multiple Cleft Lip/Palate Genes with Novel Loci on 9q21 and 2q32-35

    PubMed Central

    Marazita, Mary L.; Murray, Jeffrey C.; Lidral, Andrew C.; Arcos-Burgos, Mauricio; Cooper, Margaret E.; Goldstein, Toby; Maher, Brion S.; Daack-Hirsch, Sandra; Schultz, Rebecca; Mansilla, M. Adela; Field, L. Leigh; Liu, You-e; Prescott, Natalie; Malcolm, Sue; Winter, Robin; Ray, Ajit; Moreno, Lina; Valencia, Consuelo; Neiswanger, Katherine; Wyszynski, Diego F.; Bailey-Wilson, Joan E.; Albacha-Hejazi, Hasan; Beaty, Terri H.; McIntosh, Iain; Hetmanski, Jacqueline B.; Tunçbilek, Gökhan; Edwards, Matthew; Harkin, Louise; Scott, Rodney; Roddick, Laurence G.

    2004-01-01

    Isolated or nonsyndromic cleft lip with or without cleft palate (CL/P) is a common birth defect with a complex etiology. A 10-cM genome scan of 388 extended multiplex families with CL/P from seven diverse populations (2,551 genotyped individuals) revealed CL/P genes in six chromosomal regions, including a novel region at 9q21 (heterogeneity LOD score [HLOD]=6.6). In addition, meta-analyses with the addition of results from 186 more families (six populations; 1,033 genotyped individuals) showed genomewide significance for 10 more regions, including another novel region at 2q32-35 (P=.0004). These are the first genomewide significant linkage results ever reported for CL/P, and they represent an unprecedented demonstration of the power of linkage analysis to detect multiple genes simultaneously for a complex disorder. PMID:15185170

  2. A novel de novo 1.8 Mb microdeletion of 17q21.33 associated with intellectual disability and dysmorphic features.

    PubMed

    Preiksaitiene, E; Männik, K; Dirse, V; Utkus, A; Ciuladaite, Z; Kasnauskiene, J; Kurg, A; Kučinskas, V

    2012-11-01

    We report on a de novo 17q21.33 microdeletion, 1.8 Mb in size, detected in a patient with mild intellectual disability, growth retardation, poor weight gain, microcephaly, long face, large beaked nose, thick lower lip, micrognathia and other dysmorphic features. The deletion was detected by whole-genome genotyping BeadChip assay and involves the genomic region between 45,682,246 and 47,544,816 bp on chromosome 17. Among the 24 RefSeq genes included in this deletion are the CA10 and CACNA1G genes that are involved in brain development and neurological processes. A possible candidate gene for the prenatal and postnatal growth retardation is the CHAD gene, which product chondroadherin is a cartilage protein with cell binding properties. These three genes may be responsible for the patient's phenotype. PMID:22842074

  3. Gene duplication of the human peptide YY gene (PYY) generated the pancreatic polypeptide gene (PPY) on chromosome 17q21.1

    SciTech Connect

    Hort, Y.; Shine, J.; Herzog, H.

    1995-03-01

    Neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP) are structurally related but functionally diverse peptides, encoded by separate genes and expressed in different tissues. Although the human NPY gene has been mapped to chromosome 7, the authors demonstrate here that the genes for human PYY and PP (PPY) are localized only 10 kb apart from each another on chromosome 17q21.1. The high degree of homology between the members of this gene family, both in primary sequence and exon/intron structure, suggests that the NYP and the PYY genes arose from an initial gene duplication event, with a subsequent tandem duplication of the PYY gene being responsible for the creation of the PPY gene. A second weaker hybridization signal also found on chromosome 17q11 and results obtained by Southern blot analysis suggest that the entire PYY-PPY region has undergone a further duplication event. 27 refs., 5 figs.

  4. Common variants of SLAMF1 and ITLN1 on 1q21 are associated with type 2 diabetes in Indian population.

    PubMed

    Tabassum, Rubina; Mahajan, Anubha; Dwivedi, Om Prakash; Chauhan, Ganesh; Spurgeon, Charles J; Kumar, M V Kranthi; Ghosh, Saurabh; Madhu, S V; Mathur, Sandeep K; Chandak, Giriraj R; Tandon, Nikhil; Bharadwaj, Dwaipayan

    2012-03-01

    Though multiple studies link chromosomal regions 1q21-q23 and 20q13 with type 2 diabetes, fine mapping of these regions is yet to confirm gene(s) explaining the linkages. These candidate regions remain unexplored in Indians, which is a high-risk population for type 2 diabetes. Hypothesizing regulatory regions to have a more important role in complex disorders, we examined association of 207 common variants in proximal promoter and untranslated regions of genes on 1q21-23 and 20q13 with type 2 diabetes in 2115 North Indians. Further, top signals were replicated in an independent group of 2085 North Indians. Variants-rs11265455-SLAMF1 (odds ratios (OR)=1.32, P=1.1 × 10(-3)), rs1062827-F11R (OR=1.36, P=1.7 × 10(-3)) and rs12565932-F11R (OR=1.35, P=1.8 × 10(-3)) were top signals for association with type 2 diabetes whereas rs1333062-ITLN1 (OR=1.28, P=3.4 × 10(-3)) showed strongest association in body mass index-stratified analysis. Replication of these four variants confirmed associations of rs11265455-SLAMF1 (OR=1.27, P=9.1 × 10(-3)) and rs1333062-ITLN1 (OR=1.25, P=1.1 × 10(-3)) with type 2 diabetes. Meta-analysis further corroborated the association of rs11265455-SLAMF1 (OR random effect=1.29, P random effect=3.9 × 10(-5)) and rs1333062-ITLN1 (OR random effect=1.19, P random effect=1.8 × 10(-4)). In conclusion, the study demonstrates that variants of SLAMF1 and ITLN1, both implicated in inflammation, are associated with type 2 diabetes in Indians. PMID:22277902

  5. The gene for pancreatic polypeptide (PPY) and the anonymous marker D17S78 are within 45 kb of each other on chromosome 17q21

    SciTech Connect

    Chandrasekharappa, S.C.; King, S.E.; Lee, Y.H.; Weber, B.L.; Collins, F.S. ); Friedman, L.; King, M.C. ); Welsch, P.; Bowcock, A.M. )

    1994-05-15

    A gene for early-onset breast and ovarian cancer (BRCA1) has been localized to a small region of chromosome 17q21. A combination of genetic linkage studies, radiation-reduced hybrid analysis, and physical mapping by FISH has identified several genes/markers that lie in this interval. Among these are the gene encoding pancreatic polypeptide (PPY) and a polymorphic marker at locus D17S78. Efforts to construct a physical map of this region by isolating a large number of yeast artificial chromosome (YAC) and cosmid clones demonstrate that PPY and D17S78 are present within the same cosmid clone, and therefore no farther than 45 kb apart. This observation takes on particular significance since it excludes a recently described BRCA1 candidate gene from the interval defined by meiotic mapping. Although PPY and D17S78 were found to be no farther than 45 kb apart, identification of a smaller fragment that hybridizes to both probes would indicate that these two are much closer. The probe p131 and the gene PPY were previously mapped to 17q21-q23 and to the proximal long arm of chromosome 17, respectively. The demonstration of the close proximity of these markers should allow them to be treated as a single locus in terms of long-range genomic mapping of this region, and the genomic clones isolated should serve as useful resources for the identification of the BRCA1 gene. Analysis of a large number of a familial and spordic breast and ovarian cancers has identified frequent loss of heterozygosity near the BRCA1 locus. A recent report has suggested the responsible interval lies just telomeric to PPY, and a suggested candidate gene (MCD) for BRCA1 was found to be somatically rearranged in two of several hundred sporadic breast tumors.

  6. Metabolic Syndrome is linked to Chromosome 7q21 and associated with genetic variants in CD36 and GNAT3 in Mexican Americans

    PubMed Central

    Farook, VS; Puppala, S; Schneider, J; Fowler, SP; Chittoor, G; Dyer, TD; Allayee, H; Cole, SA; Arya, R; Black, MH; Curran, JE; Almasy, L; Buchanan, TA; Jenkinson, CP; Lehman, DM; Watanabe, RM; Blangero, J; Duggirala, R

    2014-01-01

    The prevalence of metabolic syndrome (MS) has been rising alarmingly worldwide, including in the United States, but knowledge on specific genetic determinants of MS is very limited. Therefore, we planned to identify the genetic determinants of MS as defined by National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATPIII) criteria. We performed linkage screen for MS using data from 692 Mexican Americans, who participated in the San Antonio Family Diabetes/Gallbladder Study (SAFDGS). We found strong evidence for linkage of MS on chromosome 7q (LOD = 3.6, empirical P = 6.0 × 10−5), between markers D7S2212 and D7S821. In addition, six chromosomal regions exhibited potential evidence for linkage (LOD ≥ 1.2) with MS. Further, we examined 29 single nucleotide polymorphisms (SNPs) from the fatty acid translocase (FAT or CD36, 18 SNPs) gene and guanine nucleotide binding protein, alpha transducing 3 (GNAT3, 11 SNPs) gene, located within the 1-LOD support interval region for their association with MS and its related traits. Several SNPs were associated with MS and its related traits. Remarkably, rs11760281 in GNAT3 and rs1194197 near CD36 exhibited the strongest associations with MS (P = 0.0003, relative risk [RR] = 1.6 and P = 0.004, RR = 1.7 respectively) and several other related traits. These two variants explained about 18% of the MS linkage evidence on chromosome 7q21, and together conferred approximately 3-fold increase in MS risk (RR = 2.7). In conclusion, our linkage and subsequent association studies implicate a region on chromosome 7q21 to influence MS in Mexican Americans. PMID:22456541

  7. Identification of a microdeletion at 7q21.3 with fluorescence in situ hybridization in a patient with split hand/split foot (ectrodactyly)

    SciTech Connect

    Hudgins, L.; Massa, H.; Disteche, C.

    1994-09-01

    Split hand/split foot (SHSF), often referred to as ectrodactyly or lobster claw deformity, is a human developmental disorder characterized by a deep median cleft of the hands and feet, missing digits, and fusion of remaining digits. This anomaly can be seen alone, frequently autosomal dominant, or in association with other abnormalities. One locus for this defect has been localized to chromosome 7q21.3-q22.1. We report a patient with SHSF plus mental retardation, short stature and dysmorphic features who was found to have a microdeletion at this locus detected only with the aid of fluorescence in situ hybridization (FISH). T.H. is a 7 y.o. male who was referred for evaluation of foot anomalies and mild mental retardation. History was remarkable for growth retardation of postnatal onset and hypotonia. Renal ultrasound and audiology evaluation were normal. Physical exam revealed dysplastic ears, micrognathia, long philtrum, high narrow palate, and malformations of the feet consistent with SHSF. Family history was negative for limb abnormalities and mental retardation. A number of patients with SHSF and other anomalies have been found to have deletions involving chromosome 7q21-q22; therefore, high resolution chromosome analysis was performed in T.H. but was inconclusive. Cosmids and yeast artificial chromosomes which we had previously mapped to the SHSF critical region were used as FISH probes and a microdeletion was detected. We were thus able to determine the etiology of this child`s abnormalities and provide accurate genetic counseling, which would not have been possible with standard cytogenetic techniques. This technique also allowed us to further refine the SHSF critical region. This case illustrates the utility of FISH for the rapid identification of suspect microdeletions in SHSF. This approach should also be useful as an expeditious way of defining the critical regions for the location of genes which give rise to other developmental malformations.

  8. Genome-Wide Gene by Environment Interaction Analysis Identifies Common SNPs at 17q21.2 that Are Associated with Increased Body Mass Index Only among Asthmatics

    PubMed Central

    Wang, Leyao; Murk, William; DeWan, Andrew T.

    2015-01-01

    Asthmatics have an increased risk of being overweight/obese. Although the underlying mechanisms of this are unclear, genetic factors are believed to play an essential role. To identify common genetic variants that are associated with asthma-related BMI increase, we performed a genome-wide gene by environment (asthma) interaction analysis for the outcome of BMI in the Multi-Ethnic Study of Atherosclerosis (MESA) study (N = 2474 Caucasians, 257 asthmatics), and replicated findings in the Framingham Heart Study (FHS) offspring cohort (N = 1408 Caucasians, 382 asthmatics). The replicable tagging SNP, rs2107212, was further examined in stratified analyses. Seven SNPs clustered in 17q21.2 were identified to be associated with higher BMI among asthmatics (interaction p < 5×10−7 in MESA and p < 0.05 in FHS). In both MESA and FHS asthmatics, subjects carrying the A allele on rs2107212 had significantly higher odds of obesity than non-carriers, which was not the case for non-asthmatics. We further examined BMI change subsequent to asthma diagnosis over a period of 26 years in FHS and demonstrated greater BMI increase among asthmatics compared to non-asthmatics. Asthmatics carrying the A allele at rs2107212 had significantly greater net BMI increase over the 26-year period compared to non-asthmatics. In this study, we found that common genetic variants on 17q21.2 are associated with post-asthma BMI increase among Caucasians. This finding will help elucidate pathways involved in the comorbidity of asthma and obesity. PMID:26672748

  9. Acampomelic campomelic syndrome and sex reversal associated with de novo t(12;17) translocation.

    PubMed

    Ninomiya, S; Narahara, K; Tsuji, K; Yokoyama, Y; Ito, S; Seino, Y

    1995-03-13

    The association of rare chromosomal rearrangements involving a specific 17q breakpoint with campomelic syndrome (CMPS) and/or sex reversal (SR) has led to an assignment of the CMPS1/SRA1 locus to 17q24.3-->q25.1. We describe a patient with multiple anomalies and SR, who had a de novo t(12;17) translocation. The phenotype was consistent with that of CMPS except for the lack of lower limb bowing and talipes equinovarus. Chromosome painting indicated that the breakpoints appeared to have occurred at 12q21.32 and 17q24.3 or q25.1. This study suggests that acampomelic CMPD with SR represents a variant of the CMPS1/SRA1 locus disorder. We emphasize the likelihood that CMPS may be a contiguous gene syndrome. PMID:7747782

  10. Acampomelic campomelic syndrome and sex reversal associated with de novo t(12;17) translocation

    SciTech Connect

    Ninomiya, Shinsuke; Narahara, Kouji; Tsuji, Kazushiro

    1995-03-13

    The association of rare chromosomal rearrangements involving a specific 17q breakpoint with campomelic syndrome (CMPS) and/or sex reversal (SR) has led to an assignment of the CMPS1/SRA1 locus to 17q24.3 {yields} q25.1. We describe a patient with multiple anomalies and SR, who had a de novo t(12;17) translocation. The phenotype was consistent with that of CMPS except for the lack of lower limb bowing and talipes equinovarus. Chromosome painting indicated that the breakpoints appeared to have occurred at 12q21.32 and 17q24.3 or q25.1. CMPD with SR represents a variant of the CMPS1/SRA1 locus disorder. We emphasize the likelihood that CMPS may be a contiguous gene syndrome. 18 refs., 4 figs., 1 tab.

  11. BCL2 protein expression in follicular lymphomas with t(14;18) chromosomal translocations.

    PubMed

    Masir, Noraidah; Campbell, Lisa J; Goff, Lindsey K; Jones, Margaret; Marafioti, Teresa; Cordell, Jacqueline; Clear, Andrew J; Lister, T Andrew; Mason, David Y; Lee, Abigail M

    2009-03-01

    The t(14;18)(q32;q21) chromosomal translocation induces BCL2 protein overexpression in most follicular lymphomas. However the expression of BCL2 is not always homogeneous and may demonstrate a variable degree of heterogeneity. This study analysed BCL2 protein expression pattern in 33 cases of t(14;18)-positive follicular lymphomas using antibodies against two different epitopes (i.e. the widely used antibody BCL2/124 and an alternative antibody E17). 16/33 (49%) cases demonstrated strong BCL2 expression. In 10/33 (30%) cases, BCL2 expression was heterogeneous and in some of these, its loss appeared to be correlated with cell proliferation, as indicated by Ki67 expression. Double immunofluorescence labelling confirmed an inverse BCL2/Ki67 relationship, where in 24/28 (86%) cases cellular expression of BCL2 and Ki67 was mutually exclusive. In addition, seven BCL2 'pseudo-negative' cases were identified in which immunostaining was negative with antibody BCL2/124, but positive with antibody E17. Genomic DNA sequencing of these 'pseudo-negative' cases demonstrated eleven mutations in four cases and nine of these were missense mutations. It can be concluded that in follicular lymphomas, despite carrying the t(14;18) translocations, BCL2 protein expression may be heterogeneous and loss of BCL2 could be related to cell proliferation. Secondly, mutations in translocated BCL2 genes appear to be common and may cause BCL2 pseudo-negative immunostaining. PMID:19120369

  12. Extra skeletal Soft Tissue Ewing’s Sarcoma with Variant Translocation of Chromosome t (4; 22) (q35; q12)-A Case Report

    PubMed Central

    Nagaraj, Prashanth; H, Srinivas C; Rao, Raghavendra; Manohar, Sandesh

    2013-01-01

    Introduction: Ewing’s sarcomas is a rare primitive neuroectodermal tumour (PNET) which has an annual incidence of 2.9 /million population in USA 1Jeffery Toretsky et al (2008) They are very uncommon in African and Asian population. It is commonly associated with reciprocal translocation between chromosome 11 and 12 t (11:12) or less frequently the t(21;22)(q22;ql 2) translocation. It is highly aggressive tumor which is PAS- and CD99 (MIC2)-positive relatively few variant translocations have been reported in primary Ewing’s sarcomas (ES). Case Report: We are hereby presenting a case of extra skeletal soft tissue Ewing’s sarcoma with unusual translocation of chromosome t (4, 22) (q35, q12). Patient presented to us in advanced stage with pulmonary metastasis and lower limb neurological deficit. Relatively few variant translocations have been reported in primary Ewing’s sarcomas (ES). To date, 13 variants of the EWS fusion gene have been described in literature. They are extremely rare, representing altogether < 1% of the cases’ 23we are reporting a case of a variant simple translocation of chromosome t (4; 22) (q35;1 2). In our exhaustive literature search we could find only one case of complex translocation which was identified in a dysmorphic 15-year-old girl, t (4:11; 22)(q21; q24; q12) reported by Squire Jet al (1993). Conclusion: This type of translocation is extremely rare and has not been reported in the literature so far. Clinical presentation was initial indolent but later at the time patient presented to our institute he had developed pulmonary metastases and paraplegia due to involvement of spine. Our case report will provide new insight about rare translocation types in Ewing’s sarcoma and understand their clinical behavior of Ewing’s sarcoma with such type of translocation. PMID:27298923

  13. Fractional exhaled nitric oxide in childhood is associated with 17q11.2-q12 and 17q12-q21 variants

    PubMed Central

    Timpson, Nicolas J; Salam, Muhammad T; Standl, Marie; Curtin, John A; Genuneit, Jon; Kerhof, Marjan; Kreiner-Møller, Eskil; Cáceres, Alejandro; Gref, Anna; Liang, Liming L; Taal, H Rob; Bouzigon, Emmanuelle; Demenais, Florence; Nadif, Rachel; Ober, Carole; Thompson, Emma E; Estrada, Karol; Hofman, Albert; Uitterlinden, André G; van Duijn, Cornélia; Rivadeneira, Fernando; Li, Xia; Eckel, Sandrah P; Berhane, Kiros; Gauderman, W James; Granell, Raquel; Evans, David M; St Pourcain, Beate; McArdle, Wendy; Kemp, John P; Smith, George Davey; Tiesler, Carla MT; Flexeder, Claudia; Simpson, Angela; Murray, Clare S; Fuchs, Oliver; Postma, Dirkje S; Bønnelykke, Klaus; Torrent, Maties; Andersson, Martin; Sleiman, Patrick; Hakonarson, Hakon; Cookson, William O; Moffatt, Miriam F; Paternoster, Lavinia; Melén, Erik; Sunyer, Jordi; Bisgaard, Hans; Koppelman, Gerard H; Ege, Markus; Custovic, Adnan; Heinrich, Joachim; Gilliland, Frank D; Henderson, Alexander J; Jaddoe, Vincent WV; de Jongste, Johan C

    2014-01-01

    Background The fractional concentration of nitric oxide in exhaled air (FeNO) is a biomarker of eosinophilic airway inflammation and associated with childhood asthma. Identification of common genetic variants associated with childhood FeNO may help to define biological mechanisms related to specific asthma phenotypes. Objective To identify genetic variants associated with childhood FeNO, and their relation with asthma. Methods FeNO was measured in children aged 5 to 15 years. In 14 genome-wide association (GWA) studies (N = 8,858), we examined the associations of ~2.5 million single nucleotide polymorphisms (SNPs) with FeNO. Subsequently, we assessed whether significant SNPs were expression quantitative trait loci (eQTLs) in genome-wide expression datasets of lymphoblastoid cell lines (N = 1,830), and were related with asthma in a previously published GWA dataset (cases: n=10,365; controls: n=16,110). Results We identified 3 SNPs associated with FeNO: rs3751972 in LYR motif containing 9 (LYRM9) (P = 1.97×10−10) and rs944722 in inducible nitric oxide synthase 2 (NOS2) (P = 1.28×10−9) both located at 17q11.2-q12, and rs8069176 near gasdermin B (GSDMB) (P = 1.88×10−8) at 17q12-q21. We found a cis eQTL for the transcript soluble galactoside-binding lectin 9 (LGALS9) that is in linkage disequilibrium with rs944722. Rs8069176 was associated with GSDMB and ORM1-like 3 (ORMDL3) expression. Rs8069176 at 17q12-q21, and not rs3751972 and rs944722 at 17q11.2-q12, were associated with physician-diagnosed asthma. Conclusion This study identified 3 variants associated with FeNO, explaining 0.95% of the variance. Identification of functional SNPs and haplotypes in these regions might provide novel insight in the regulation of FeNO. This study highlights that both shared and distinct genetic factors affect FeNO and childhood asthma. PMID:24315451

  14. Delineation of a de novo 7q21.3q31.1 Deletion by CGH-SNP Arrays in a Girl with Multiple Congenital Anomalies Including Severe Glaucoma.

    PubMed

    Martínez-Jacobo, L; Córdova-Fletes, C; Ortiz-López, R; Rivas, F; Saucedo-Carrasco, C; Rojas-Martínez, A

    2013-09-01

    In this study, we present a female patient with a constitutional de novo deletion in 7q21.3q31.1 as determined by G-banding and CGH-SNP arrays. She exhibited, among other features, psychomotor retardation, congenital severe bilateral glaucoma, a cleft palate, and heart defect. Microarray assay disclosed a deleted 12.5-Mb region roughly 88 kb downstream the ectrodactyly critical region; thus, the patient's final karyotype was 46,XX.arr 7q21.3q31.1(96,742,140-109,246,085)×1 dn. This girl represents the fourth patient described so far with congenital glaucoma and a deletion encompassing or overlapping the 7q21.3q31.1 region, and confirms the presence of a locus or loci related to such a clinical feature. According to our results, the proneness to ocular defects secondary to 7q intermediate deletions could be caused by co-deletion of TAC1, HBP1, and a small cluster of cytochrome P450 genes (subfamily 3A). This conclusion is supported by their functional roles and expression locations as well as because TAC1 is related to the functional pathway of the MYOC gene whose mutations are linked to glaucoma. Moreover, given that this girl is clinically reminiscent of several phenotypes related to diverse deletions within 7q21q32, our results and observations offer a general overview of the gene content of deletions/phenotypes overlapping 7q21.3q31.1 and confirm that loci distal to DLX genes including the CUX1 gene and potential regulatory elements downstream from DLX5 are unrelated to ectrodactyly. PMID:24167464

  15. Delineation of a de novo 7q21.3q31.1 Deletion by CGH-SNP Arrays in a Girl with Multiple Congenital Anomalies Including Severe Glaucoma

    PubMed Central

    Martínez-Jacobo, L.; Córdova-Fletes, C.; Ortiz-López, R.; Rivas, F.; Saucedo-Carrasco, C.; Rojas-Martínez, A.

    2013-01-01

    In this study, we present a female patient with a constitutional de novo deletion in 7q21.3q31.1 as determined by G-banding and CGH-SNP arrays. She exhibited, among other features, psychomotor retardation, congenital severe bilateral glaucoma, a cleft palate, and heart defect. Microarray assay disclosed a deleted 12.5-Mb region roughly 88 kb downstream the ectrodactyly critical region; thus, the patient's final karyotype was 46,XX.arr 7q21.3q31.1(96,742,140-109,246,085)×1 dn. This girl represents the fourth patient described so far with congenital glaucoma and a deletion encompassing or overlapping the 7q21.3q31.1 region, and confirms the presence of a locus or loci related to such a clinical feature. According to our results, the proneness to ocular defects secondary to 7q intermediate deletions could be caused by co-deletion of TAC1, HBP1, and a small cluster of cytochrome P450 genes (subfamily 3A). This conclusion is supported by their functional roles and expression locations as well as because TAC1 is related to the functional pathway of the MYOC gene whose mutations are linked to glaucoma. Moreover, given that this girl is clinically reminiscent of several phenotypes related to diverse deletions within 7q21q32, our results and observations offer a general overview of the gene content of deletions/phenotypes overlapping 7q21.3q31.1 and confirm that loci distal to DLX genes including the CUX1 gene and potential regulatory elements downstream from DLX5 are unrelated to ectrodactyly. PMID:24167464

  16. Identifying Gene Disruptions in Novel Balanced de novo Constitutional Translocations in Childhood Cancer Patients by Whole Genome Sequencing

    PubMed Central

    Ritter, Deborah I.; Haines, Katherine; Cheung, Hannah; Davis, Caleb F.; Lau, Ching C.; Berg, Jonathan S.; Brown, Chester W.; Thompson, Patrick A.; Gibbs, Richard; Wheeler, David A.; Plon, Sharon E.

    2014-01-01

    Purpose We applied whole genome sequencing to children diagnosed with neoplasms and found to carry apparently balanced constitutional translocations, to discover novel genic disruptions. Methods We applied SV calling programs CREST, Break Dancer, SV-STAT and CGAP-CNV, and developed an annotative filtering strategy to achieve nucleotide resolution at the translocations. Results We identified the breakpoints for t(6;12) (p21.1;q24.31) disrupting HNF1A in a patient diagnosed with hepatic adenomas and Maturity Onset Diabetes of the Young (MODY). Translocation as the disruptive event of HNF1A, a gene known to be involved in MODY3, has not been previously reported. In a subject with Hodgkin’s lymphoma and subsequent low-grade glioma, we identified t(5;18) (q35.1;q21.2), disrupting both SLIT3 and DCC, genes previously implicated in both glioma and lymphoma. Conclusions These examples suggest that implementing clinical whole genome sequencing in the diagnostic work-up of patients with novel but apparently balanced translocations may reveal unanticipated disruption of disease-associated genes and aid in prediction of the clinical phenotype. PMID:25569436

  17. Update on a linkage trend between schizophrenia (SZ) and the 11q21-22 region in pedigrees of Eastern Quebec

    SciTech Connect

    Merette, C.; Rouillard, E.; Marcotte, P.

    1994-09-01

    At the 1993 meeting of the ASHG, we presented preliminary results on the observation of a linkage trend (Z{sub max} = 2.69) using a recessive model in one large pedigree (255) from Eastern Quebec showing 10 individuals affected by SZ. Our sample is still in progress and we now present additional results after (1) extending pedigree 255 (adding a few genotypes and phenotypes that were unknown in 1993); (2) genotyping 10 new markers in the 11q21-22 region; (3) performing three-point analyses and (4) adding two new SZ pedigrees to our initial sample of four. Results: The extension of pedigree 255 now yields a maximum lod score of 3.06 with marker D11S35. The maximum lod score is still observed at D11S35 after genotyping 10 other markers including INT-2, DRD2 and CD3D. Lod scores greater than 1.5 are also observed with markers D11D901, D11S876 and D11S919 in family 255. Three-point and two-point analyses yielded consistent results. The maximum lod scores were comparable and they were all observed in the close vicinity of D11S35. A maximum lod score of 1.35 was obtained in one of the two new SZ pedigrees. The heterogeneity analysis of the total sample of 6 SZ pedigrees, using HOMOG, favored the hypothesis of linkage under heterogeneity 1284 to 1 (Z=3.11).

  18. The gene for the ataxia-telagiectasia variant, Nijmegen breakage syndrome, maps to a 1-cM interval on chromosome 8q21

    SciTech Connect

    Saar, K.; Stumm, M.; Wegner, R.D.

    1997-03-01

    Nijmegen breakage syndrome (NBS; Seemanova II syndrome) and Berlin breakage syndrome (BBS), also known as ataxia-telangiectasia variants, are two clinically indistinguishable autosomal recessive familial cancer syndromes that share with ataxia-telangiectasia similar cellular, immunological, and chromosomal but not clinical findings. Classification in NBS and BBS was based on complementation of their hypersensitivity to ionizing radiation in cell-fusion experiments. Recent investigations have questioned the former classification into two different disease entities, suggesting that NBS/BBS is caused by mutations in a single radiosensitivity gene. We now have performed a whole-genome screen in 14 NBS/BBS families and have localized the gene for NBS/BBS to a 1-cM interval on chromosome 8q21, between markers D8S271 and D8S270, with a peak LOD score of 6.86 at D8S1811. This marker also shows strong allelic association to both Slavic NBS and German BBS patients, suggesting the existence of one major mutation of Slavic origin. Since the same allele is seen in both former complementation groups, genetic homogeneity of NBS/BBS can be considered as proved. 21 refs., 2 figs., 2 tabs.

  19. Modeling partial monosomy for human chromosome 21q11.2-q21.1 reveals haploinsufficient genes influencing behavior and fat deposition.

    PubMed

    Migdalska, Anna M; van der Weyden, Louise; Ismail, Ozama; White, Jacqueline K; Sánchez-Andrade, Gabriela; Logan, Darren W; Arends, Mark J; Adams, David J

    2012-01-01

    Haploinsufficiency of part of human chromosome 21 results in a rare condition known as Monosomy 21. This disease displays a variety of clinical phenotypes, including intellectual disability, craniofacial dysmorphology, skeletal and cardiac abnormalities, and respiratory complications. To search for dosage-sensitive genes involved in this disorder, we used chromosome engineering to generate a mouse model carrying a deletion of the Lipi-Usp25 interval, syntenic with 21q11.2-q21.1 in humans. Haploinsufficiency for the 6 genes in this interval resulted in no gross morphological defects and behavioral analysis performed using an open field test, a test of anxiety, and tests for social interaction were normal in monosomic mice. Monosomic mice did, however, display impaired memory retention compared to control animals. Moreover, when fed a high-fat diet (HFD) monosomic mice exhibited a significant increase in fat mass/fat percentage estimate compared with controls, severe fatty changes in their livers, and thickened subcutaneous fat. Thus, genes within the Lipi-Usp25 interval may participate in memory retention and in the regulation of fat deposition. PMID:22276124

  20. De novo partial duplication 7(q11.2{r_arrow}q21.2) in a dysmorphic, developmentally retarded boy

    SciTech Connect

    Ross, M.; Pinsky, L.; Teebi, A.

    1994-09-01

    Chromosomal abnormalities involving chromosome 7q are rare; we report a case of partial duplication 7q. The propositus was born at 34 weeks by cesarian section, decided because of oligohydramnios, severe intrauterine growth retardation and fetal immobility. At birth, the baby was under the 5th percentile for height, weight and head circumference and had dysmorphic features, including slight asymmetry of the face, bilateral epicanthus, hypoplastic nasal bridge, short globular nose, asymmetrical dysplastic ears, fifth finger clinodactyly, short second and fifth toe. Ultrasound examination showed atrial and ventricular septal defects. At 18 months, the child had a fracture of the femur, secondary to a minor trauma; skeletal X-rays showed generalized osteoporosis and normal healing. The karyotype with GTG-banding showed a de novo partial duplication of the long arm of chromosome 7 (46,XX,dup(7)(q11.23{r_arrow}q21.2)). Fluorescence in situ hybridization with a painting probe specific for chromosome 7 confirmed the intra-chromosomal rearrangement. The patient`s phenotype and his chromosomal abnormality do not match the previously reported cases of partial trisomy 7q. This case confirms the importance of FISH for the delineation of the chromosomal inbalance in structural chromosomal aberrations.

  1. Multicolor FISH mapping with Alu-PCR-amplified YAC clone DNA determines the order of markers in the BRCA1 region on chromosome 17q12-q21

    SciTech Connect

    Flejter, W.J.; Glover, T.W.; Barcroft, C.L.; Guo, Sun Wei; Boehnke, M.; Chandrasekharappa, S.; Collins, F.S. Howard Hughes Medical Institute, Ann Arbor, MI ); Lynch, E.D. ); Hayes, S. ); Weber, B.L. )

    1993-09-01

    A gene designated BRCA1, implicated in the susceptibility to early-onset familial breast cancer, has recently been localized to chromosome 17q12-q21. To date, the order of DNA markers mapped within this region has been based on genetic linkage analysis. The authors report the use of multicolor fluorescence in situ hybridization to establish a physically based map of five polymorphic DNA markers and 10 cloned genes spanning this region. Three cosmid clones and Alu-PCR-Generated products derived from 12 yeast artificial chromosome clones representing each of these markers were used in two-color mapping experiments to determine an initial proximity of markers relative to each other on metaphase chromosomes. Interphase mapping was then employed to determine the order and orientation of closely spaced loci by direct visualization of fluorescent signals following hybridization of three probes, each detected in a different color. Statistical analysis of the combined data suggests that the order of markers in the BRCA1 regions is cen-THRA1-TOP2-GAS-OF2-17HSD-248yg9-RNU2-OF3-PPY/p131-EPB3-Mfd188-WNT3-HOX2-GP3A-tel. This map is consistent with that determined by radiation-reduced hybrid mapping and will facilitate positional cloning strategies in efforts to isolate and characterize the BRCA1 gene. 27 refs., 2 figs., 3 tabs.

  2. Isolation of region-specific cosmids by hybridization with microdissection clones from human chromosome 10q11. 1-q21. 1

    SciTech Connect

    Karakawa, Katsu; Takami, Koji; Fujita, Shoichi Osaka Univ. Medical School, Fukushima-ku, Osaka ); Nakamura, Tsutomu; Takai, Shin-ichiro; Nishisho, Isamu ); Jones, C. ); Ohta, Tohru; Jinno, Yoshihiro; Niikawa, Norio )

    1993-08-01

    A region-specific plasmid library composed of 20,000 recombinants was constructed by microdissection of human chromosome 10 (10q11.2-q21.1) and subsequent amplification with the primer-linker method of polymerase chain reaction (PCR). Hybridization with total human DNA showed that 32 of 217 microclones studied contained highly repetitive sequences. Further analysis of the remaining 185 microclones proved that 43 microclones, each having an insert longer than 200 bp, contained unique sequences of human chromosome 10 origin. Twenty-five microclones randomly selected from the 43 were used directly as probes to isolate corresponding cosmid clones, resulting in 32 cosmids corresponding to 14 microclones. Of the 25 cosmids that could be mapped by fluorescence in situ hybridization, 24 proved to originate from the microdissected or adjacent region (10p11.2-q22.3)and 1 from a rather distal region (10q24.3-q25.1). In addition, 15 of the 32 cosmids revealed restriction fragment length polymorphisms, including 1 with a variable number of tandem repeats marker. The microdissection library and the obtained cosmids are valuable resources for constructing high-resolution physical and linkage maps of the pericentromeric region of chromosome 10, where the gene predisposing to multiple endocrine neoplasia type 2A (MEN2A) has been mapped. 30 refs., 3 figs., 3 tabs.

  3. X-linked [alpha]-thalassemia/mental retardation (ATR-X) syndrome: Localization to Xq12-q21. 31 by X inactivation and linkage analysis

    SciTech Connect

    Gibbons, R.J.; Buckle, V.J.; Higgs, D.R.; Suthers, G.K. ); Wilkie, A.O.M. )

    1992-11-01

    The authors have examined seven pedigrees that include individuals with a recently described X-linked form of severe mental retardation associated with [alpha]-thalassemia (ATR-X syndrome). Using hematologic and molecular approaches, they have shown that intellectually normal female carriers of this syndrome may be identified by the presence of rare cells containing HbH (hemoglobin H) inclusions in their peripheral blood and by an extremely skewed pattern of X inactivation seen in cells from a variety of tissues. Linkage analysis has localized the ATR-X locus to an interval of approximately 11 cM between the loci DXS106 and DXYS1X (Xq12-q21.31), with a peak LOD score of 5.4 (recombination fraction of 0) at DCS72. These findings provide the basis for genetic counseling, assessment of carrier risk, and prenatal diagnosis of the ATR-X syndrome. Furthermore, they represent an important step in developing strategies to understand how the mutant ATR-X allele causes mental handicap, dysmorphism, and down-regulation of the [alpha]-globin genes. 54 refs., 6 figs., 4 tabs.

  4. Plasminogen activator inhibitor type 1 gene is located at region q21. 3-q22 of chromosome 7 and genetically linked with cystic fibrosis

    SciTech Connect

    Klinger, K.W.; Winqvist, R.; Riccio, A.; Andreasen, P.A.; Sartorio, R.; Nielsen, L.S.; Stuart, N.; Stanislovitis, P.; Watkins, P.; Douglas, R.

    1987-12-01

    The regional chromosomal location of the human gene for plasminogen activator inhibitor type 1 (PAI1) was determined by three independent methods of gene mapping. PAI1 was localized first to 7cen-q32 and then to 7q21.3-q22 by Southern blot hybridization analysis of a panel of human and mouse somatic cell hybrids with a PAI1 cDNA probe and in situ hybridization, respectively. The authors frequent HindIII restriction fragment length polymorphism (RFLP) of the PAI1 gene with an information content of 0.369. In family studies using this polymorphism, genetic linkage was found between PAI1 and the loci for erythropoietin (EPO), paraoxonase (PON), the met protooncogene (MET), and cystic fibrosis (CF), all previously assigned to the middle part of the long arm of chromosome 7. The linkage with EPO was closest with an estimated genetic distance of 3 centimorgans, whereas that to CF was 20 centimorgans. A three-point genetic linkage analysis and data from previous studies showed that the most likely order of these loci is EPO, PAI1, PON, (MET, CF), with PAI1 being located centromeric to CF. The PAI1 RFLP may prove to be valuable in ordering genetic markers in the CF-linkage group and may also be valuable in genetic analysis of plasminogen activation-related diseases, such as certain thromboembolic disorders and cancer.

  5. Genomic Comparison of Translocating and Non-Translocating Escherichia coli

    PubMed Central

    Bachmann, Nathan L.; Katouli, Mohammad; Polkinghorne, Adam

    2015-01-01

    Translocation of E. coli across the gut epithelium can result in fatal sepsis in post-surgical patients. In vitro and in vivo experiments have identified the existence of a novel pathotype of translocating E. coli (TEC) that employs an unknown mechanism for translocating across epithelial cells to the mesenteric lymph nodes and the blood stream in both humans and animal models. In this study the genomes of four TEC strains isolated from the mesenteric lymph nodes of a fatal case of hospitalised patient (HMLN-1), blood of pigs after experimental shock (PC-1) and after non-lethal haemorrhage in rats (KIC-1 and KIC-2) were sequenced in order to identify the genes associated with their adhesion and/or translocation. To facilitate the comparison, the genomes of a non-adhering, non-translocating E. coli (46–4) and adhering but non-translocating E. coli (73–89) were also sequenced and compared. Whole genome comparison revealed that three (HMLN-1, PC-1 and KIC-2) of the four TEC strains carried a genomic island that encodes a Type 6 Secretion System that may contribute to adhesion of the bacteria to gut epithelial cells. The human TEC strain HMLN-1 also carried the invasion ibeA gene, which was absent in the animal TEC strains and is likely to be associated with host-specific translocation. Phylogenetic analysis revealed that the four TEC strains were distributed amongst three distinct E. coli phylogroups, which was supported by the presence of phylogroup specific fimbriae gene clusters. The genomic comparison has identified potential genes that can be targeted with knock-out experiments to further characterise the mechanisms of E. coli translocation. PMID:26317913

  6. t(15;21) translocations leading to the concurrent downregulation of RUNX1 and its transcription factor partner genes SIN3A and TCF12 in myeloid disorders.

    PubMed

    L'Abbate, Alberto; Tolomeo, Doron; De Astis, Francesca; Lonoce, Angelo; Lo Cunsolo, Crocifissa; Mühlematter, Dominique; Schoumans, Jacqueline; Vandenberghe, Peter; Van Hoof, Achilles; Palumbo, Orazio; Carella, Massimo; Mazza, Tommaso; Storlazzi, Clelia Tiziana

    2015-01-01

    Through a combined approach integrating RNA-Seq, SNP-array, FISH and PCR techniques, we identified two novel t(15;21) translocations leading to the inactivation of RUNX1 and its partners SIN3A and TCF12. One is a complex t(15;21)(q24;q22), with both breakpoints mapped at the nucleotide level, joining RUNX1 to SIN3A and UBL7-AS1 in a patient with myelodysplasia. The other is a recurrent t(15;21)(q21;q22), juxtaposing RUNX1 and TCF12, with an opposite transcriptional orientation, in three myeloid leukemia cases. Since our transcriptome analysis indicated a significant number of differentially expressed genes associated with both translocations, we speculate an important pathogenetic role for these alterations involving RUNX1. PMID:26671595

  7. Abdominal radiation causes bacterial translocation

    SciTech Connect

    Guzman-Stein, G.; Bonsack, M.; Liberty, J.; Delaney, J.P.

    1989-02-01

    The purpose of this study was to determine if a single dose of radiation to the rat abdomen leads to bacterial translocation into the mesenteric lymph nodes (MLN). A second issue addressed was whether translocation correlates with anatomic damage to the mucosa. The radiated group (1100 cGy) which received anesthesia also was compared with a control group and a third group which received anesthesia alone but no abdominal radiation. Abdominal radiation lead to 100% positive cultures of MLN between 12 hr and 4 days postradiation. Bacterial translocation was almost nonexistent in the control and anesthesia group. Signs of inflammation and ulceration of the intestinal mucosa were not seen until Day 3 postradiation. Mucosal damage was maximal by Day 4. Bacterial translocation onto the MLN after a single dose of abdominal radiation was not apparently dependent on anatomical, histologic damage of the mucosa.

  8. Structural insights into ribosome translocation.

    PubMed

    Ling, Clarence; Ermolenko, Dmitri N

    2016-09-01

    During protein synthesis, tRNA and mRNA are translocated from the A to P to E sites of the ribosome thus enabling the ribosome to translate one codon of mRNA after the other. Ribosome translocation along mRNA is induced by the universally conserved ribosome GTPase, elongation factor G (EF-G) in bacteria and elongation factor 2 (EF-2) in eukaryotes. Recent structural and single-molecule studies revealed that tRNA and mRNA translocation within the ribosome is accompanied by cyclic forward and reverse rotations between the large and small ribosomal subunits parallel to the plane of the intersubunit interface. In addition, during ribosome translocation, the 'head' domain of small ribosomal subunit undergoes forward- and back-swiveling motions relative to the rest of the small ribosomal subunit around the axis that is orthogonal to the axis of intersubunit rotation. tRNA/mRNA translocation is also coupled to the docking of domain IV of EF-G into the A site of the small ribosomal subunit that converts the thermally driven motions of the ribosome and tRNA into the forward translocation of tRNA/mRNA inside the ribosome. Despite recent and enormous progress made in the understanding of the molecular mechanism of ribosome translocation, the sequence of structural rearrangements of the ribosome, EF-G and tRNA during translocation is still not fully established and awaits further investigation. WIREs RNA 2016, 7:620-636. doi: 10.1002/wrna.1354 For further resources related to this article, please visit the WIREs website. PMID:27117863

  9. Breakpoint heterogeneity in (2;3)(p15-23;q26) translocations involving EVI1 in myeloid hemopathies.

    PubMed

    De Braekeleer, Marc; Guéganic, Nadia; Tous, Corine; Le Bris, Marie-Josée; Basinko, Audrey; Morel, Frédéric; Douet-Guilbert, Nathalie

    2015-02-01

    Several chromosomal rearrangements involving band 3q26 are known to induce EVI1 overexpression. They include inv(3)(q21q26), t(3;3)(q21;q26), t(3;21)(q26;q22) and t(3;12)(q26;p13). Translocations involving the short arm of chromosome 2 and 3q26 have been reported in more than 50 patients with myeloid disorders. However, although the breakpoints on 2p are scattered over a long segment, their distribution had only been analyzed in 9 patients. We performed fluorescent in situ hybridization with a library of BAC (Bacterial Artificial Chromosome) clones in 4 patients with t(2;3)(p15-23;q26). Our results combined with those of the 9 previously reported patients showed scattering of the breakpoints in 2 regions. A 1.08Mb region in band 2p21 encompassing the MTA3, ZFP36L2 and THADA genes was documented in 5 patients. A second region of 1.83Mb in band 2p16.1 was identified in 8 patients. Four patients showed clustering around the BCL11A gene and the remaining 4 around a long intergenic non-coding RNA, FLJ30838. These regions are characterized by the presence of regulatory sequences (CpG islands and promoters) that could be instrumental in EVI1 overexpression. PMID:25486926

  10. Isolation of a gene (DLG3) encoding a second member of the discs-large family on chromosome 17q12-q21

    SciTech Connect

    Smith, S.A.; Holik, P.; Stevens, J.

    1996-01-15

    The discs-large family is a collection of proteins that have a common structural organization and are thought to be involved in signal transduction and mediating protein-protein interactions at the cytoplasmic surface of the cell membrane. The defining member of this group of proteins is the gene product of the Drosophila lethal (1) discs large (dlg) 1 locus, which was originally identified by the analysis of recessive lethal mutants. Germline mutations in dlg result in loss of apical-basolateral polarity, disruption of normal cell-cell adhesion, and neoplastic overgrowth of the imaginal disc epithelium. We have isolated and characterized a novel human gene, DLG3, that encodes a new member of the discs-large family of proteins. The putative DLG3 gene product has a molecular weight of 66 kDa and contains a discs-large homologous region, an src oncogene homology motif 3, and a domain with homology to guanylate kinase. The DLG3 gene is located on chromosome 17, in the same segment, 17q12-q21, as the related gene, DLG2. The products of the DLG2 and DLG3 genes show 36% identity and 58% similarity to each other, and both show nearly 60% sequence similarity to p55, an erythroid phosphoprotein that is a component of the red cell membrane. We suggest that p55, DLG2, and DLG3 are closely related members of a gene family, whose protein products have a common structural organization and probably a similar function. 25 refs., 3 figs.

  11. Quantitative analysis of methylation status at 11p15 and 7q21 for the genetic diagnosis of Beckwith-Wiedemann syndrome and Silver-Russell syndrome.

    PubMed

    Lee, Beom Hee; Kim, Gu-Hwan; Oh, Tae Jeong; Kim, Joo Hyun; Lee, Jin-Joo; Choi, Seung Hoon; Lee, Joo Yeon; Kim, Jae-Min; Choi, In Hee; Kim, Yoo-Mi; Choi, Jin-Ho; Yoo, Han-Wook

    2013-09-01

    Methylation-specific (MS) multiplex ligation-dependent probe amplification (MLPA) at two differentially methylated regions (DMRs) at chromosome 11p15, H19-DMR and LIT1-DMR, and microsatellite analysis for uniparental disomy (UPD) at chromosome 7 or 11, have been recommended for the genetic diagnosis of the Beckwith-Wiedemann syndrome (BWS) and the Silver-Russell syndrome (SRS). In this study, the efficacy of the MS pyrosequencing method at H19-DMR and LIT1-DMR at 11p15 and SGCE-DMR at 7q21 was evaluated for the genetic diagnosis of BWS (n=18) and SRS (n=20) patients. Epigenetic alterations or UPD were detected in 83% of BWS and 50% of SRS individuals by MS-MLPA, but the detection rate increased to 95% of BWS and 70% of SRS by MS pyrosequencing. Thirteen BWS patients (72%) harbored loss-of-methylation (LOM) at LIT1-DMR and two patients (11%) harbored gain-of-methylation (GOM) at H19-DMR, whereas two patients (11%) had both LOM at LIT1-DMR and GOM at H19-DMR, reflecting paternal UPD 11. Thirteen SRS patients (65%) harbored LOM at H19-DMR, whereas one patient (5%) had GOM at SGCE-DMR, reflecting maternal UPD 7. Birth anthropometric profiles were significantly correlated to methylation scores at either H19-DMR or LIT1-DMR. In conclusion, MS pyrosequencing enhanced the detection rate of molecular defects in BWS and SRS. Moreover, it indicates that methylation status at 11p15.5 might have an important role in fetal growth. PMID:23803580

  12. Fine-Mapping of 18q21.1 Locus Identifies Single Nucleotide Polymorphisms Associated with Nonsyndromic Cleft Lip with or without Cleft Palate

    PubMed Central

    Mitra, Amit K.; Stessman, Holly A. F.; Schaefer, Robert J.; Wang, Wen; Myers, Chad L.; Van Ness, Brian G.; Beiraghi, Soraya

    2016-01-01

    Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common congenital birth defects. NSCL/P is a complex multifactorial disease caused by interactions between multiple environmental and genetic factors. However, the causal single nucleotide polymorphism (SNP) signature profile underlying the risk of familial NSCL/P still remains unknown. We previously reported a 5.7-Mb genomic region on chromosome 18q21.1 locus that potentially contributes to autosomal dominant, low-penetrance inheritance of NSCL/P. In the current study, we performed exome sequencing on 12 familial genomes (six affected individuals, two obligate carriers, and four seemingly unaffected individuals) of a six-generation family to identify candidate SNPs associated with NSCL/P risk. Subsequently, targeted bidirectional DNA re-sequencing of polymerase chain reaction (PCR)-amplified high-risk regions of MYO5B gene and sequenom iPLEX genotpying of 29 candidate SNPs were performed on a larger set of 33 members of this NSCL/P family (10 affected + 4 obligate carriers + 19 unaffected relatives) to find SNPs significantly associated with NSCL/P trait. SNP vs. NSCL/P association analysis showed the MYO5B SNP rs183559995 GA genotype had an odds ratio of 18.09 (95% Confidence Interval = 1.86–176.34; gender-adjusted P = 0.0019) compared to the reference GG genotype. Additionally, the following SNPs were also found significantly associated with NSCL/P risk: rs1450425 (LOXHD1), rs6507992 (SKA1), rs78950893 (SMAD7), rs8097060, rs17713847 (SCARNA17), rs6507872 (CTIF), rs8091995 (CTIF), and rs17715416 (MYO5B). We could thus identify mutations in several genes as key candidate SNPs associated with the risk of NSCL/P in this large multi-generation family. PMID:27242896

  13. Fine-Mapping of 18q21.1 Locus Identifies Single Nucleotide Polymorphisms Associated with Nonsyndromic Cleft Lip with or without Cleft Palate.

    PubMed

    Mitra, Amit K; Stessman, Holly A F; Schaefer, Robert J; Wang, Wen; Myers, Chad L; Van Ness, Brian G; Beiraghi, Soraya

    2016-01-01

    Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common congenital birth defects. NSCL/P is a complex multifactorial disease caused by interactions between multiple environmental and genetic factors. However, the causal single nucleotide polymorphism (SNP) signature profile underlying the risk of familial NSCL/P still remains unknown. We previously reported a 5.7-Mb genomic region on chromosome 18q21.1 locus that potentially contributes to autosomal dominant, low-penetrance inheritance of NSCL/P. In the current study, we performed exome sequencing on 12 familial genomes (six affected individuals, two obligate carriers, and four seemingly unaffected individuals) of a six-generation family to identify candidate SNPs associated with NSCL/P risk. Subsequently, targeted bidirectional DNA re-sequencing of polymerase chain reaction (PCR)-amplified high-risk regions of MYO5B gene and sequenom iPLEX genotpying of 29 candidate SNPs were performed on a larger set of 33 members of this NSCL/P family (10 affected + 4 obligate carriers + 19 unaffected relatives) to find SNPs significantly associated with NSCL/P trait. SNP vs. NSCL/P association analysis showed the MYO5B SNP rs183559995 GA genotype had an odds ratio of 18.09 (95% Confidence Interval = 1.86-176.34; gender-adjusted P = 0.0019) compared to the reference GG genotype. Additionally, the following SNPs were also found significantly associated with NSCL/P risk: rs1450425 (LOXHD1), rs6507992 (SKA1), rs78950893 (SMAD7), rs8097060, rs17713847 (SCARNA17), rs6507872 (CTIF), rs8091995 (CTIF), and rs17715416 (MYO5B). We could thus identify mutations in several genes as key candidate SNPs associated with the risk of NSCL/P in this large multi-generation family. PMID:27242896

  14. Paracentric inversion of chromosome 7 (46,XX,inv(7)(q21.2q22)) in a newborn with hypoplastic left heart syndrome

    SciTech Connect

    Kuforjii, T.A.; Pillers, D.M.; Silberbach, M.

    1994-09-01

    Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease that is uniformly fatal without surgical intervention. Fetal echocardiography allows prenatal diagnosis, but this condition may not become apparent until after the mid-second trimester. We report a term baby with severe HLHS who had an 18 week fetal ultrasound that reportedly demonstrated a normal heart. There was no family history of congenital heart disease. She was phenotypically female with no dysmorphic features. Physical examination was otherwise normal. She expired at 48 hours of age. The autopsy was noncontributory. The karyotype was 46,XX, but there was an apparently balanced paracentric inversion of the long arm of chromosome 7 (46,XX,inv(7)(q21.2q22)). The mother`s chromosome study was normal without any inversion, and the father was not available for study. Hypoplastic left heart syndrome has been associated with extracardiac anomalies and chromosomal abnormalities including 45,XO,11q-, and trisomy 18. It has also been reported in 5 members spanning 3 generations of a family with a spectrum of left heart defects suggesting an autosomal dominant pattern with high penetrance. First-degree relatives of infants with HLHS have a thirteen percent incidence of related cardiovascular malformations, a frequency higher than predicted by a multifactorial model of inheritance, suggesting that at least a portion of HLHS have a genetic basis. Karyotype analysis, including high resolution banding, may help define the etiology of this condition. Chromosome 7 has not been implicated in HLHS. This case emphasizes the need for genetic analysis, including a pedigree, of affected families. It also underscores the importance of screening by karyotype analysis to determine whether defects of the long arm of chromosome 7 are important in the pathogenesis of hypoplastic left heart syndrome.

  15. A 0.7 Mb de novo duplication at 7q21.3 including the genes DLX5 and DLX6 in a patient with split-hand/split-foot malformation.

    PubMed

    Velinov, Milen; Ahmad, Ausaf; Brown-Kipphut, Brigette; Shafiq, Mustafa; Blau, Jonathan; Cooma, Ruby; Roth, Philip; Iqbal, M Anwar

    2012-12-01

    Split-hand/split-foot malformation (SHFM1) has been reported to be caused by deletions, duplications or rearrangements involving the 7q21.3 region harboring DSS1, DLX5, and DLX6. We report on a female patient with unilateral syndactyly of the third and fourth fingers of the right hand and overgrowth and lateral deviation of the right great toe. There was a split foot malformation on the right, with absent fifth toe. The left hand was apparently normal and left foot was intact. The patient has no hearing loss. We performed conventional G-banding karyotype analysis, array comparative genomic hybridization (aCGH) and fluorescence in situ hybridization (FISH). G-banding karyotype result was normal 46,XX. However, a duplication of 719 kb (96,303,736-97,022,335; NCBI build36/hg18, March 2006) was identified at the 7q21.3 region by aCGH. The array result was also confirmed by FISH analysis. The duplicated region harbors only DLX5 and DLX6, which are known for their role in SHFM1. Additionally, FISH analysis of parental samples showed de novo origin of this abnormality in the patient. This is the first report that highlights the duplication of 719 kb at 7q21.3, harboring only DLX5 and DLX6 associated with the SHFM1 phenotype. PMID:23169702

  16. Downside risk of wildlife translocation.

    PubMed

    Chipman, R; Slate, D; Rupprecht, C; Mendoza, M

    2008-01-01

    Translocation has been used successfully by wildlife professionals to enhance or reintroduce populations of rare or extirpated wildlife, provide hunting or wildlife viewing opportunities, farm wild game, and reduce local human-wildlife conflicts. However, accidental and intentional translocations may have multiple unintended negative consequences, including increased stress and mortality of relocated animals, negative impacts on resident animals at release sites, increased conflicts with human interests, and the spread of diseases. Many wildlife professionals now question the practice of translocation, particularly in light of the need to contain or eliminate high profile, economically important wildlife diseases and because using this technique may jeopardize international wildlife disease management initiatives to control rabies in raccoons, coyotes, and foxes in North America. Incidents have been documented where specific rabies variants (Texas gray fox, canine variant in coyotes, and raccoon) have been moved well beyond their current range as a result of translocation, including the emergence of raccoon rabies in the eastern United States. Here, we review and discuss the substantial challenges of curtailing translocation in the USA, focusing on movement of animals by the public, nuisance wildlife control operators, and wildlife rehabilitators. PMID:18634483

  17. Protein translocation: what's the problem?

    PubMed Central

    Corey, Robin A.; Allen, William J.; Collinson, Ian

    2016-01-01

    We came together in Leeds to commemorate and celebrate the life and achievements of Prof. Stephen Baldwin. For many years we, together with Sheena Radford and Roman Tuma (colleagues also of the University of Leeds), have worked together on the problem of protein translocation through the essential and ubiquitous Sec system. Inspired and helped by Steve we may finally be making progress. My seminar described our latest hypothesis for the molecular mechanism of protein translocation, supported by results collected in Bristol and Leeds on the tractable bacterial secretion process–commonly known as the Sec system; work that will be published elsewhere. Below is a description of the alternative and contested models for protein translocation that we all have been contemplating for many years. This review will consider their pros and cons. PMID:27284038

  18. Protein translocation: what's the problem?

    PubMed

    Corey, Robin A; Allen, William J; Collinson, Ian

    2016-06-15

    We came together in Leeds to commemorate and celebrate the life and achievements of Prof. Stephen Baldwin. For many years we, together with Sheena Radford and Roman Tuma (colleagues also of the University of Leeds), have worked together on the problem of protein translocation through the essential and ubiquitous Sec system. Inspired and helped by Steve we may finally be making progress. My seminar described our latest hypothesis for the molecular mechanism of protein translocation, supported by results collected in Bristol and Leeds on the tractable bacterial secretion process-commonly known as the Sec system; work that will be published elsewhere. Below is a description of the alternative and contested models for protein translocation that we all have been contemplating for many years. This review will consider their pros and cons. PMID:27284038

  19. The mechanics of ribosomal translocation.

    PubMed

    Achenbach, John; Nierhaus, Knud H

    2015-07-01

    The ribosome translates the sequence of codons of an mRNA into the corresponding sequence of amino acids as it moves along the mRNA with a codon-step width of about 10 Å. The movement of the million-dalton complex ribosome is triggered by the universal elongation factor G (EF2 in archaea and eukaryotes) and is termed translocation. Unraveling the molecular details of translocation is one of the most challenging tasks of current ribosome research. In the last two years, enormous progress has been obtained by highly-resolved X-ray and cryo-electron microscopic structures as well as by sophisticated biochemical approaches concerning the trigger and control of the movement of the tRNA2·mRNA complex inside the ribosome during translocation. This review inspects and surveys these achievements. PMID:25514765

  20. Fine mapping of juvenile primary open angle glaucoma (POAG) on 1q21-q31 and exculsion of adult-POAG from the respective region

    SciTech Connect

    Child, A.; Sarfarazi, M.; Crick, R.P.

    1994-09-01

    Juvenile POAG is an autosomal dominant eye disorder which has recently been mapped to 1q21-q24, in a region of 14-23 cM. We report here linkage analysis of 9 microsatellite repeat markers spanning this region in families from England, Scotland and Sardinia. We have observed no recombinants with D1S433 (Z=2.86) and obtained looser linkage with D1S196 ({theta}=0.03; Z=6.38), D1S431 ({theta}=0.14; Z=2.74), D1S210 ({theta}=0.06; Z=1.32), D1S452 ({theta}=0.18; Z=0.729) and D1S242 ({theta}=0.08; Z=2.29). In one family, a critical recombinant in an affected individual localizes the J-POAG locus between D1S452 and D1S242 in a 3 cM region. However, other recombinants in two normal individuals from different families suggests that J-POAG may be localized in a 1 cM distance between D1S433 and D1S431. These unaffected individuals have well passed the age-of-onset in their respective pedigrees. This result suggests that either these two recombinant individuals are gene carriers (i.e., non-penetrants) or there are more than one gene in this region causing the same disease. The possibility of the latter is less likely, since in addition to a total of 4 non-penetrant individuals in our panel, other such cases have also been reported previously. This in turn suggests that the precentage of non-penetrant cases in J-POAG may be considerably higher than it was previously appreciated. Study of 14 families with adult-onset POAG revealed no segregation with the above-mentioned linked microsatellite markers. Our findings confirm, for the first time, that adult-POAG is genetically distinct from the J-POAG. Genetic linkage study of adult families with additional STRPs is currently in progress.

  1. Variations in the FRA10AC1 Fragile Site and 15q21 Are Associated with Cerebrospinal Fluid Aβ1-42 Level

    PubMed Central

    Li, Qingqin S.; Parrado, Antonio R.; Samtani, Mahesh N.; Narayan, Vaibhav A.

    2015-01-01

    Proteolytic fragments of amyloid and post-translational modification of tau species in Cerebrospinal fluid (CSF) as well as cerebral amyloid deposition are important biomarkers for Alzheimer’s Disease. We conducted genome-wide association study to identify genetic factors influencing CSF biomarker level, cerebral amyloid deposition, and disease progression. The genome-wide association study was performed via a meta-analysis of two non-overlapping discovery sample sets to identify genetic variants other than APOE ε4 predictive of the CSF biomarker level (Aβ1–42, t-Tau, p-Tau181P, t-Tau:Aβ1–42 ratio, and p-Tau181P:Aβ1–42 ratio) in patients enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study. Loci passing a genome-wide significance threshold of P < 5 x 10−8 were followed-up for replication in an independent sample set. We also performed joint meta-analysis of both discovery sample sets together with the replication sample set. In the discovery phase, we identified variants in FRA10AC1 associated with CSF Aβ1–42 level passing the genome-wide significance threshold (directly genotyped SNV rs10509663 PFE = 1.1 x 10−9, imputed SNV rs116953792 PFE = 3.5 x 10−10), rs116953792 (Pone-sided = 0.04) achieved replication. This association became stronger in the joint meta-analysis (directly genotyped SNV rs10509663 PFE = 1.7 x 10−9, imputed SNV rs116953792 PFE = 7.6 x 10−11). Additionally, we identified locus 15q21 (imputed SNV rs1503351 PFE = 4.0 x 10−8) associated with CSF Aβ1–42 level. No other variants passed the genome-wide significance threshold for other CSF biomarkers in either the discovery sample sets or joint analysis. Gene set enrichment analyses suggested that targeted genes mediated by miR-33, miR-146, and miR-193 were enriched in various GWAS analyses. This finding is particularly important because CSF biomarkers confer disease susceptibility and may be predictive of the likelihood of disease progression in

  2. Genome-wide association study identifies 5q21 and 9p24.1 (KDM4C) loci associated with alcohol withdrawal symptoms.

    PubMed

    Wang, Ke-Sheng; Liu, Xuefeng; Zhang, Qunyuan; Wu, Long-Yang; Zeng, Min

    2012-04-01

    Several genome-wide association (GWA) studies of alcohol dependence (AD) and alcohol-related phenotypes have been conducted; however, little is known about genetic variants influencing alcohol withdrawal symptoms (AWS). We conducted the first GWA study of AWS using 461 cases of AD with AWS and 408 controls in Caucasian population in the Collaborative Study on the Genetics of Alcoholism (COGA) sample. Logistic regression analysis of AWS as a binary trait, adjusted for age and sex, was performed using PLINK. We identified 51 SNPs associated with AWS with p < 10(-4). The first best signal was rs770182 (p = 3.65 × 10(-6)) at 5q21 near EFNA5 gene which was replicated in the Australian twin-family study of 273 families (p = 0.0172). Furthermore, three SNPs (rs10975990, rs10758821 and rs1407862) within KDM4C gene at 9p24.1 showed p < 10(-4) (p = 7.15 × 10(-6), 2.79 × 10(-5) and 4.93 × 10(-5), respectively) in the COGA sample while one SNP rs12001158 within KDM4C with p = 1.97 × 10(-4) in the COGA sample was replicated in the family sample (p = 0.01). Haplotype analysis further supported the associations of single-marker analyses of KDM4C in the COGA sample. Moreover, two SNPs (rs2046593 and rs10497668) near FSIP2 at 2q32.1 with moderate associations with AWS in the COGA sample (p = 2.66 × 10(-4) and 9.48 × 10(-5), respectively) were replicated in the family sample (p = 0.0013 and 0.0162, respectively). In addition, several SNPs in GABRA1, GABRG1, and GABRG3 were associated with AWS (p < 10(-2)) in the COGA sample. In conclusion, we identified several loci associated with AWS. These findings offer the potential for new insights into the pathogenesis of AD and AWS. PMID:22072270

  3. Partners with reciprocal translocations: genetic counseling for the 'double translocation'.

    PubMed

    Cook, L; Hartsfield, J K; Vance, G H

    1998-05-01

    SV at age 2 years presented with multiple congenital anomalies including an absent left kidney, anal stenosis, vertebral abnormalities, partial sacral agenesis, microcephaly, dysmorphic facial features, growth deficiency, and developmental delay. She was found to have a complex chromosomal rearrangement derived from balanced translocations in each parent. PMID:9660061

  4. Bacterial translocation in experimental uremia.

    PubMed

    de Almeida Duarte, Joãn Bosco; de Aguilar-Nascimento, José Eduardo; Nascimento, Mariana; Nochi, Rubens Jardim

    2004-08-01

    The aim of this study was to investigate whether or not experimental uremia would induce bacterial translocation. Forty male Wistar rats were randomized into two groups: uremic (n = 20) and control (n = 20). Under anesthesia, the upper and lower left renal poles and the marginal lateral parenchyma were excised in uremic group. Seven days later, in a second operation, the liver, spleen and the mesenteric lymph nodes (MLN) were excised and cultured. Blood samples were sent for biochemical analysis (BUN, creatinine, sodium and potassium) and cultured. Specimens of the jejunum (1 cm below the Treitz angle) and ileum (1 cm above the ileocecal valve) were collected and sent for histological examination and scored for the degree of inflammation of the mucosa using a classification proposed by Chiu et al. in 1970. Uremic rats presented higher BUN, creatinine and potassium than controls. Bacterial translocation was more frequent in uremic than in control animals (8/20 (40%) vs. 1/20 (5%); p = 0.02). Translocation in uremic rats was observed mainly at the MLN (all eight cases). Both at the jejunum (uremic = 3 [0-5] vs. control = 2 [0-4]; p = 0.04) and the ileum (uremic - 2 [0-5] vs. control = 0 [0-3]; p = 0.01), inflammation score was higher in uremic rats than in controls. The intestinal mucosa barrier is impaired and bacterial translocation occurs in experimental uremia. PMID:15497213

  5. Novel 6p rearrangements and recurrent translocation breakpoints in retinoblastoma cell lines identified by spectral karyotyping and mBAND analyses.

    PubMed

    Paderova, Jana; Orlic-Milacic, Marija; Yoshimoto, Maisa; da Cunha Santos, Gilda; Gallie, Brenda; Squire, Jeremy A

    2007-12-01

    Gain of the short arm of chromosome 6, usually through isochromosome 6p formation, is present in approximately 50% of retinoblastoma tumors. The minimal region of gain maps to chromosome band 6p22. Two genes, DEK and E2F3, are implicated as candidate oncogenes. However, chromosomal translocations have been overlooked as a potential mechanism of activation of oncogenes at 6p22 in retinoblastoma. Here, we report combined spectral karyotyping), 4',6-diamidino-2-phenylindole banding, mBAND, and locus-specific fluorescence in situ hybridization analyses of four retinoblastoma cell lines, RB1021, RB247c, RB383, and Y79. In RB1021 and RB247c, 6p undergoes structural rearrangements involving a common translocation breakpoint at 6p22. These data imply that 6p translocations may represent another mechanism of activation of 6p oncogene(s) in a subset of retinoblastomas, besides the copy number increase. In addition to 6p22, other recurrent translocation breakpoints identified in this study are 4p16, 11p15, 17q21.3, and 20q13. Common regions of gain map to chromosomal arms 1q, 2p, 6p, 17q, and 21q. PMID:18036396

  6. Paternal adjacent I segregation of an insertional translocation results in partial 4q monosomy and 4q trisomy in two siblings

    SciTech Connect

    Hegman, K.; Spikes, A.S.; Orr-Urteger, A.

    1994-09-01

    A genetic evaluation was requested for a 6 week old infant with multiple congenital malformations including mild craniofacial anomalies, truncal hypotonia, hypospadias and a VSD. Blood obtained for chromosome analysis revealed an abnormal chromosome 4. Paternal chromosome analysis showed a 46,XY,inv ins(3;4)(p21.32;q25q21.2),inv(4)(p15.3q21.3) karyotype. Therefore, the proband`s chromosome 4 was the unbalanced product of this insertional translocation from the father resulting in partial monosomy 4q. Additionally, the derivative 4 had a pericentric inversion which was also seen in the father`s chromosome 4. During genetic counseling, the proband`s 2 year-old brother was evaluated. Although he was not felt to be dysmorphic, he was described as having impulsive behavior. Chromosome analysis on this child revealed 46,XY,der(3)inv ins(3;4)(p21.32;q25q21.2)pat. This karyotype results in partial trisomy 4q. FISH using two-color {open_quotes}painting{close_quotes} probes for chromosomes 3 and 4 confirmed the G-banded interpretation in this family. The segregation seen in this family was due to adjacent I segregation with both reciprocal products observed in the two children. Few patients with partial 4q trisomy or partial 4q monosomy have been described in the literature. This family revealed both possible unbalanced products from adjacent I segregation with partial 4q monosomy showing multiple congenital anomalies and partial 4q trisomy showing very few phenotypic abnormalities.

  7. Activation of the p53 pathway by the MDM2 inhibitor nutlin-3a overcomes BCL2 overexpression in a preclinical model of diffuse large B-cell lymphoma associated with t(14;18)(q32;q21)

    PubMed Central

    Drakos, E; Singh, R R; Rassidakis, G Z; Schlette, E; Li, J; Claret, F X; Ford, R J; Vega, F; Medeiros, L J

    2011-01-01

    p53 is frequently wild type (wt) in diffuse large B-cell lymphoma (DLBCL) associated with t(14;18)(q32;q21) that overexpresses BCL2. Nutlin-3a is a small molecule that activates the p53 pathway by disrupting p53–MDM2 interaction. We show that nutlin-3a activates p53 in DLBCL cells associated with t(14;18)(q32;q21), BCL2 overexpression and wt p53, resulting in cell cycle arrest and apoptosis. Nutlin-3a treatment had similar effects on DLBCL cells of activated B-cell phenotype with wt p53. Cell cycle arrest was associated with upregulation of p21. Nutlin-3a-induced apoptosis was accompanied by BAX and PUMA upregulation, BCL-XL downregulation, serine-70 dephosphorylation of BCL2, direct binding of BCL2 by p53, caspase-9 upregulation and caspase-3 cleavage. Cell death was reduced when p53-dependent transactivation activity was inhibited by pifithrin-α (PFT-α), or PFT-μ inhibited direct p53 targeting of mitochondria. Nutlin-3a sensitized activation of the intrinsic apoptotic pathway by BCL2 inhibitors in t(14;18)-positive DLBCL cells with wt p53, and enhanced doxorubicin cytotoxicity against t(14;18)-positive DLBCL cells with wt or mutant p53, the latter in part via p73 upregulation. Nutlin-3a treatment in a xenograft animal lymphoma model inhibited growth of t(14;18)-positive DLBCL tumors, associated with increased apoptosis and decreased proliferation. These data suggest that disruption of the p53–MDM2 interaction by nutlin-3a offers a novel therapeutic approach for DLBCL associated with t(14;18)(q32;q21). PMID:21394100

  8. Specific chromosomal IG translocations have different prognoses in chronic lymphocytic leukemia

    PubMed Central

    Nguyen-Khac, Florence; Chapiro, Elise; Lesty, Claude; Grelier, Aurore; Luquet, Isabelle; Radford-Weiss, Isabelle; Lefebvre, Christine; Fert-Ferrer, Sandra; Callet-Bauchu, Evelyne; Lippert, Eric; Raggueneau, Victoria; Michaux, Lucienne; Barin, Carole; Collonge-Rame, Marie-Agnes; Mugneret, Francine; Eclache, Virginie; Taviaux, Sylvie; Dastugue, Nicole; Richebourg, Steven; Struski, Stéphanie; Talmant, Pascaline; Baranger, Laurence; Gachard, Nathalie; Gervais, Carine; Quilichini, Benoit; Settegrana, Catherine; Maloum, Karim; Davi, Frederic; Merle-Béral, Hélène

    2011-01-01

    Background Chromosomal translocations are usually analyzed as a single entity, and are associated with a poor outcome in chronic lymphocytic leukemia. Translocations involving immunoglobulin genes are recurrent, but uncommon (<5%), and their individual prognosis is not clear. The two most frequent partners are BCL2 (18q21) and BCL3 (19q13). Designs and methods Herein, 75 cases are reported of chronic lymphocytic leukemia and t(14;18) (BCL2-CLLs). Our series benefits from morphological, immunological and cytogenetical reviews. The IGHV status analyses were performed by referring laboratories. Comparison was made with our previously published series of chronic lymphocytic leukemia patients with t(14;19) (BCL3-CLLs, n=29). Results Compared with BCL3-CLLs, lymphocytosis was lower in BCL2-CLLs (p<0.008), and splenomegaly was less frequent (p<0.0001). There were more “typical” morphologies (p<0.005) and Matutes scores >4 (p<0.001) in the BCL2-CLLs group, and less CD38 expression (p<0.04). More variant BCL2-translocations were observed (t(18;22), n=11; 2t(2;18), n=2; p<0.02), and BCL2-translocation was frequently single (p<0.002). Complex karyotypes (p<0.02), trisomy 12 (p<0.03), 6q deletion (p<0.002) and TP53 deletion (p<0.02) were less frequent in BCL2-CLLs, whereas 13q deletion was more frequent (p<0.005). The IGHV gene was frequently mutated in BCL2-CLLs (p<0.0001). Treatment-free survival was longer in BCL2-CLLs (p<0.0001). Conclusions BCL2-CLL.S express CD5 and lack expression of CD38, and have a Matutes score ≥4, frequent trisomy 12, no ATM and 6q deletions, and a mutated IGHV status. Compared to BCL3-CLLs, BCL2-CLLs are much less aggressive; indicating that identifying individual translocations and cytogenetic partners would allow improved patient stratification. PMID:22432063

  9. 7q21.3 Deletion involving enhancer sequences within the gene DYNC1I1 presents with intellectual disability and split hand-split foot malformation with decreased penetrance.

    PubMed

    Delgado, Sara; Velinov, Milen

    2015-01-01

    Split hand-split food malformation (SHFM) is a congenital defect of limb development that involves the central rays of the autopod and presents with median clefts of the hands and feet. It often includes syndactyly and aplasia/hypoplasia of the phalanges. SHFM is a genetic condition with high genetic heterogeneity, with at least 6 associated chromosomal loci. A locus in chromosomal region 7q21.3, associated with SHFM is referred to as SHFM1. Genes considered to be associated with SHFM1 are DLX5 and DLX6. These two genes participate in the Wnt pathway that has a role in limb development. The gene DYNC1I1, located proximally (centromeric) to the SHFM1 locus was recently reported to include enhancer sequences involved in limb development in its exons 15 and 17. These sequences were shown to cis-regulate the function of the adjacent SHFM associated genes. We report a family, in which the father and three of his sons carry an approximately 1 Mb deletion in this chromosomal region, arr[hg19]7q21.3(94,769,383-95,801,045)x1. The deleted region is located proximally (centromerically) adjacent to the SHFM region at 7q21.3. It does not include the SHFM candidate genes DLX5 and DLX6, but includes the enhancer sequences within DYNC111 and six other genes centromeric to DYNC1I1. All deletion carriers have various degrees of intellectual disability while two of them have SHFM. This family is the eighth reported family where a chromosome 7q21.3 deletion co-segregating with SHFM involves the enhancer regions within gene DYNC111, but does not involve the genes DLX5 and DLX 6. This is also the third family where decreased penetrance of enhancer-associated SHFM is demonstrated. Intellectual disability was not observed in the previously reported families and may be associated with deficiency of one or more of the 6 genes included in the reported deletion centromeric to DYNC1I1. PMID:26075025

  10. Suitability of amphibians and reptiles for translocation.

    PubMed

    Germano, Jennifer M; Bishop, Phillip J

    2009-02-01

    Translocations are important tools in the field of conservation. Despite increased use over the last few decades, the appropriateness of translocations for amphibians and reptiles has been debated widely over the past 20 years. To provide a comprehensive evaluation of the suitability of amphibians and reptiles for translocation, we reviewed the results of amphibian and reptile translocation projects published between 1991 and 2006. The success rate of amphibian and reptile translocations reported over this period was twice that reported in an earlier review in 1991. Success and failure rates were independent of the taxonomic class (Amphibia or Reptilia) released. Reptile translocations driven by human-wildlife conflict mitigation had a higher failure rate than those motivated by conservation, and more recent projects of reptile translocations had unknown outcomes. The outcomes of amphibian translocations were significantly related to the number of animals released, with projects releasing over 1000 individuals being most successful. The most common reported causes of translocation failure were homing and migration of introduced individuals out of release sites and poor habitat. The increased success of amphibian and reptile translocations reviewed in this study compared with the 1991 review is encouraging for future conservation projects. Nevertheless, more preparation, monitoring, reporting of results, and experimental testing of techniques and reintroduction questions need to occur to improve translocations of amphibians and reptiles as a whole. PMID:19143783

  11. Linkage map construction involving a reciprocal translocation.

    PubMed

    Farré, A; Benito, I Lacasa; Cistué, L; de Jong, J H; Romagosa, I; Jansen, J

    2011-03-01

    This paper is concerned with a novel statistical-genetic approach for the construction of linkage maps in populations obtained from reciprocal translocation heterozygotes of barley (Hordeum vulgare L.). Using standard linkage analysis, translocations usually lead to 'pseudo-linkage': the mixing up of markers from the chromosomes involved in the translocation into a single linkage group. Close to the translocation breakpoints recombination is severely suppressed and, as a consequence, ordering markers in those regions is not feasible. The novel strategy presented in this paper is based on (1) disentangling the "pseudo-linkage" using principal coordinate analysis, (2) separating individuals into translocated types and normal types and (3) separating markers into those close to and those more distant from the translocation breakpoints. The methods make use of a consensus map of the species involved. The final product consists of integrated linkage maps of the distal parts of the chromosomes involved in the translocation. PMID:21153624

  12. Core binding factor beta (CBFB) haploinsufficiency due to an interstitial deletion at 16q21q22 resulting in delayed cranial ossification, cleft palate, congenital heart anomalies, and feeding difficulties but favorable outcome.

    PubMed

    Khan, Aneal; Hyde, R Katherine; Dutra, Amalia; Mohide, Patrick; Liu, Paul

    2006-11-01

    The core binding factor beta gene (CBFB), essential to bone morphogenesis, is located at 16q22.1. Homozygous deficiency of CBFB leads to ossification defects in mice. CBFB forms a heterodimer with RUNX2 (CBFA1) during embryonic bone development. RUNX2 mutations lead to cleidocranial dysplasia in humans. We describe an infant boy with an interstitial deletion of 16q21q22, delayed skull ossification, cleft palate, and heart anomalies who had a difficult course in infancy but eventually improved and is healthy. He was found to have CBFB haploinsufficiency, but did not have mutations in RUNX2. We suggest that 16q21q22 deletion be considered when there are antenatal or postnatal findings of enlarged cranial sutures with or without cleft palate. The finding of CBFB haploinsufficiency in our case and the similarity of cranial ossification defects with a mouse model of CBFB deletion suggest a role for CBFB in cranial bone development in humans. PMID:17022082

  13. THRA1 and D17S183 flank an interval of < 4 cM for the breast-ovarian cancer gene (BRCA1) on chromosome 17q21.

    PubMed Central

    Bowcock, A M; Anderson, L A; Friedman, L S; Black, D M; Osborne-Lawrence, S; Rowell, S E; Hall, J M; Solomon, E; King, M C

    1993-01-01

    In order to pinpoint the locale of the gene for early-onset familial breast and ovarian cancer (BRCA1), polymorphisms were developed within the locus for thyroid hormone receptor alpha (THRA1) and for several anonymous sequences at chromosome 17q12-q21. The THRA1 polymorphism is a dinucleotide repeat with 10 alleles and heterozygosity.79. Gene mapping in extended families with inherited, early-onset breast and ovarian cancer indicates that BRCA1 is distal to THRA1 and proximal to D17S183 (SCG43), an interval of < 4 cM. This locale excludes HER2, THRA1, WNT3, HOX2, NGFR, PHB, COLIA1, NME1, and NME2 as candidates for BRCA1 but does not exclude RARA or EDH17B. Resolving the remaining recombination events in these families by new polymorphisms in the THRA1-D17S183 interval will facilitate positional cloning of the breast-ovarian cancer gene on chromosome 17q12-q21. PMID:8460637

  14. THRA1 and D17S183 flank an interval of <4 cM for the breast-ovarian cancer gene (BRCA1) on chromosome 17q21

    SciTech Connect

    Bowcock, A.M.; Osborne-Lawrence, S. ); Anderson, L.A.; Friedman, L.S.; Rowell, S.E.; Hall, J.M.; King, M.C. ); Black, D.M.; Solomon, E. )

    1993-04-01

    In order to pinpoint the locale of the gene for early-onset familial breast and ovarian cancer (BRCA1), polymorphisms were developed within the locus for thyroid hormone receptor alpha (THRA1) and for several anonymous sequences at chromosome 17q12-q21. The THRA1 polymorphism is a dinucleotide repeat with 10 alleles and heterozygosity .79. Gene mapping in extended families with inherited, early-onset breast and ovarian cancer indicates that BRCA1 is distal to THRA1 and proximal to D17S183 (SCG43), an interval of <4 cM. This locale excludes HER2, THRA1, WNT3, HOX2, NGFR, PHB, COLIA1, NME1, and NME2 as candidates for BRCA1 but does not exclude RARA or EDH17B. Resolving the remaining recombination events in these families by new polymorphisms in the THRA1-D17S183 interval will facilitate positional cloning of the breast-ovarian cancer gene on chromosome 17q12-q21. 16 refs., 3 figs., 1 tab.

  15. Problems with mitigation translocation of herpetofauna.

    PubMed

    Sullivan, Brian K; Nowak, Erika M; Kwiatkowski, Matthew A

    2015-02-01

    Mitigation translocation of nuisance animals is a commonly used management practice aimed at resolution of human-animal conflict by removal and release of an individual animal. Long considered a reasonable undertaking, especially by the general public, it is now known that translocated subjects are negatively affected by the practice. Mitigation translocation is typically undertaken with individual adult organisms and has a much lower success rate than the more widely practiced conservation translocation of threatened and endangered species. Nonetheless, the public and many conservation practitioners believe that because population-level conservation translocations have been successful that mitigation translocation can be satisfactorily applied to a wide variety of human-wildlife conflict situations. We reviewed mitigation translocations of reptiles, including our own work with 3 long-lived species (Gila monsters [Heloderma suspectum], Sonoran desert tortoises [Gopherus morafkai], and western diamond-backed rattlesnakes [Crotalus atrox]). Overall, mitigation translocation had a low success rate when judged either by effects on individuals (in all studies reviewed they exhibited increased movement or increased mortality) or by the success of the resolution of the human-animal conflict (translocated individuals often returned to the capture site). Careful planning and identification of knowledge gaps are critical to increasing success rates in mitigation translocations in the face of increasing pressure to find solutions for species threatened by diverse anthropogenic factors, including climate change and exurban and energy development. PMID:25040040

  16. A unique complex translocation involving six different chromosomes in a case of childhood acute lymphoblastic leukemia with the Philadelphia chromosome and adverse prognosis.

    PubMed

    Achkar, Walid Al; Wafa, Abdulsamad; Mkrtchyan, Hasmik; Moassass, Faten; Liehr, Thomas

    2010-09-01

    Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. Approximately 84% of cases of ALL are classified as B-precursor ALL, 14% of cases are T-cell and 2% of cases are B-cell (B-)ALL. About one third of B-ALL cases show an abnormal karyotype. Combining data obtained by immunophenotyping, karyotyping and molecular cytogenetic analyses allows for a better understanding of this heterogeneous disease. This study reports an exceptional B-ALL case with a poor prognosis and unique complex chromosomal aberrations not previously observed, i.e., a translocation involving the six chromosomal regions 1q42, 4q21, 4q24, 4q35 (twice), 8q22 and 10p15.3 besides 9q34 and 22q11.2. PMID:22966383

  17. Translocation (Y;12) in lipoma.

    PubMed

    Liang, Cher-Wei; Mariño-Enríquez, Adrian; Johannessen, Catherine; Hornick, Jason L; Dal Cin, Paola

    2011-01-01

    Lipomas are the most common benign mesenchymal neoplasm in adults, and have been extensively characterized at the cytogenetic level. Chromosomal aberrations have been observed in the majority of lipomas, two-thirds of which involve chromosomal region 12q14.3. To date, structural rearrangements have been reported affecting every chromosome except chromosome Y. Here we report a case of a lipoma that shows a novel apparently balanced translocation involving chromosomes Y and 12. Fluorescence in situ hybridization using a break-apart HMGA2 in-house probe set detected a single signal on the normal chromosome 12 but not on either the derivative chromosome Y or 12, indicating a cryptic loss of 12q14.3, where HMGA2 is mapped. Immunohistochemical studies, however, revealed overexpression of HMGA2 with nuclear expression in the majority of tumor cells, whereas MDM2 and CDK4 were negative. The overexpression of HMGA2 may be caused by a cryptic chromosomal aberration affecting either the cytogenetically unaltered HMGA2 allele or HMGA2 regulators elsewhere. The current case broadens our knowledge about the translocation partners of HMGA2 in lipomas and highlights the biological complexity in regulating HMGA2 expression. PMID:21356192

  18. An apparently de novo translocation in a neonate involving chromosomes 3 and 19 [t(3:19)(p21;q13.1)

    SciTech Connect

    Shah, H.O.; Buttice, L.S.; Chester, M.

    1994-09-01

    A 7 1/2-week-old infant female was referred for cytogenetic evaluation after she developed a left inguinal hernia containing a gonadal mass. She had been born to a 25-year-old mother after approximately 31 weeks gestation. This was the couple`s first pregnancy. She was small for gestational age. Her weight was 835 g, length was 32 cm, head circumference was 26 cm at birth. She developed hypothyroidism requiring synthroid. There were no other obvious dysmorphisms. The cytogenetic findings with G-banding revealed an apparently-balanced translocation involving chromosomes 3 and 19. The patient`s karyotype revealed 46,XX,t(3;19)(q21;q13.1). Parental chromosomes were found to be normal. Because of the increased risk for developmental and other congenital problems in an individual with a {open_quotes}de novo translocation{close_quotes} (even when the rearrangement appears balanced), this infant is being followed regularly. Evaluation at 5 months of age revealed a small but thriving female infant who is alert and developmentally appropriate. She is still receiving synthroid. We are in the process of analyzing this case further using chromosome paint probes for chromosomes 3 and 19 to identify the break points more precisely. This would allow us to assess with greater accuracy if this is a {open_quotes}balanced{close_quotes} translocation.

  19. Frequent copy number gains at 1q21 and 1q32 are associated with overexpression of the ETS transcription factors ETV3 and ELF3 in breast cancer irrespective of molecular subtypes.

    PubMed

    Mesquita, Bárbara; Lopes, Paula; Rodrigues, Ana; Pereira, Deolinda; Afonso, Mariana; Leal, Conceição; Henrique, Rui; Lind, Guro E; Jerónimo, Carmen; Lothe, Ragnhild A; Teixeira, Manuel R

    2013-02-01

    Several ETS transcription factors are involved in the pathogenesis of human cancers by different mechanisms. As gene copy number gain/amplification is an alternative mechanism of oncogenic activation and 1q gain is the most common copy number change in breast carcinoma, we investigated how that genomic change impacts in the expression of the three 1q ETS family members ETV3, ELK4, and ELF3. We have first evaluated 141 breast carcinomas for genome-wide copy number changes by chromosomal CGH and showed that 1q21 and 1q32 were the two chromosome bands with most frequent genomic copy number gains. Second, we confirmed by FISH with locus-specific BAC clones that cases showing 1q gain/amplification by CGH showed copy number increase of the ETS genes ETV3 (located in 1q21~23), ELF3, and ELK4 (both in 1q32). Third, gene expression levels of the three 1q ETS genes, as well as their potential targets MYC and CRISP3, were evaluated by quantitative real-time PCR. We here show for the first time that the most common genomic copy number gains in breast cancer, 1q21 and 1q32, are associated with overexpression of the ETS transcription factors ETV3 and ELF3 (but not ELK4) at these loci irrespective of molecular subtypes. Among the three 1q ETS genes, ELF3 has a relevant role in breast carcinogenesis and is also the most likely target of the 1q copy number increase. The basal-like molecular subtype presented the worst prognosis regarding disease-specific survival, but no additional prognostic value was found for 1q copy number status or ELF3 expression. In addition, we show that there is a correlation between the expression of the oncogene MYC, irrespectively of copy number gain at its loci in 8q24, and the expression of both the transcriptional repressor ETV3 and the androgen respondent ELK4. PMID:23329352

  20. Identification of TRPC6 as a possible candidate target gene within an amplicon at 11q21-q22.2 for migratory capacity in head and neck squamous cell carcinomas

    PubMed Central

    2013-01-01

    Background Cytogenetic and gene expression analyses in head and neck squamous cell carcinomas (HNSCC) have allowed identification of genomic aberrations that may contribute to cancer pathophysiology. Nevertheless, the molecular consequences of numerous genetic alterations still remain unclear. Methods To identify novel genes implicated in HNSCC pathogenesis, we analyzed the genomic alterations present in five HNSCC-derived cell lines by array CGH, and compared high level focal gene amplifications with gene expression levels to identify genes whose expression is directly impacted by these genetic events. Next, we knocked down TRPC6, one of the most highly amplified and over-expressed genes, to characterize the biological roles of TRPC6 in carcinogenesis. Finally, real time PCR was performed to determine TRPC6 gene dosage and mRNA levels in normal mucosa and human HNSCC tissues. Results The data showed that the HNSCC-derived cell lines carry most of the recurrent genomic abnormalities previously described in primary tumors. High-level genomic amplifications were found at four chromosomal sites (11q21-q22.2, 18p11.31-p11.21, 19p13.2-p13.13, and 21q11) with associated gene expression changes in selective candidate genes suggesting that they may play an important role in the malignant behavior of HNSCC. One of the most dramatic alterations of gene transcription involved the TRPC6 gene (located at 11q21-q22.2) which has been recently implicated in tumour invasiveness. siRNA-induced knockdown of TRPC6 expression in HNSCC-derived cells dramatically inhibited HNSCC-cell invasion but did not significantly alter cell proliferation. Importantly, amplification and concomitant overexpression of TRPC6 was also found in HNSCC tumour samples. Conclusions Altogether, these data show that TRPC6 is likely to be a target for 11q21–22.2 amplification that confers enhanced invasive behavior to HNSCC cells. Therefore, TRPC6 may be a promising therapeutic target in the treatment of HNSCC

  1. Angelman syndrome and severe infections in a patient with de novo 15q11.2-q13.1 deletion and maternally inherited 2q21.3 microdeletion.

    PubMed

    Neubert, Gerda; von Au, Katja; Drossel, Katrin; Tzschach, Andreas; Horn, Denise; Nickel, Renate; Kaindl, Angela M

    2013-01-10

    Angelman syndrome is a neurodevelopmental disorder characterized by mental retardation, severe speech disorder, facial dysmorphism, secondary microcephaly, ataxia, seizures, and abnormal behaviors such as easily provoked laughter. It is most frequently caused by a de novo maternal deletion of chromosome 15q11-q13 (about 70-90%), but can also be caused by paternal uniparental disomy of chromosome 15q11-q13 (3-7%), an imprinting defect (2-4%) or in mutations in the ubiquitin protein ligase E3A gene UBE3A mostly leading to frame shift mutation. In addition, for patients with overlapping clinical features (Angelman-like syndrome), mutations in methyl-CpG binding protein 2 gene MECP2 and cyclin-dependent kinase-like 5 gene CDKL5 as well as a microdeletion of 2q23.1 including the methyl-CpG binding domain protein 5 gene MBD5 have been described. Here, we describe a patient who carries a de novo 5Mb-deletion of chromosome 15q11.2-q13.1 known to be associated with Angelman syndrome and a further, maternally inherited deletion 2q21.3 (~364kb) of unknown significance. In addition to classic features of Angelman syndrome, she presented with severe infections in the first year of life, a symptom that has not been described in patients with Angelman syndrome. The 15q11.2-q13.1 deletion contains genes critical for Prader-Willi syndrome, the Angelman syndrome causing genes UBE3A and ATP10A/C, and several non-imprinted genes: GABRB3 and GABRA5 (both encoding subunits of GABA A receptor), GOLGA6L2, HERC2 and OCA2 (associated with oculocutaneous albinism II). The deletion 2q21.3 includes exons of the genes RAB3GAP1 (associated with Warburg Micro syndrome) and ZRANB3 (not disease-associated). Despite the normal phenotype of the mother, the relevance of the 2q21.3 microdeletion for the phenotype of the patient cannot be excluded, and further case reports will need to address this point. PMID:23124039

  2. Haloarchaeal Protein Translocation via the Twin Arginine Translocation Pathway

    SciTech Connect

    Pohlschroder Mechthild

    2009-02-03

    Protein transport across hydrophobic membranes that partition cellular compartments is essential in all cells. The twin arginine translocation (Tat) pathway transports proteins across the prokaryotic cytoplasmic membranes. Distinct from the universally conserved Sec pathway, which secretes unfolded proteins, the Tat machinery is unique in that it secretes proteins in a folded conformation, making it an attractive pathway for the transport and secretion of heterologously expressed proteins that are Sec-incompatible. During the past 7 years, the DOE-supported project has focused on the characterization of the diversity of bacterial and archaeal Tat substrates as well as on the characterization of the Tat pathway of a model archaeon, Haloferax volcanii, a member of the haloarchaea. We have demonstrated that H. volcanii uses this pathway to transport most of its secretome.

  3. Phosphorus Compounds in Translocating Phloem

    PubMed Central

    Bieleski, R. L.

    1969-01-01

    Phosphate-32P was introduced into a turnip leaf, and 3 hr later, the vascular bundles were stripped from the petiole and their phosphate ester pattern was studied. The pattern did not alter along their length and was like that of other tissues. Pumpkin leaves were painted with phosphate-32P; and later, the petioles were cut, the sieve tube exudates were collected and their phosphate ester patterns were studied. Exudates collected after 10 min had a high proportion of their 32P present in Pi and nucleoside triphosphates, while exudates collected after long translocation times (4-22 hr) had a lower proportion in these, and a higher proportion in hexose monophosphates and UDP glucose. In general, the ester patterns were like those of other tissues. The results indicate that sieve tubes are metabolically active, and that Pi is the primary form in which phosphorus moves in the phloem. Images PMID:16657091

  4. DNA translocation through graphene nanopores.

    PubMed

    Merchant, Christopher A; Healy, Ken; Wanunu, Meni; Ray, Vishva; Peterman, Neil; Bartel, John; Fischbein, Michael D; Venta, Kimberly; Luo, Zhengtang; Johnson, A T Charlie; Drndić, Marija

    2010-08-11

    We report on DNA translocations through nanopores created in graphene membranes. Devices consist of 1-5 nm thick graphene membranes with electron-beam sculpted nanopores from 5 to 10 nm in diameter. Due to the thin nature of the graphene membranes, we observe larger blocked currents than for traditional solid-state nanopores. However, ionic current noise levels are several orders of magnitude larger than those for silicon nitride nanopores. These fluctuations are reduced with the atomic-layer deposition of 5 nm of titanium dioxide over the device. Unlike traditional solid-state nanopore materials that are insulating, graphene is an excellent electrical conductor. Use of graphene as a membrane material opens the door to a new class of nanopore devices in which electronic sensing and control are performed directly at the pore. PMID:20698604

  5. Intersubunit movement is required for ribosomal translocation

    PubMed Central

    Horan, Lucas H.; Noller, Harry F.

    2007-01-01

    Translocation of tRNA and mRNA during protein synthesis is believed to be coupled to structural changes in the ribosome. The “ratchet model,” based on cryo-EM reconstructions of ribosome complexes, invokes relative movement of the 30S and 50S ribosomal subunits in this process; however, evidence that directly demonstrates a requirement for intersubunit movement during translocation is lacking. To address this problem, we created an intersubunit disulfide cross-link to restrict potential movement. The cross-linked ribosomes were unable to carry out polypeptide synthesis; this inhibition was completely reversed upon reduction of the disulfide bridge. In vitro assays showed that the cross-linked ribosomes were specifically blocked in elongation factor G-dependent translocation. These findings show that intersubunit movement is required for ribosomal translocation, accounting for the universal two-subunit architecture of ribosomes. PMID:17360328

  6. Identification of follicular lymphoma by polymerase chain reaction amplification of the t(14;18) translocation: An improved method for staging of malignancy and detection of minimal residual disease

    SciTech Connect

    La Spada, A.R.; Lakey, C.; Hanke, D.C.

    1994-09-01

    60 to 85% of follicular non-Hodgkin`s lymphomas have a reciprocal translocation between chromosomes 14 and 18 (t(14q21;18q32)). As a result of this translocation, the joining region of the immunoglobulin heavy chain gene (J{sub H}) on chromosome 14 is juxtaposed to the bcl-2 gene on chromosome 18. Polymerase chain reaction (PCR) amplification across the translocation breakpoint may be used to detect follicular lymphoma cells in the peripheral blood and bone marrow, as morphological examination for lymphoma cells is extremely insensitive. We performed PCR assays with a universal J{sub H} primer and pairs of major breakpoint region (MBR) primers or minor cluster region (MCR) primers from the bcl-2 gene. PCR products were then visualized on ethidium-stained agarose gels, along with size markers and appropriate positive and negative controls. We began by comparing the PCR assay to Southern blot analysis and found that Southern blot analysis detected 9 translocations in 24 follicular lymphomas (37.5%), while PCR amplification detected 13 (58.3%), making it the more sensitive technique. By using adjacent MBR and MCR primer pairs in the PCR assay, we were also able to attain very high specificities (>95%). As detection of minimal residual disease after therapy is likely important for the prognosis and further management of these patients, we decided to use our PCR assay to evaluate peripheral blood stem cell preparations from patients undergoing autologous bone marrow transplantation. Of the 26 patients analyzed thus far, 4 (15%) have been found positive for MBR translocations. These results indicate that PCR amplification of the t(14;18) translocation is a sensitive and specific method for detection of follicular lymphoma cells, and therefore has potential application as a tool not only for the staging but also for the management of this malignancy.

  7. What Drives the Translocation of Proteins?

    NASA Astrophysics Data System (ADS)

    Simon, Sanford M.; Peskin, Charles S.; Oster, George F.

    1992-05-01

    We propose that protein translocation across membranes is driven by biased random thermal motion. This "Brownian ratchet" mechanism depends on chemical asymmetries between the cis and trans sides of the membrane. Several mechanisms could contribute to rectifying the thermal motion of the protein, such as binding and dissociation of chaperonins to the translocating chain, chain coiling induced by pH and/or ionic gradients, glycosylation, and disulfide bond formation. This helps explain the robustness and promiscuity of these transport systems.

  8. Development of Five Dual-Color, Double-Fusion Fluorescence in Situ Hybridization Assays for the Detection of Common MLL Translocation Partners

    PubMed Central

    Keefe, Jeannette G.; Sukov, William R.; Knudson, Ryan A.; Nguyen, Lai P.; Williamson, Cynthia; Sinnwell, Jason P.; Ketterling, Rhett P.

    2010-01-01

    Chromosomal rearrangements involving the mixed lineage leukemia (MLL) gene at 11q23 are frequent in adult and childhood acute leukemia and have been associated with an unfavorable prognosis. Recent evidence suggests that MLL gene partners may influence prognosis. Five translocations account for ∼80% of MLL rearrangements: t(4;11)(q21;q23), AFF1/MLL; t(6;11)(q27;q23), MLLT4/MLL; t(9;11)(p22;q23), MLLT3/MLL; t(11;19)(q23;p13.1), MLL/ELL; and t(11;19)(q23;p13.3), MLL/MLLT1. We have designed dual-color, double-fusion fluorescence in situ hybridization (D-FISH) probe sets to identify these translocations. A blinded study was performed for each probe set using 25 normal bone marrow samples, 25 t(4;11), 20 t(6;11), 20 t(9;11), 18 t(11;19p13.1), and 20 t(11;19p13.3) leukemia specimens as defined by chromosome analysis. The findings demonstrated abnormal D-FISH results for 24 of 25 AFF1/MLL, 19 of 20 MLLT4/MLL, all 20 MLLT3/MLL, all 18 MLL/ELL, and all 20 MLL/MLLT1 samples, confirming the efficacy of these D-FISH assays in detecting these common MLL/partner translocations. Our D-FISH assays were more accurate than chromosome analysis at distinguishing disruption of 19p13.1/ELL from that of 19p13.3/MLLT1. We also demonstrated a statistically significant increase in complex/unbalanced MLL/partner translocations occurring in pediatric patients versus adult patients (P = 0.02). A normal cutoff of 0.6% was established, suggesting an application for these assays in minimal residual disease detection and disease monitoring. PMID:20539022

  9. Recombination suppression in the vicinity of the breakpoints of a balanced 1:11 autosomal translocation associated with schizophrenia and other forms of major mental illness

    SciTech Connect

    He, L.; Blackwood, D.H.R.; Maclean, A.W.

    1994-09-01

    The frequency and extent of pairing failure around human translocations is unknown. We have examined the pattern of recombination around the breakpoints of a balanced autosomal translocation t(1:11)(q43:q21) associated with major mental illness. We have postulated that the association with mental illness in the family has not arisen by chance, but rather that functional disruption of a gene at or near a breakpoint site is responsible. Efforts to isolate the breakpoints for molecular analysis of the region are now at an advanced stage. On the other hand if pairing failure is occurring in the family in the region of the breakpoints, a susceptibility allele for mental illness, acting independently of the translocation, may be located some distance away. DNA was available from seventeen carriers and ten non-translocation carriers, giving a total of thirty-one informative meioses spanning 4 generations. The derivative one and eleven chromosomes were also isolated in somatic cell hybrids and were used to confirm allele phase. We genotyped the pedigree members using nine markers covering 30 cMs on either side of both the chromosome one and eleven breakpoints. No recombinants were found with markers within 3 cMs of either breakpoint. Four markers at an average of 7 cMs respectively on either side of the two breakpoints gave a total of three crossovers from thirty-one meioses versus an expected 9, demonstrating (p<0.05) significant recombination suppression. By contrast, examination of chromosome regions at greater distances from the breakpoints showed recombination rates similar to those expected from CEPH data with no evidence of suppression. We conclude that crossover suppression occurs in this family but is restricted to a region within 7 cMs of the breakpoints.

  10. Stress and translocation: alterations in the stress physiology of translocated birds.

    PubMed

    Dickens, Molly J; Delehanty, David J; Romero, L Michael

    2009-06-01

    Translocation and reintroduction have become major conservation actions in attempts to create self-sustaining wild populations of threatened species. However, avian translocations have a high failure rate and causes for failure are poorly understood. While 'stress' is often cited as an important factor in translocation failure, empirical evidence of physiological stress is lacking. Here we show that experimental translocation leads to changes in the physiological stress response in chukar partridge, Alectoris chukar. We found that capture alone significantly decreased the acute glucocorticoid (corticosterone, CORT) response, but adding exposure to captivity and transport further altered the stress response axis (the hypothalamic-pituitary-adrenal axis) as evident from a decreased sensitivity of the negative feedback system. Animals that were exposed to the entire translocation procedure, in addition to the reduced acute stress response and disrupted negative feedback, had significantly lower baseline CORT concentrations and significantly reduced body weight. These data indicate that translocation alters stress physiology and that chronic stress is potentially a major factor in translocation failure. Under current practices, the restoration of threatened species through translocation may unwittingly depend on the success of chronically stressed individuals. This conclusion emphasizes the need for understanding and alleviating translocation-induced chronic stress in order to use most effectively this important conservation tool. PMID:19324794

  11. Stress and translocation: alterations in the stress physiology of translocated birds

    PubMed Central

    Dickens, Molly J.; Delehanty, David J.; Romero, L. Michael

    2009-01-01

    Translocation and reintroduction have become major conservation actions in attempts to create self-sustaining wild populations of threatened species. However, avian translocations have a high failure rate and causes for failure are poorly understood. While ‘stress’ is often cited as an important factor in translocation failure, empirical evidence of physiological stress is lacking. Here we show that experimental translocation leads to changes in the physiological stress response in chukar partridge, Alectoris chukar. We found that capture alone significantly decreased the acute glucocorticoid (corticosterone, CORT) response, but adding exposure to captivity and transport further altered the stress response axis (the hypothalamic–pituitary–adrenal axis) as evident from a decreased sensitivity of the negative feedback system. Animals that were exposed to the entire translocation procedure, in addition to the reduced acute stress response and disrupted negative feedback, had significantly lower baseline CORT concentrations and significantly reduced body weight. These data indicate that translocation alters stress physiology and that chronic stress is potentially a major factor in translocation failure. Under current practices, the restoration of threatened species through translocation may unwittingly depend on the success of chronically stressed individuals. This conclusion emphasizes the need for understanding and alleviating translocation-induced chronic stress in order to use most effectively this important conservation tool. PMID:19324794

  12. Ratcheting up protein translocation with anthrax toxin

    PubMed Central

    Feld, Geoffrey K; Brown, Michael J; Krantz, Bryan A

    2012-01-01

    Energy-consuming nanomachines catalyze the directed movement of biopolymers in the cell. They are found both dissolved in the aqueous cytosol as well as embedded in lipid bilayers. Inquiries into the molecular mechanism of nanomachine-catalyzed biopolymer transport have revealed that these machines are equipped with molecular parts, including adjustable clamps, levers, and adaptors, which interact favorably with substrate polypeptides. Biological nanomachines that catalyze protein transport, known as translocases, often require that their substrate proteins unfold before translocation. An unstructured protein chain is likely entropically challenging to bind, push, or pull in a directional manner, especially in a way that produces an unfolding force. A number of ingenious solutions to this problem are now evident in the anthrax toxin system, a model used to study protein translocation. Here we highlight molecular ratchets and current research on anthrax toxin translocation. A picture is emerging of proton-gradient-driven anthrax toxin translocation, and its associated ratchet mechanism likely applies broadly to other systems. We suggest a cyclical thermodynamic order-to-disorder mechanism (akin to a heat-engine cycle) is central to underlying protein translocation: peptide substrates nonspecifically bind to molecular clamps, which possess adjustable affinities; polypeptide substrates compress into helical structures; these clamps undergo proton-gated switching; and the substrate subsequently expands regaining its unfolded state conformational entropy upon translocation. PMID:22374876

  13. Defining chromosomal translocation risks in cancer.

    PubMed

    Hogenbirk, Marc A; Heideman, Marinus R; de Rink, Iris; Velds, Arno; Kerkhoven, Ron M; Wessels, Lodewyk F A; Jacobs, Heinz

    2016-06-28

    Chromosomal translocations are a hallmark of cancer. Unraveling the molecular mechanism of these rare genetic events requires a clear distinction between correlative and causative risk-determinants, where technical and analytical issues can be excluded. To meet this goal, we performed in-depth analyses of publicly available genome-wide datasets. In contrast to several recent reports, we demonstrate that chromosomal translocation risk is causally unrelated to promoter stalling (Spt5), transcriptional activity, or off-targeting activity of the activation-induced cytidine deaminase. Rather, an open chromatin configuration, which is not promoter-specific, explained the elevated translocation risk of promoter regions. Furthermore, the fact that gene size directly correlates with the translocation risk in mice and human cancers further demonstrated the general irrelevance of promoter-specific activities. Interestingly, a subset of translocations observed in cancer patients likely initiates from double-strand breaks induced by an access-independent process. Together, these unexpected and novel insights are fundamental in understanding the origin of chromosome translocations and, consequently, cancer. PMID:27303044

  14. Defining chromosomal translocation risks in cancer

    PubMed Central

    Hogenbirk, Marc A.; Heideman, Marinus R.; de Rink, Iris; Velds, Arno; Kerkhoven, Ron M.; Wessels, Lodewyk F. A.; Jacobs, Heinz

    2016-01-01

    Chromosomal translocations are a hallmark of cancer. Unraveling the molecular mechanism of these rare genetic events requires a clear distinction between correlative and causative risk-determinants, where technical and analytical issues can be excluded. To meet this goal, we performed in-depth analyses of publicly available genome-wide datasets. In contrast to several recent reports, we demonstrate that chromosomal translocation risk is causally unrelated to promoter stalling (Spt5), transcriptional activity, or off-targeting activity of the activation-induced cytidine deaminase. Rather, an open chromatin configuration, which is not promoter-specific, explained the elevated translocation risk of promoter regions. Furthermore, the fact that gene size directly correlates with the translocation risk in mice and human cancers further demonstrated the general irrelevance of promoter-specific activities. Interestingly, a subset of translocations observed in cancer patients likely initiates from double-strand breaks induced by an access-independent process. Together, these unexpected and novel insights are fundamental in understanding the origin of chromosome translocations and, consequently, cancer. PMID:27303044

  15. Driven Polymer Translocation into a Crosslinked Gel

    NASA Astrophysics Data System (ADS)

    Sean, David; Slater, Gary

    2015-03-01

    In a typical polymer translocation setup, a thin membrane is used to separate two chambers and a polyelectrolyte is driven by an electric field to translocate from one side of the membrane to the other via a small nanopore. However, the high translocation rate that results from the forces required to drive this process makes optical and/or electrical analysis of the translocating polymer challenging. Using coarse-grained Langevin Dynamics simulations we investigate how the translocation process can be slowed down by placing a crosslinked gel on the trans-side of the membrane. Since the driving electric field is localized in the neighborhood of the nanopore, electrophoretic migration is only achieved by a ``pushing'' action from the polymer segment residing in the nanopore. For the case of a flexible polymer we find that the polymer fills the gel pores via multiple ``herniation'' processes, whereas for a semi-flexible chain in a tight gel there are no hernias and the polymer follows a smooth curvilinear path. Moreover, for the case of a semi-flexible polymer the gel makes the translocation process more uniform by reducing the acceleration at the end of the process.

  16. Translocation of DNA across bacterial membranes.

    PubMed Central

    Dreiseikelmann, B

    1994-01-01

    DNA translocation across bacterial membranes occurs during the biological processes of infection by bacteriophages, conjugative DNA transfer of plasmids, T-DNA transfer, and genetic transformation. The mechanism of DNA translocation in these systems is not fully understood, but during the last few years extensive data about genes and gene products involved in the translocation processes have accumulated. One reason for the increasing interest in this topic is the discussion about horizontal gene transfer and transkingdom sex. Analyses of genes and gene products involved in DNA transfer suggest that DNA is transferred through a protein channel spanning the bacterial envelope. No common model exists for DNA translocation during phage infection. Perhaps various mechanisms are necessary as a result of the different morphologies of bacteriophages. The DNA translocation processes during conjugation, T-DNA transfer, and transformation are more consistent and may even be compared to the excretion of some proteins. On the basis of analogies and homologies between the proteins involved in DNA translocation and protein secretion, a common basic model for these processes is presented. PMID:7968916

  17. Microbiology of bacterial translocation in humans

    PubMed Central

    O'Boyle, C; MacFie, J; Mitchell, C; Johnstone, D; Sagar, P; Sedman, P

    1998-01-01

    Background—Gut translocation of bacteria has been shown in both animal and human studies. Evidence from animal studies that links bacterial translocation to the development of postoperative sepsis and multiple organ failure has yet to be confirmed in humans. 
Aims—To examine the spectrum of bacteria involved in translocation in surgical patients undergoing laparotomy and to determine the relation between nodal migration of bacteria and the development of postoperative septic complications. 
Methods—Mesenteric lymph nodes (MLN), serosal scrapings, and peripheral blood from 448 surgical patients undergoing laparotomy were analysed using standard microbiological techniques. 
Results—Bacterial translocation was identified in 69 patients (15.4%). The most common organism identified was Escherichia coli (54%). Both enteric bacteria, typical of indigenous intestinal flora, and non-enteric bacteria were isolated. Postoperative septic complications developed in 104 patients (23%). Enteric organisms were responsible in 74% of patients. Forty one per cent of patients who had evidence of bacterial translocation developed sepsis compared with 14% in whom no organisms were cultured (p<0.001). Septic morbidity was more frequent when a greater diversity of bacteria resided within the MLN, but this was not statistically significant. 
Conclusion—Bacterial translocation is associated with a significant increase in the development of postoperative sepsis in surgical patients. The organisms responsible for septic morbidity are similar in spectrum to those observed in the mesenteric lymph nodes. These data strongly support the gut origin hypothesis of sepsis in humans. 

 Keywords: bacterial translocation; mesenteric lymph nodes; serosal scrapings; enteric bacteria; postoperative sepsis PMID:9505882

  18. Molecular studies of free and translocation trisomy

    SciTech Connect

    Robinson, W.P.; Bernasconi, F.; Lefort, G.

    1994-09-01

    Twenty cases of trisomy 13 were examined with molecular markers to determine the origin of the extra chromosome. Six cases had translocation trisomy: two de novo rob(13q;14q), one paternally derived rob(13q;14q), two de novo t(13q;13q), and one mosaic de novo t(13q;14q), one paternally derived rob(13q;14q), two de novo t(13q;13q), and one mosaic de novo t(13q;13q)r(13). Eighteen of nineteen informative patients were consistant with a maternal origin of the extra chromosome. Lack of a third allele at any locus in any of the three t(13q;13q) cases indicate that all were most likely isochromosomes of post-meiotic origin. In addition, two free trisomy cases were compatible with a somatic origin. Two mosaic free trisomy-13 cases, however, were both consistent with a maternal meiotic origin. The patient with a paternal inheritance of the translocation chromosome was purely coincidental. Since there is not a significantly increased risk for unbalanced offspring of a t(13;14) carrier and most trisomies are maternal in origin, this result should not be surprising; however it illustrates that one cannot infer the origin of translocation trisomy based on parental origin of the translocation. One balanced (non-trisomic) case with a non-mosaic 45,-13,-13,+t(13;13) karyotype was also investigated and was determined to be a somatic Robertsonian translocation between the maternal and paternal homologs, as has been found for all homologous Robertsonian translocations so far investigated. It is therefore also incorrect to assume in de novo translocation cases that the two involved chromosomes are even from the same parent. We cannot therefore infer anything about the origin of the chromosomes 13 and 14 involved in the two cases with de novo t(13q;14q) plus a maternally derived trisomy 13.

  19. The human insulin-like growth factor-binding protein 4 gene maps to chromosome region 17q12-q21. 1 and is close to the gene for hereditary breast-ovarian cancer

    SciTech Connect

    Tonin, P.; Vivier, A.; Morgan, K.; Narod, S.; Pollack, M. ); Ehrenborg, E.; Zazzi, H.; Luthman, H.; Larsson, C. ); Lenoir, G. )

    1993-11-01

    The gene for insulin-like growth factor-binding protein 4 (IGFBP4) codes for a serum protein that binds to the family of insulin-like growth factors and modulates their activity. It has been mapped by in situ hybridization to chromosome region 17q12-q21.1. The authors have developed a CA-repeat polymorphism from a cosmid clone containing IGFBP4. By linkage analysis, IGFBP4 maps to the chromosome 17q interval THRA1-D17S579. This interval also contains the gene for hereditary breast-ovarian cancer, BRCA1. Genetic recombination between IGFBP4 and BRCA1 places IGFBP4 centromeric to the cancer susceptibility gene and effectively excludes it as a candidate gene for BRCA1. IGFBP4 is, however, one of the closest known centromeric markers for BRCA1; the estimated recombination fraction is 0.015. IGFBP4 and D17S579 together define a 2.8-cM interval that contains BRCA1. 18 refs., 3 figs., 1 tab.

  20. The gene encoding the glutamate receptor subunit GluR5 is located on human chromosome 21q21.1-22.1 in the vicinity of the gene for familial amyotrophic lateral sclerosis.

    PubMed Central

    Eubanks, J H; Puranam, R S; Kleckner, N W; Bettler, B; Heinemann, S F; McNamara, J O

    1993-01-01

    Genomic clones of the human non-N-methyl-D-aspartate (non-NMDA) glutamate receptor subunit GluR5 were isolated by high-stringency screening of a cosmid library using the rat cDNA as a probe. The chromosomal localization of the human GluR5 gene has been established. Southern hybridization of DNA isolated from mapping panels of Chinese hamster-human hybrid cell lines and high-resolution in situ suppression hybridization localize the GluR5 gene to chromosome 21q21.1-22.1. This coincides with the localization of a mutant gene causing familial amyotrophic lateral sclerosis (ALS), as Siddique et al. established by linkage analyses [Siddique, T., Figlewicz, D. A., Pericak-Vance, M. A., Haines, J. L., Rouleau, G., Jeffers, A. J., Sapp, P., Hung, W. Y., Bebout, J., McKenna-Yasek, D., Deng, G., Horvitz, H. R., Gusella, J. F., Brown, R. H. & Roses, A. D. (1991) N. Engl. J. Med. 324, 1381-1384]. Convergent evidence from other investigators suggests that chronic pathologic activation of motor neurons via non-NMDA glutamate receptors might induce excitotoxic injury of motor neurons, culminating in ALS. Together with the demonstration that GluR5 transcripts are expressed in the ventral horn of the spinal cord, the region in which susceptible motor neurons reside, the chromosomal localization suggests that a mutated GluR5 gene may be responsible for the familial form of ALS. Images PMID:8419920

  1. Stochastic resonance during a polymer translocation process.

    PubMed

    Mondal, Debasish; Muthukumar, M

    2016-04-14

    We have studied the occurrence of stochastic resonance when a flexible polymer chain undergoes a single-file translocation through a nano-pore separating two spherical cavities, under a time-periodic external driving force. The translocation of the chain is controlled by a free energy barrier determined by chain length, pore length, pore-polymer interaction, and confinement inside the donor and receiver cavities. The external driving force is characterized by a frequency and amplitude. By combining the Fokker-Planck formalism for polymer translocation and a two-state model for stochastic resonance, we have derived analytical formulas for criteria for emergence of stochastic resonance during polymer translocation. We show that no stochastic resonance is possible if the free energy barrier for polymer translocation is purely entropic in nature. The polymer chain exhibits stochastic resonance only in the presence of an energy threshold in terms of polymer-pore interactions. Once stochastic resonance is feasible, the chain entropy controls the optimal synchronization conditions significantly. PMID:27083746

  2. Stochastic resonance during a polymer translocation process

    NASA Astrophysics Data System (ADS)

    Mondal, Debasish; Muthukumar, M.

    2016-04-01

    We have studied the occurrence of stochastic resonance when a flexible polymer chain undergoes a single-file translocation through a nano-pore separating two spherical cavities, under a time-periodic external driving force. The translocation of the chain is controlled by a free energy barrier determined by chain length, pore length, pore-polymer interaction, and confinement inside the donor and receiver cavities. The external driving force is characterized by a frequency and amplitude. By combining the Fokker-Planck formalism for polymer translocation and a two-state model for stochastic resonance, we have derived analytical formulas for criteria for emergence of stochastic resonance during polymer translocation. We show that no stochastic resonance is possible if the free energy barrier for polymer translocation is purely entropic in nature. The polymer chain exhibits stochastic resonance only in the presence of an energy threshold in terms of polymer-pore interactions. Once stochastic resonance is feasible, the chain entropy controls the optimal synchronization conditions significantly.

  3. Stochastic resonance during a polymer translocation process

    NASA Astrophysics Data System (ADS)

    Mondal, Debasish; Muthukumar, Murugappan

    We study the translocation of a flexible polymer in a confined geometry subjected to a time-periodic external drive to explore stochastic resonance. We describe the equilibrium translocation process in terms of a Fokker-Planck description and use a discrete two-state model to describe the effect of the external driving force on the translocation dynamics. We observe that no stochastic resonance is possible if the associated free-energy barrier is purely entropic in nature. The polymer chain experiences a stochastic resonance effect only in presence of an energy threshold in terms of polymer-pore interaction. Once stochastic resonance is feasible, the chain entropy controls the optimal synchronization conditions significantly.

  4. DNA nanopore translocation in glutamate solutions

    NASA Astrophysics Data System (ADS)

    Plesa, C.; van Loo, N.; Dekker, C.

    2015-08-01

    Nanopore experiments have traditionally been carried out with chloride-based solutions. Here we introduce silver/silver-glutamate-based electrochemistry as an alternative, and study the viscosity, conductivity, and nanopore translocation characteristics of potassium-, sodium-, and lithium-glutamate solutions. We show that it has a linear response at typical voltages and can be used to detect DNA translocations through a nanopore. The glutamate anion also acts as a redox-capable thickening agent, with high-viscosity solutions capable of slowing down the DNA translocation process by up to 11 times, with a corresponding 7 time reduction in signal. These results demonstrate that glutamate can replace chloride as the primary anion in nanopore resistive pulse sensing.

  5. Analyzing disease risks associated with translocations.

    PubMed

    Sainsbury, Anthony W; Vaughan-Higgins, Rebecca J

    2012-06-01

    Translocations of species are expected to be used increasingly to counter the undesirable effects of anthropogenic changes to ecosystems, including loss of species. Methods to assess the risk of disease associated with translocations have been compiled in a comprehensive manual of disease-risk analysis for movement of domestic animals. We used this manual to devise a qualitative method for assessing the probability of the occurrence of disease in wild animals associated with translocations. We adapted the method such that we considered a parasite (any agent of infectious or noninfectious disease) a hazard if it or the host had crossed an ecological or geographical barrier and was novel to the host. We included in our analyses hazards present throughout the translocation pathway derived from the interactions between host immunity and the parasite, the effect of parasites on populations, the effect of noninfectious disease agents, and the effect of stressors on host-parasite interactions. We used the reintroduction of Eurasian Cranes (Grus grus) to England to demonstrate our method. Of the 24 hazards identified, 1 was classified as high risk (coccidia) and 5 were medium risk (highly pathogenic avian influenza virus, Mycobacterium avium, Aspergillus fumigatus, tracheal worms [Syngamus sp. and Cyathostoma sp.], and Tetrameres spp.). Seventeen other hazards were considered low or very low risk. In the absence of better information on the number, identity, distribution, and pathogenicity of parasites of wild animals, there is uncertainty in the risk of disease to translocated animals and recipient populations. Surveys of parasites in source and destination populations and detailed health monitoring after release will improve the information available for future analyses of disease risk. We believe our method can be adapted to assess the risks of disease in other translocated populations. PMID:22533691

  6. Translocation t(11;14) (q13;q32) and genomic imbalances in multi-ethnic multiple myeloma patients: a Malaysian study.

    PubMed

    Ni, Ivyna Bong Pau; Ching, Ng Ching; Meng, Chang Kian; Zakaria, Zubaidah

    2012-07-11

    More than 50% of myeloma cases have normal karyotypes under conventional cytogenetic analysis due to low mitotic activity and content of plasma cells in the bone marrow. We used a polymerase chain reaction (PCR)-based translocation detection assay to detect BCL1/JH t(11;14) (q13;q32) in 105 myeloma patients, and randomly selected 8 translocation positive samples for array comparative genomic hybridization (aCGH) analysis. Our findings revealed 14.3% of myeloma samples were positive for BCL1/JH t(11;14) (q13;q32) translocation (n=15 of 105). We found no significant correlation between this translocation with age (P=0.420), gender (P=0.317), ethnicity (P=0.066) or new/relapsed status of multiple myeloma (P=0.412) at 95% confidence interval level by χ(2)test. In addition, aCGH results showed genomic imbalances in all samples analyzed. Frequent chromosomal gains were identified at regions 1q, 2q, 3p, 3q, 4p, 4q, 5q, 7q, 9q, 11q, 13q, 15q, 21q, 22q and Xq, while chromosomal losses were detected at 4q and 14q. Copy number variations at genetic loci that contain NAMPT, IVNS1ABP and STK17B genes are new findings that have not previously been reported in myeloma patients. Besides fluorescence in situ hybridization, PCR is another rapid, sensitive and simple technique that can be used for detecting BCL1/JH t(11;14)(q13;q32) translocation in multiple myeloma patients. Genes located in the chromosomal aberration regions in our study, such as NAMPT, IVNS1ABP, IRF2BP2, PICALM, STAT1, STK17B, FBXL5, ACSL1, LAMP2, SAMSN1 and ATP8B4 might be potential prognostic markers and therapeutic targets in the treatment and management of multiple myeloma patients positive for BCL1/JH t(11;14) (q13;q32) translocation. PMID:23087808

  7. Translocation t(11;14) (q13;q32) and genomic imbalances in multi-ethnic multiple myeloma patients: a Malaysian study

    PubMed Central

    Ni, Ivyna Bong Pau; Ching, Ng Ching; Meng, Chang Kian; Zakaria, Zubaidah

    2012-01-01

    More than 50% of myeloma cases have normal karyotypes under conventional cytogenetic analysis due to low mitotic activity and content of plasma cells in the bone marrow. We used a polymerase chain reaction (PCR)-based translocation detection assay to detect BCL1/JH t(11;14) (q13;q32) in 105 myeloma patients, and randomly selected 8 translocation positive samples for array comparative genomic hybridization (aCGH) analysis. Our findings revealed 14.3% of myeloma samples were positive for BCL1/JH t(11;14) (q13;q32) translocation (n=15 of 105). We found no significant correlation between this translocation with age (P=0.420), gender (P=0.317), ethnicity (P=0.066) or new/relapsed status of multiple myeloma (P=0.412) at 95% confidence interval level by χ2 test. In addition, aCGH results showed genomic imbalances in all samples analyzed. Frequent chromosomal gains were identified at regions 1q, 2q, 3p, 3q, 4p, 4q, 5q, 7q, 9q, 11q, 13q, 15q, 21q, 22q and Xq, while chromosomal losses were detected at 4q and 14q. Copy number variations at genetic loci that contain NAMPT, IVNS1ABP and STK17B genes are new findings that have not previously been reported in myeloma patients. Besides fluorescence in situ hybridization, PCR is another rapid, sensitive and simple technique that can be used for detecting BCL1/JH t(11;14)(q13;q32) translocation in multiple myeloma patients. Genes located in the chromosomal aberration regions in our study, such as NAMPT, IVNS1ABP, IRF2BP2, PICALM, STAT1, STK17B, FBXL5, ACSL1, LAMP2, SAMSN1 and ATP8B4 might be potential prognostic markers and therapeutic targets in the treatment and management of multiple myeloma patients positive for BCL1/JH t(11;14) (q13;q32) translocation. PMID:23087808

  8. Protein Translocation across the Rough Endoplasmic Reticulum

    PubMed Central

    Mandon, Elisabet C.; Trueman, Steven F.; Gilmore, Reid

    2013-01-01

    The rough endoplasmic reticulum is a major site of protein biosynthesis in all eukaryotic cells, serving as the entry point for the secretory pathway and as the initial integration site for the majority of cellular integral membrane proteins. The core components of the protein translocation machinery have been identified, and high-resolution structures of the targeting components and the transport channel have been obtained. Research in this area is now focused on obtaining a better understanding of the molecular mechanism of protein translocation and membrane protein integration. PMID:23251026

  9. What drives the translocation of proteins?

    PubMed Central

    Simon, S M; Peskin, C S; Oster, G F

    1992-01-01

    We propose that protein translocation across membranes is driven by biased random thermal motion. This "Brownian ratchet" mechanism depends on chemical asymmetries between the cis and trans sides of the membrane. Several mechanisms could contribute to rectifying the thermal motion of the protein, such as binding and dissociation of chaperonins to the translocating chain, chain coiling induced by pH and/or ionic gradients, glycosylation, and disulfide bond formation. This helps explain the robustness and promiscuity of these transport systems. Images PMID:1349170

  10. Detection of interchromosomal translocations within the Triticeae by RFLP analysis.

    PubMed

    King, I P; Purdie, K A; Liu, C J; Reader, S M; Pittaway, T S; Orford, S E; Miller, T E

    1994-10-01

    Twenty-three wheat/alien addition or substitution lines were screened using restriction fragment length polymorphisms for the presence or absence of 4/5 and 4/7 reciprocal translocations in the alien chromosomes. Such translocations have previously been identified in wheat and rye. Group 4 and group 5 Aegilops umbellulata, Triticum urartu, and Thinopyrum bessarabicum chromosomes were found to carry 4/5 translocations. Evidence for a 4/7 translocation was also found in Secale montanum. The presence of the 4/5 translocations in T. urartu indicates that the translocation predates the polyploidization of wheat. The implications of these results are discussed. PMID:18470131

  11. Genome-Wide Linkage Scan for Prostate Cancer Susceptibility in Finland: Evidence for a Novel Locus on 2q37.3 and confirmation of signal on 17q21-q22

    PubMed Central

    Cropp, Cheryl D.; Simpson, Claire L; Wahlfors, Tiina; Ha, Nati; George, Asha; Jones, MaryPat S.; Harper, Ursula; Ponciano-Jackson, Damaris; Green, Tiffany A.; Tammela, Teuvo L. J.; Bailey-Wilson, Joan; Schleutker, Johanna

    2011-01-01

    Genome-wide linkage studies have been used to localize rare and highly penetrant prostate cancer (PRCA) susceptibility genes. Linkage studies performed in different ethnic backgrounds and populations have been somewhat disparate, resulting in multiple, often irreproducible signals because of genetic heterogeneity and high sporadic background of the disease. Our first genome-wide linkage study and subsequent fine-mapping study of Finnish hereditary prostate cancer (HPC) families gave evidence of linkage to one region. Here, we conducted subsequent scans with microsatellites and SNPs in a total of 69 Finnish HPC families. GENEHUNTER-PLUS was used for parametric and non-parametric analyses. Our microsatellite genome-wide linkage study provided evidence of linkage to 17q12-q23, with a heterogeneity LOD (HLOD) score of 3.14 in a total of 54 of the 69 families. Genome-wide SNP analysis of 59 of the 69 families gave a highest HLOD score of 3.40 at 2q37.3 under a dominant high penetrance model. Analyzing all 69 families by combining microsatellite and SNP maps also yielded HLOD scores of > 3.3 in two regions (2q37.3 and 17q12-q21.3). These significant linkage peaks on chromosome 2 and 17 confirm previous linkage evidence of a locus on 17q from other populations and provide a basis for continued research into genetic factors involved in PRCA. Fine-mapping analysis of these regions is ongoing and candidate genes at linked loci are currently under analysis. PMID:21207418

  12. Safety of probiotics: translocation and infection.

    PubMed

    Liong, Min-Tze

    2008-04-01

    The long history of safety has contributed to the acceptance of probiotics as a safe food adjunct. Consequently, many probiotic products and their applications have been granted GRAS (generally regarded as safe) status. However, this classification has been frequently generalized for all probiotic strains regardless of their application. Cases of probiotics from the genera Lactobacillus, Leuconostoc, Pediococcus, Enterococcus, and Bifidobacterium have been isolated from infection sites, leading to the postulation that these probiotics can translocate. Probiotic translocation is difficult to induce in healthy humans, and even if it does occur, detrimental effects are rare. Despite this, various reports have documented health-damaging effects of probiotic translocation in immunocompromised patients. Due to probiotics' high degree of safety and their morphological confusion with other pathogenic bacteria, they are often overlooked as contaminants and are least suspected as pathogens. However, the antibiotic resistance of some strains has increased the complexity of their eradication. Probiotic translocation and infection deserve further investigation and should become a facet of safety assessment so the negative effects of probiotics do not outweigh the benefits. PMID:18366533

  13. Familial cryptic translocation in Angelman syndrome

    SciTech Connect

    Weyerts, L.K.; Wiley, J.E.; Loud, K.M.

    1994-09-01

    The majority of patients with Angelman syndrome have been shown to have a cytogenetic or molecular deletion on the maternally derived chromosome 15. We report on a case of Angelman syndrome in which this deletion occurs as an unbalanced cryptic translocation involving chromosomes 14 and 15. The proband was diagnosed clinically as having Angelman syndrome. Multiple cytogenetic studies were done without detecting any deletion. When DNA probes (Oncor) specific for the Prader Willi/Angelman locus became available, the patient was restudied and found to be deleted for {open_quotes}region A{close_quotes} (D15S11) but not for {open_quotes}region B{close_quotes} (GABRB3). No other abnormality was detected. The proband`s mother was then studied. The chromosome 15 marker probe and D15S11 were detected on different chromosomes. Using alpha-satellite probes, a cryptic 14;15 translocation was uncovered. This balanced translocation was also found to be carried by the sister of the proband. This case, along with a case presented at the 1993 ASHG meeting, illustrates the need for using acrocentric probes when studying Angelman syndrome patients. The proband was studied using additional probes specific for this region and found to be deleted for SNRPN but not for D15S10. The breakpoint of the translocation in this patient delineates the smallest deletion of the Angelman syndrome region reported to date and therefore may represent the specific gene involved.

  14. Investigating binding particles distribution effects on polymer translocation through nanopore

    NASA Astrophysics Data System (ADS)

    Haji Abdolvahab, Rouhollah

    2016-03-01

    Chaperone driven polymer translocation is an important model for biopolymer's translocation in vivo. Binding proteins spatial distribution is a significant factor in calculating the translocation time of the polymer in this type of translocation. Here using a dynamical Monte Carlo simulation we compare the results of the usual uniform distribution with the exponential distribution of different rates for a stiff polymer. Our simulation results show that just by changing the chaperones spatial distribution the translocation time of the biopolymer will change by as large as an order. It can change the translocation regime of the polymer completely from a diffusive to a ballistic one. Although generally increasing the exponential rate and the background concentration will increase the translocation velocity, it is not always true and one should consider both the sequence and the background concentration. We show that the results depend on the sequence and changing the distribution rates for increasing the translocation velocity will change the whole Probability Density Function (PDF) of the polymer translocation time accordance to its sequence. The translocation time sequence dependency will change in the extreme cases e.g. in the high exponential rate. Investigating the binding protein size, λ, also shows the importance of the so called parking lot effect in distribution dependency of the translocation velocity. Although there is not any important dependency for λ = 1, translocation time depends clearly on the chaperone spatial distribution for the case of λ ≥ 2.

  15. Translocation strategies for multiple species depend on interspecific interaction type.

    PubMed

    Plein, Michaela; Bode, Michael; Moir, Melinda L; Vesk, Peter A

    2016-06-01

    Conservation translocations, anthropogenic movements of species to prevent their extinction, have increased substantially over the last few decades. Although multiple species are frequently moved to the same location, current translocation guidelines consider species in isolation. This practice ignores important interspecific interactions and thereby risks translocation failure. We model three different two-species systems to illustrate the inherent complexity of multispecies translocations and to assess the influence of different interaction types (consumer-resource, mutualism, and competition) on translocation strategies. We focus on how these different interaction types influence the optimal founder population sizes for successful translocations and the order in which the species are moved (simultaneous or sequential). Further, we assess the effect of interaction strength in simultaneous translocations and the time delay between translocations when moving two species sequentially. Our results show that translocation decisions need to reflect the type of interaction. While all translocations of interacting species require a minimum founder population size, which is demarked by an extinction boundary, consumer-resource translocations also have a maximum founder population limit. Above the minimum founder size, increasing the number of translocated individuals leads to a substantial increase in the extinction boundary of competitors and consumers, but not of mutualists. Competitive and consumer-resource systems benefit from sequential translocations, but the order of translocations does not change the outcomes for mutualistic interaction partners noticeably. Interspecific interactions are important processes that shape population dynamics and should therefore be incorporated into the quantitative planning of multispecies translocations. Our findings apply whenever interacting species are moved, for example, in reintroductions, conservation introductions, biological

  16. A new approach to polymer translocation

    NASA Astrophysics Data System (ADS)

    Dubbeldam, Johan; Rostiashvili, Vakhtang; Milchev, Andrey; Vilgis, Thomas

    2011-03-01

    Polymer translocation is ubiquitous in nature. It plays a role in phenomena like virus infections and in trafficking of proteins through pores in a cell membrane. Many theoretical models have been developed to explain scaling properties of simple polymer chains through tiny nanopores. This has not resolved the controversies in this field, however. In this paper we employ novel methods to shed light on the results that were obtained using the different models that are in use today. We use, for example fractional Brownian motion to explain the scaling of the variance in the translocation length with time and find good agreement between simulation results and theoretical predictions. An extension of the theory to nanopores with more complex geometries are discussed.

  17. Translocation in the nonpolytrichaceous moss grimmia laevigata

    SciTech Connect

    Alpert, P. )

    1989-10-01

    A superficially rhizomatous habit suggested that the moss Grimmia laevigata might function as a clonal, rhizomatous plant and translocate photoassimilates to below ground organs, even though the species is outside the order Polytrichales, which includes the only mosses known to posses sieve cells. Labelling with {sup 14}CO{sub 2} indicated that at least 10% of newly assimilated carbon was translocated out of leafy shoot portions within 26 hr. Of this carbon, approximately 75% was apparently moved into leafless, basal shoot portions and 25% into below ground stems. Infrared gas analysis of net CO{sup 2} flux was used to check that labelling gave a realistic measure of photosynthesis. Physiological integration and clonal spread may account for the unusual ability of this moss to colonize extremely xeric microsites.

  18. Pore formation and translocation of melittin.

    PubMed Central

    Matsuzaki, K; Yoneyama, S; Miyajima, K

    1997-01-01

    Melittin, a bee venom, is a basic amphiphilic peptide, which mainly acts on the lipid matrix of membranes, lysing various cells. To elucidate the molecular mechanism, we investigated its interactions with phospholipid vesicles. The peptide formed a pore with a short lifetime in the membrane, as revealed by the release of an anionic fluorescent dye, calcein, from the liposomes. Our new double-labeling method clarified that the pore size increased with the peptide-to-lipid ratio. Upon the disintegration of the pore, a fraction of the peptides translocated across the bilayer. The pore formation was coupled with the translocation, which was proved by three fluorescence experiments recently developed by our laboratory. A novel model for the melittin pore formation was discussed in comparison with other pore-forming peptides. PMID:9251799

  19. Origin of translocation barriers for polyelectrolyte chains.

    PubMed

    Kumar, Rajeev; Muthukumar, M

    2009-11-21

    For single-file translocations of a charged macromolecule through a narrow pore, the crucial step of arrival of an end at the pore suffers from free energy barriers, arising from changes in intrachain electrostatic interaction, distribution of ionic clouds and solvent molecules, and conformational entropy of the chain. All contributing factors to the barrier in the initial stage of translocation are evaluated by using the self-consistent field theory for the polyelectrolyte and the coupled Poisson-Boltzmann description for ions without radial symmetry. The barrier is found to be essentially entropic due to conformational changes. For moderate and high salt concentrations, the barriers for the polyelectrolyte chain are quantitatively equivalent to that of uncharged self-avoiding walks. Electrostatic effects are shown to increase the free energy barriers, but only slightly. The degree of ionization, electrostatic interaction strength, decreasing salt concentration, and the solvent quality all result in increases in the barrier. PMID:19929072

  20. A novel selection system for chromosome translocations in Saccharomyces cerevisiae.

    PubMed Central

    Tennyson, Rachel B; Ebran, Nathalie; Herrera, Anissa E; Lindsley, Janet E

    2002-01-01

    Chromosomal translocations are common genetic abnormalities found in both leukemias and solid tumors. While much has been learned about the effects of specific translocations on cell proliferation, much less is known about what causes these chromosome rearrangements. This article describes the development and use of a system that genetically selects for rare translocation events using the yeast Saccharomyces cerevisiae. A translocation YAC was created that contains the breakpoint cluster region from the human MLL gene, a gene frequently involved in translocations in leukemia patients, flanked by positive and negative selection markers. A translocation between the YAC and a yeast chromosome, whose breakpoint falls within the MLL DNA, physically separates the markers and forms the basis for the selection. When RAD52 is deleted, essentially all of the selected and screened cells contain simple translocations. The detectable translocation rates are the same in haploids and diploids, although the mechanisms involved and true translocation rates may be distinct. A unique double-strand break induced within the MLL sequences increases the number of detectable translocation events 100- to 1000-fold. This novel system provides a tractable assay for answering basic mechanistic questions about the development of chromosomal translocations. PMID:11973293

  1. Unforced polymer translocation compared to the forced case.

    PubMed

    Lehtola, V V; Linna, R P; Kaski, K

    2010-03-01

    We present results for unforced polymer translocation from simulations using Langevin dynamics in two dimensions (2D) to four dimensions and stochastic rotation dynamics supporting hydrodynamic modes in three dimensions (3D). We compare our results to forced translocation and a simplified model where the polymer escapes from an infinite pore. The simple model shows that the scaling behavior of unforced translocation is independent of the dimension of the side to which the polymer is translocating. We find that, unlike its forced counterpart, unforced translocation dynamics is insensitive to pore design. Hydrodynamics is seen to markedly speed up the unforced translocation process but not to affect the scaling relations. Average mean-squared displacement shows scaling with average transition time in unforced but not in forced translocation. The waiting-time distribution in unforced translocation follows closely Poissonian distribution. Our measured transfer probabilities align well with those obtained from an equilibrium theory in 3D, but somewhat worse in 2D, where a polymer's relaxation toward equilibrium with respect to its translocation time is slower. Consequently, in stark contrast to forced translocation, unforced translocation is seen to remain close to equilibrium and shows clear universality. PMID:20365761

  2. Translocation and encapsulation of siRNA inside carbon nanotubes

    NASA Astrophysics Data System (ADS)

    Mogurampelly, Santosh; Maiti, Prabal K.

    2013-01-01

    We report spontaneous translocation of small interfering RNA (siRNA) inside carbon nanotubes (CNTs) of various diameters and chirality using all atom molecular dynamics simulations with explicit solvent. We use umbrella sampling method to calculate the free energy landscape of the siRNA entry and translocation event. Free energy profiles show that siRNA gains free energy while translocating inside CNT, and barrier for siRNA exit from CNT ranges from 40 to 110 kcal/mol depending on CNT chirality and salt concentration. The translocation time τ decreases with the increase of CNT diameter with a critical diameter of 24 Å for the translocation. In contrast, double strand DNA of the same sequence does not translocate inside CNT due to large free energy barrier for the translocation. This study helps in understanding the nucleic acid transport through nanopores at microscopic level and may help designing carbon nanotube based sensor for siRNA.

  3. Stepwise translocation of nucleic acid motors

    PubMed Central

    Myong, Sua; Ha, Taekjip

    2010-01-01

    Summary Recent single molecule studies have made a significant contribution to the understanding of the molecular mechanism involved in the movement of motor proteins which process DNA and RNA. Measurement of stepsize in two disparate motors, NS3 helicase and ribosome both revealed three basepair steps which consist of three hidden substeps. Combined with previous structural studies, NS3 is likely taking a single nucleotide step of translocation coupled to one ATP binding event and this mode may be conserved in multitude of helicases. Such a stepwise translocation movement appears to occur through main contacts with the phosphate backbone. Double stranded RNA and DNA motor, RIG-I and Φ29 respectively showed translocation on a duplex while tracking exclusively a single stranded RNA/DNA in a directional manner, 5′ to 3′ in both cases. Spontaneous dynamics displayed by ribosome ratcheting and SSB (single stranded DNA binding protein) diffusing on DNA were rectified by interacting cofactors and proteins, EF-G and RecA respectively. PMID:20061135

  4. Stepwise nucleosome translocation by RSC remodeling complexes.

    PubMed

    Harada, Bryan T; Hwang, William L; Deindl, Sebastian; Chatterjee, Nilanjana; Bartholomew, Blaine; Zhuang, Xiaowei

    2016-01-01

    The SWI/SNF-family remodelers regulate chromatin structure by coupling the free energy from ATP hydrolysis to the repositioning and restructuring of nucleosomes, but how the ATPase activity of these enzymes drives the motion of DNA across the nucleosome remains unclear. Here, we used single-molecule FRET to monitor the remodeling of mononucleosomes by the yeast SWI/SNF remodeler, RSC. We observed that RSC primarily translocates DNA around the nucleosome without substantial displacement of the H2A-H2B dimer. At the sites where DNA enters and exits the nucleosome, the DNA moves largely along or near its canonical wrapping path. The translocation of DNA occurs in a stepwise manner, and at both sites where DNA enters and exits the nucleosome, the step size distributions exhibit a peak at approximately 1-2 bp. These results suggest that the movement of DNA across the nucleosome is likely coupled directly to DNA translocation by the ATPase at its binding site inside the nucleosome. PMID:26895087

  5. Kinetics of C-14 Translocation in Soybean

    PubMed Central

    Fisher, Donald B.

    1970-01-01

    The kinetics of 14C-assimilates in the soybean leaf were studied in pulse labeling and steady state labeling experiments. 14C-Sucrose apparently served as the ultimate source, at least, of translocated 14C-sucrose. However, since the specific activity of leaf sucrose reached a maximum within 5 minutes after pulse labeling, whereas that of exported sucrose did not reach a maximum until at least 20 minutes, it appeared that there were two sucrose compartments in the leaf. A possible physical basis for the two compartments may be the mesophyll (a photosynthetic compartment) and a specialized “paraveinal mesophyll” (a nonphotosynthetic compartment), through which photosynthate must pass on its way to the veins. The 14C kinetics of sterol glucoside, and probably esterified sterol glucoside, were similar to those for 14C-sucrose export. Sterol glucoside was labeled only in its glucose moiety and was the only stem lipid which became strongly labeled during 14C-sucrose translocation. These sterol derivatives may act as membrane carriers of sucrose between the translocation stream and surrounding cells. The kinetics of 14C-sucrose and its movement to the veins are discussed with reference to compartmentation within the leaf and metabolic exchange with other compounds, particularly with starch. Although a simple compartmental model gave a fairly accurate description of 14C-sucrose kinetics, an entirely accurate model could not be provided, primarily because of loss of 14C from sucrose, at an unknown rate, to starch. PMID:16657287

  6. Stepwise nucleosome translocation by RSC remodeling complexes

    PubMed Central

    Harada, Bryan T; Hwang, William L; Deindl, Sebastian; Chatterjee, Nilanjana; Bartholomew, Blaine; Zhuang, Xiaowei

    2016-01-01

    The SWI/SNF-family remodelers regulate chromatin structure by coupling the free energy from ATP hydrolysis to the repositioning and restructuring of nucleosomes, but how the ATPase activity of these enzymes drives the motion of DNA across the nucleosome remains unclear. Here, we used single-molecule FRET to monitor the remodeling of mononucleosomes by the yeast SWI/SNF remodeler, RSC. We observed that RSC primarily translocates DNA around the nucleosome without substantial displacement of the H2A-H2B dimer. At the sites where DNA enters and exits the nucleosome, the DNA moves largely along or near its canonical wrapping path. The translocation of DNA occurs in a stepwise manner, and at both sites where DNA enters and exits the nucleosome, the step size distributions exhibit a peak at approximately 1–2 bp. These results suggest that the movement of DNA across the nucleosome is likely coupled directly to DNA translocation by the ATPase at its binding site inside the nucleosome. DOI: http://dx.doi.org/10.7554/eLife.10051.001 PMID:26895087

  7. Bolaamphiphiles Promote Phospholipid Translocation Across Vesicle Membranes

    PubMed Central

    Forbes, Christopher C.; DiVittorio, Kristy M.; Smith, Bradley D.

    2008-01-01

    A series of membrane-spanning bolaamphiphiles (molecules with two hydrophilic end-groups connected by a hydrophobic linker) were prepared by a modular synthetic method and evaluated for their abilities to affect the dynamics of a surrounding bilayer membrane. The goal was to determine if the bolaamphiphiles promote the translocation of phospholipids across vesicle membranes. The bolaamphiphiles were incorporated at low levels (up to 5 mol%) in vesicles composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC). Inward translocation assays were performed using fluorescent, NBD-labeled phospholipid probes with phosphocholine (PC) or phosphoglycerol (PG) head-groups. The membrane-spanning bolaamphiphiles promote the translocation of both phospholipid probes in the order PG > PC, while shorter bolaamphiphiles (structures that must adopt a U-shape and keep both end-groups in the same leaflet of the membrane), and regular amphiphiles with one hydrophilic end-group, are inactive. These results are an exception to the rule-of-thumb that membrane-spanning bolaamphiphiles are inherently membrane stabilizing molecules that inhibit all types of membrane transport. PMID:16834395

  8. Financial Costs of Large Carnivore Translocations – Accounting for Conservation

    PubMed Central

    Weise, Florian J.; Stratford, Ken J.; van Vuuren, Rudolf J.

    2014-01-01

    Human-carnivore conflict continues to present a major conservation challenge around the world. Translocation of large carnivores is widely implemented but remains strongly debated, in part because of a lack of cost transparency. We report detailed translocation costs for three large carnivore species in Namibia and across different translocation scenarios. We consider the effect of various parameters and factors on costs and translocation success. Total translocation cost for 30 individuals in 22 events was $80,681 (US Dollars). Median translocation cost per individual was $2,393, and $2,669 per event. Median cost per cheetah was $2,760 (n = 23), and $2,108 per leopard (n = 6). One hyaena was translocated at a cost of $1,672. Tracking technology was the single biggest cost element (56%), followed by captive holding and feeding. Soft releases, prolonged captivity and orphaned individuals also increased case-specific costs. A substantial proportion (65.4%) of the total translocation cost was successfully recovered from public interest groups. Less than half the translocations were confirmed successes (44.4%, 3 unknown) with a strong species bias. Four leopards (66.7%) were successfully translocated but only eight of the 20 cheetahs (40.0%) with known outcome met these strict criteria. None of the five habituated cheetahs was translocated successfully, nor was the hyaena. We introduce the concept of Individual Conservation Cost (ICC) and define it as the cost of one successfully translocated individual adjusted by costs of unsuccessful events of the same species. The median ICC for cheetah was $6,898 and $3,140 for leopard. Translocations are costly, but we demonstrate that they are not inherently more expensive than other strategies currently employed in non-lethal carnivore conflict management. We conclude that translocation should be one available option for conserving large carnivores, but needs to be critically evaluated on a case-by-case basis. PMID

  9. Financial costs of large carnivore translocations--accounting for conservation.

    PubMed

    Weise, Florian J; Stratford, Ken J; van Vuuren, Rudolf J

    2014-01-01

    Human-carnivore conflict continues to present a major conservation challenge around the world. Translocation of large carnivores is widely implemented but remains strongly debated, in part because of a lack of cost transparency. We report detailed translocation costs for three large carnivore species in Namibia and across different translocation scenarios. We consider the effect of various parameters and factors on costs and translocation success. Total translocation cost for 30 individuals in 22 events was $80,681 (US Dollars). Median translocation cost per individual was $2,393, and $2,669 per event. Median cost per cheetah was $2,760 (n = 23), and $2,108 per leopard (n = 6). One hyaena was translocated at a cost of $1,672. Tracking technology was the single biggest cost element (56%), followed by captive holding and feeding. Soft releases, prolonged captivity and orphaned individuals also increased case-specific costs. A substantial proportion (65.4%) of the total translocation cost was successfully recovered from public interest groups. Less than half the translocations were confirmed successes (44.4%, 3 unknown) with a strong species bias. Four leopards (66.7%) were successfully translocated but only eight of the 20 cheetahs (40.0%) with known outcome met these strict criteria. None of the five habituated cheetahs was translocated successfully, nor was the hyaena. We introduce the concept of Individual Conservation Cost (ICC) and define it as the cost of one successfully translocated individual adjusted by costs of unsuccessful events of the same species. The median ICC for cheetah was $6,898 and $3,140 for leopard. Translocations are costly, but we demonstrate that they are not inherently more expensive than other strategies currently employed in non-lethal carnivore conflict management. We conclude that translocation should be one available option for conserving large carnivores, but needs to be critically evaluated on a case-by-case basis. PMID

  10. Measurement of background translocation frequencies in individuals with clones

    SciTech Connect

    Wade, M.J.

    1996-08-01

    In the leukemia case the unseparated B and T lymphocytes had a high translocation frequency even after 0.0014, respectively. After purging all clones from the data, the translocation frequencies for Bio 8 and Bio 23 were 0.00750.0014 and 0.0073 metaphases were scored for chromosomal aberrations,, specifically reciprocal translocations, using fluorescence in situ hybridization (FISH). Metaphase spreads were used from two healthy, unexposed individuals (not exposed to radiation, chemotherapy or radiotherapy) and one early B- precursor acute lymphocytic leukemia (ALL) patient (metaphase spreads from both separated T lymphocytes and unseparated B and T lymphocytes were scored). All three individuals had an abnormally high translocation frequency. The high translocation frequencies resulted from clonal expansion of specific translocated chromosomes. I show in this thesis that by purging (discounting or removing) clones from the data of unexposed individuals, one can obtain true background translocation frequencies. In two cases, Bio 8 and Bio 23, the measured translocation frequency for chromosomes 1, 2 and 4 was 0.0124 purging all of the clones from the data. This high translocation frequency may be due to a low frequency of some clones and may not be recognized. The separated T lymphocytes had a higher translocation frequency than expected.

  11. Genomic Heterogeneity of Translocation Renal Cell Carcinoma

    PubMed Central

    Couturier, Jérôme; Molinié, Vincent; Escudier, Bernard; Camparo, Philippe; Su, Xiaoping; Yao, Hui; Tamboli, Pheroze; Lopez-Terrada, Dolores; Picken, Maria; Garcia, Marileila; Multani, Asha S.; Pathak, Sen; Wood, Christopher G.; Tannir, Nizar M.

    2013-01-01

    Purpose Translocation renal cell carcinoma (tRCC) is a rare subtype of kidney cancer involving the TFEB/TFE3 genes. We aimed to investigate the genomic and epigenetic features of this entity. Experimental design Cytogenomic analysis was performed with 250K single-nucleotide polymorphism microarrays on 16 tumor specimens and 4 cell lines. LINE-1 methylation, a surrogate marker of DNA methylation, was performed on 27 cases using pyrosequencing. Results tRCC showed cytogenomic heterogeneity, with 31.2% and 18.7% of cases presenting similarities with clear-cell and papillary RCC profiles, respectively. The most common alteration was a 17q gain in 7 tumors (44%), followed by a 9p loss in 6 cases (37%). Less frequent were losses of 3p and 17p in 5 cases (31%) each. Patients with 17q gain were older (P = 0.0006), displayed more genetic alterations (P < 0.003) and had a worse outcome (P = 0.002) than patients without it. Analysis comparing gene-expression profiling of a subset of tumors bearing 17q gain and those without suggest large scale dosage effects and TP53 haploinsufficiency without any somatic TP53 mutation identified. Cell-line based cytogenetic studies revealed that 17q gain can be related to isochromosome 17 and/or to multiple translocations occurring around 17q breakpoints. Finally, LINE-1 methylation was lower in tRCC tumors from adults compared to tumors from young patients (71.1% vs. 76.7%, P = 0.02). Conclusions Our results reveal genomic heterogeneity of tRCC with similarities to other renal tumor subtypes and raise important questions about the role of TFEB/TFE3 translocations and other chromosomal imbalances in tRCC biology. PMID:23817689

  12. Microbial Translocation Across the GI Tract*

    PubMed Central

    Brenchley, Jason M.; Douek, Daniel C.

    2012-01-01

    The lumen of the gastrointestinal (GI) tract is home to an enormous quantity of different bacterial species, our microbiota, that thrive in an often symbiotic relationship with the host. Given that the healthy host must regulate contact between the microbiota and its immune system to avoid overwhelming systemic immune activation, humans have evolved several mechanisms to attenuate systemic microbial translocation (MT) and its consequences. However, several diseases are associated with the failure of one or more of these mechanisms, with consequent immune activation and deleterious effects on health. Here, we discuss the mechanisms underlying MT, diseases associated with MT, and therapeutic interventions that aim to decrease it. PMID:22224779

  13. Geographic Translocation of Bats: Known and Potential Problems

    PubMed Central

    2003-01-01

    Natural, accidental, and intentional translocation of bats, both intra- and intercontinentally, has been documented. Some bats have been translocated while incubating infectious diseases, including rabies or related lyssavirus infections; others have escaped confinement en route to or at their destinations, while others have been released deliberately. Known events and potential consequences of bat translocation are reviewed, including a proposed solution to the attendant problems. PMID:12533276

  14. The Type III Secretion Translocation Pore Senses Host Cell Contact

    PubMed Central

    Armentrout, Erin I.; Rietsch, Arne

    2016-01-01

    Type III secretion systems (T3SS) are nano-syringes used by a wide range of Gram-negative pathogens to promote infection by directly injecting effector proteins into targeted host cells. Translocation of effectors is triggered by host-cell contact and requires assembly of a pore in the host-cell plasma membrane, which consists of two translocator proteins. Our understanding of the translocation pore, how it is assembled in the host cell membrane and its precise role in effector translocation, is extremely limited. Here we use a genetic technique to identify protein-protein contacts between pore-forming translocator proteins, as well as the T3SS needle-tip, that are critical for translocon function. The data help establish the orientation of the translocator proteins in the host cell membrane. Analysis of translocon function in mutants that break these contacts demonstrates that an interaction between the pore-forming translocator PopD and the needle-tip is required for sensing host cell contact. Moreover, tethering PopD at a dimer interface also specifically prevents host-cell sensing, arguing that the translocation pore is actively involved in detecting host cell contact. The work presented here therefore establishes a signal transduction pathway for sensing host cell contact that is initiated by a conformational change in the translocation pore, and is subsequently transmitted to the base of the apparatus via a specific contact between the pore and the T3SS needle-tip. PMID:27022930

  15. Chaperone-assisted translocation of flexible polymers in three dimensions

    NASA Astrophysics Data System (ADS)

    Suhonen, P. M.; Linna, R. P.

    2016-01-01

    Polymer translocation through a nanometer-scale pore assisted by chaperones binding to the polymer is a process encountered in vivo for proteins. Studying the relevant models by computer simulations is computationally demanding. Accordingly, previous studies are either for stiff polymers in three dimensions or flexible polymers in two dimensions. Here, we study chaperone-assisted translocation of flexible polymers in three dimensions using Langevin dynamics. We show that differences in binding mechanisms, more specifically, whether a chaperone can bind to a single site or multiple sites on the polymer, lead to substantial differences in translocation dynamics in three dimensions. We show that the single-binding mode leads to dynamics that is very much like that in the constant-force driven translocation and accordingly mainly determined by tension propagation on the cis side. We obtain β ≈1.26 for the exponent for the scaling of the translocation time with polymer length. This fairly low value can be explained by the additional friction due to binding particles. The multiple-site binding leads to translocation the dynamics of which is mainly determined by the trans side. For this process we obtain β ≈1.36 . This value can be explained by our derivation of β =4 /3 for constant-bias translocation, where translocated polymer segments form a globule on the trans side. Our results pave the way for understanding and utilizing chaperone-assisted translocation where variations in microscopic details lead to rich variations in the emerging dynamics.

  16. The protein translocation machinery of the endoplasmic reticulum.

    PubMed

    Walter, P; Gilmore, R; Müller, M; Blobel, G

    1982-12-24

    The rough endoplasmic reticulum (r.e.r.) has been postulated to possess a single translation-coupled translocation system (in multiple copies) that effects signal sequence-mediated translocation of all secretory and lysosomal proteins and integration of all integral membrane proteins whose port of entry is the rough endoplasmic reticulum (G. Blobel 1980 Proc. natn. Acad. Sci. U.S.A. 77, 1496-1500). Two proteins have been isolated that are components of the r.e.r. translocation system. Their properties and function in protein translocation across and integration into membranes are discussed. PMID:6131460

  17. Multistep protein unfolding during nanopore translocation

    NASA Astrophysics Data System (ADS)

    Rodriguez-Larrea, David; Bayley, Hagan

    2013-04-01

    Cells are divided into compartments and separated from the environment by lipid bilayer membranes. Essential molecules are transported back and forth across the membranes. We have investigated how folded proteins use narrow transmembrane pores to move between compartments. During this process, the proteins must unfold. To examine co-translocational unfolding of individual molecules, we tagged protein substrates with oligonucleotides to enable potential-driven unidirectional movement through a model protein nanopore, a process that differs fundamentally from extension during force spectroscopy measurements. Our findings support a four-step translocation mechanism for model thioredoxin substrates. First, the DNA tag is captured by the pore. Second, the oligonucleotide is pulled through the pore, causing local unfolding of the C terminus of the thioredoxin adjacent to the pore entrance. Third, the remainder of the protein unfolds spontaneously. Finally, the unfolded polypeptide diffuses through the pore into the recipient compartment. The unfolding pathway elucidated here differs from those revealed by denaturation experiments in solution, for which two-state mechanisms have been proposed.

  18. Adsorption-driven translocation of polymer chain into nanopores

    NASA Astrophysics Data System (ADS)

    Yang, Shuang; Neimark, Alexander V.

    2012-06-01

    The polymer translocation into nanopores is generally facilitated by external driving forces, such as electric or hydrodynamic fields, to compensate for entropic restrictions imposed by the confinement. We investigate the dynamics of translocation driven by polymer adsorption to the confining walls that is relevant to chromatographic separation of macromolecules. By using the self-consistent field theory, we study the passage of a chain trough a small opening from cis to trans compartments of spherical shape with adsorption potential applied in the trans compartment. The chain transfer is modeled as the Fokker-Plank diffusion along the free energy landscape of the translocation pass represented as a sum of the free energies of cis and trans parts of the chain tethered to the pore opening. We investigate how the chain length, the size of trans compartment, the magnitude of adsorption potential, and the extent of excluded volume interactions affect the translocation time and its distribution. Interplay of these factors brings about a variety of different translocation regimes. We show that excluded volume interactions within a certain range of adsorption potentials can cause a local minimum on the free energy landscape, which is absent for ideal chains. The adsorption potential always leads to the decrease of the free energy barrier, increasing the probability of successful translocation. However, the translocation time depends non-monotonically of the magnitude of adsorption potential. Our calculations predict the existence of the critical magnitude of adsorption potential, which separates favorable and unfavorable regimes of translocation.

  19. Adsorption-driven translocation of polymer chain into nanopores.

    PubMed

    Yang, Shuang; Neimark, Alexander V

    2012-06-01

    The polymer translocation into nanopores is generally facilitated by external driving forces, such as electric or hydrodynamic fields, to compensate for entropic restrictions imposed by the confinement. We investigate the dynamics of translocation driven by polymer adsorption to the confining walls that is relevant to chromatographic separation of macromolecules. By using the self-consistent field theory, we study the passage of a chain trough a small opening from cis to trans compartments of spherical shape with adsorption potential applied in the trans compartment. The chain transfer is modeled as the Fokker-Plank diffusion along the free energy landscape of the translocation pass represented as a sum of the free energies of cis and trans parts of the chain tethered to the pore opening. We investigate how the chain length, the size of trans compartment, the magnitude of adsorption potential, and the extent of excluded volume interactions affect the translocation time and its distribution. Interplay of these factors brings about a variety of different translocation regimes. We show that excluded volume interactions within a certain range of adsorption potentials can cause a local minimum on the free energy landscape, which is absent for ideal chains. The adsorption potential always leads to the decrease of the free energy barrier, increasing the probability of successful translocation. However, the translocation time depends non-monotonically of the magnitude of adsorption potential. Our calculations predict the existence of the critical magnitude of adsorption potential, which separates favorable and unfavorable regimes of translocation. PMID:22697566

  20. Microbial translocation in the pathogenesis of HIV infection and AIDS.

    PubMed

    Marchetti, Giulia; Tincati, Camilla; Silvestri, Guido

    2013-01-01

    In pathogenic simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) infections, the translocation of microbial products from the gastrointestinal (GI) tract to portal and systemic circulation has been proposed as a major driver of the chronic immune activation that is associated with disease progression. Consistently, microbial translocation is not present in nonpathogenic SIV infections of natural host species. In vivo studies demonstrated that HIV/SIV-associated microbial translocation results from a series of immunopathological events occurring at the GI mucosa: (i) early and severe mucosal CD4(+) depletion, (ii) mucosal immune hyperactivation/persistent inflammation; (iii) damage to the integrity of the intestinal epithelium with enterocyte apoptosis and tight junction disruption; and (iv) subverted the gut microbiome, with a predominance of opportunistic bacteria. Direct in situ evidence of microbial translocation has been provided for SIV-infected rhesus macaques showing translocated microbial products in the intestinal lamina propria and distant sites. While the mechanisms by which microbial translocation causes immune activation remain controversial, a key pathogenic event appears to be innate immunity activation via Toll-like receptors and other pathogen recognition receptors. Accumulating clinical observations suggest that microbial translocation might affect HIV disease progression, response to therapy, and non-AIDS comorbidities. Given its detrimental effect on overall immunity, several interventions to prevent/block microbial translocation are currently under investigation as novel therapeutic agents for HIV/AIDS. PMID:23297256

  1. Polypeptide translocation by the AAA+ ClpXP protease machine

    PubMed Central

    Barkow, Sarah R.; Levchenko, Igor; Baker, Tania A.; Sauer, Robert T.

    2009-01-01

    In the AAA+ ClpXP protease, ClpX uses repeated cycles of ATP hydrolysis to pull native proteins apart and to translocate the denatured polypeptide into ClpP for degradation. Here, we probe polypeptide features important for translocation. ClpXP degrades diverse synthetic peptide substrates despite major differences in side-chain chirality, size, and polarity. Moreover, translocation occurs without a peptide –NH and with 10 methylenes between successive peptide bonds. Pulling on homopolymeric tracts of glycine, proline, and lysine also allows efficient ClpXP degradation of a stably folded protein. Thus, minimal chemical features of a polypeptide chain are sufficient for translocation and protein unfolding by the ClpX machine. These results suggest that the translocation pore of ClpX is highly elastic, allowing interactions with a wide-range of chemical groups, a feature likely to be shared by many AAA+ unfoldases. PMID:19549599

  2. Range-wide success of red-cockaded woodpecker translocations.

    SciTech Connect

    Edwards, John W.; Costa, Ralph

    2004-12-31

    Edwards, John W.; Costa, Ralph. 2004. Range-wide success of red-cockaded woodpecker translocations. In: Red-cockaded woodpecker; Road to Recovery. Proceedings of the 4th Red-cockaded woodpecker Symposium. Ralph Costa and Susan J. Daniels, eds. Savannah, Georgia. January, 2003. Chapter 6. Translocation. Pp 307-311. Abstract: Red-cockaded woodpeckers (Picoides borealis) have declined range-wide during the past century, suffering from habitat loss and the effects of fire exclusion in older southern pine forests. Red-cockaded woodpecker translocations are a potentially important tool in conservation efforts to reestablish red-cockaded woodpeckers in areas from which they have been extirpated. Currently, translocations are critical in ongoing efforts to save and restore the many existing small populations. We examined the effects of demographic and environmental factors on the range-wide success of translocations between 1989 and 1995.

  3. [Mechanism of tRNA translocation on the ribosome].

    PubMed

    Rodnina, M V; Semenkov, Iu P; Savelsbergh, A; Katunin, V I; Peske, F; Wilden, B; Wintermeyer, W

    2001-01-01

    During the translocation step of the elongation cycle of peptide synthesis two tRNAs together with the mRNA move synchronously and rapidly on the ribosome. Translocation is catalyzed by the elongation factor G (EF-G) and requires GTP hydrolysis. The fundamental biochemical features of the process were worked out in the 1970-80s, to a large part by A.S. Spirin and his colleagues. Recent results from pre-steady-state kinetic analysis and cryoelectron microscopy suggest that translocation is a multistep dynamic process that entails large-scale structural rearrangements of both ribosome and EF-G. Kinetic and thermodynamic data, together with the structural information on the conformational changes of the ribosome and of EF-G, provide a detailed mechanistic model of translocation and suggest a mechanism of translocation catalysis by EF-G. PMID:11524952

  4. Toward a structural understanding of co-translational protein translocation.

    PubMed

    Voorhees, Rebecca M; Hegde, Ramanujan S

    2016-08-01

    The translocation of most eukaryotic secreted and integral membrane proteins occurs co-translationally at the endoplasmic reticulum (ER). These nascent polypeptides are recognized on the ribosome by the signal recognition particle (SRP), targeted to the ER, and translocated across or inserted into the membrane by the Sec61 translocation channel. Structural analysis of these co-translational processes has been challenging due to the size, complexity, and flexibility of the targeting and translocation machinery. Recent technological advances in cryo-electron microscopy (cryo-EM) have resulted in increasingly powerful tools to study large, heterogeneous, and low-abundance samples. These advances are being utilized to obtain near-atomic resolution reconstructions of functional translation, targeting, and translocation intermediates, paving the way to a mechanistic understanding of protein biogenesis. PMID:27155805

  5. Multistep current signal in protein translocation through graphene nanopores.

    PubMed

    Bonome, Emma Letizia; Lepore, Rosalba; Raimondo, Domenico; Cecconi, Fabio; Tramontano, Anna; Chinappi, Mauro

    2015-05-01

    In nanopore sensing experiments, the properties of molecules are probed by the variation of ionic currents flowing through the nanopore. In this context, the electronic properties and the single-layer thickness of graphene constitute a major advantage for molecule characterization. Here we analyze the translocation pathway of the thioredoxin protein across a graphene nanopore, and the related ionic currents, by integrating two nonequilibrium molecular dynamics methods with a bioinformatic structural analysis. To obtain a qualitative picture of the translocation process and to identify salient features we performed unsupervised structural clustering on translocation conformations. This allowed us to identify some specific and robust translocation intermediates, characterized by significantly different ionic current flows. We found that the ion current strictly anticorrelates with the amount of pore occupancy by thioredoxin residues, providing a putative explanation of the multilevel current scenario observed in recently published translocation experiments. PMID:25866995

  6. Strandwise translocation of a DNA glycosylase on undamaged DNA

    SciTech Connect

    Qi, Yan; Nam, Kwangho; Spong, Marie C.; Banerjee, Anirban; Sung, Rou-Jia; Zhang, Michael; Karplus, Martin; Verdine, Gregory L.

    2012-05-14

    Base excision repair of genotoxic nucleobase lesions in the genome is critically dependent upon the ability of DNA glycosylases to locate rare sites of damage embedded in a vast excess of undamaged DNA, using only thermal energy to fuel the search process. Considerable interest surrounds the question of how DNA glycosylases translocate efficiently along DNA while maintaining their vigilance for target damaged sites. Here, we report the observation of strandwise translocation of 8-oxoguanine DNA glycosylase, MutM, along undamaged DNA. In these complexes, the protein is observed to translocate by one nucleotide on one strand while remaining untranslocated on the complementary strand. We further report that alterations of single base-pairs or a single amino acid substitution (R112A) can induce strandwise translocation. Molecular dynamics simulations confirm that MutM can translocate along DNA in a strandwise fashion. These observations reveal a previously unobserved mode of movement for a DNA-binding protein along the surface of DNA.

  7. Translocations of amphibians: Proven management method or experimental technique

    USGS Publications Warehouse

    Seigel, Richard A.; Dodd, C. Kenneth, Jr.

    2002-01-01

    In an otherwise excellent review of metapopulation dynamics in amphibians, Marsh and Trenham (2001) make the following provocative statements (emphasis added): If isolation effects occur primarily in highly disturbed habitats, species translocations may be necessary to promote local and regional population persistence. Because most amphibians lack parental care, they areprime candidates for egg and larval translocations. Indeed, translocations have already proven successful for several species of amphibians. Where populations are severely isolated, translocations into extinct subpopulations may be the best strategy to promote regional population persistence. We take issue with these statements for a number of reasons. First, the authors fail to cite much of the relevant literature on species translocations in general and for amphibians in particular. Second, to those unfamiliar with current research in amphibian conservation biology, these comments might suggest that translocations are a proven management method. This is not the case, at least in most instances where translocations have been evaluated for an appropriate period of time. Finally, the authors fail to point out some of the negative aspects of species translocation as a management method. We realize that Marsh and Trenham's paper was not concerned primarily with translocations. However, because Marsh and Trenham (2001) made specific recommendations for conservation planners and managers (many of whom are not herpetologists or may not be familiar with the pertinent literature on amphibians), we believe that it is essential to point out that not all amphibian biologists are as comfortable with translocations as these authors appear to be. We especially urge caution about advocating potentially unproven techniques without a thorough review of available options.

  8. Minimizing the cost of translocation failure with decision-tree models that predict species' behavioral response in translocation sites.

    PubMed

    Ebrahimi, Mehregan; Ebrahimie, Esmaeil; Bull, C Michael

    2015-08-01

    The high number of failures is one reason why translocation is often not recommended. Considering how behavior changes during translocations may improve translocation success. To derive decision-tree models for species' translocation, we used data on the short-term responses of an endangered Australian skink in 5 simulated translocations with different release conditions. We used 4 different decision-tree algorithms (decision tree, decision-tree parallel, decision stump, and random forest) with 4 different criteria (gain ratio, information gain, gini index, and accuracy) to investigate how environmental and behavioral parameters may affect the success of a translocation. We assumed behavioral changes that increased dispersal away from a release site would reduce translocation success. The trees became more complex when we included all behavioral parameters as attributes, but these trees yielded more detailed information about why and how dispersal occurred. According to these complex trees, there were positive associations between some behavioral parameters, such as fight and dispersal, that showed there was a higher chance, for example, of dispersal among lizards that fought than among those that did not fight. Decision trees based on parameters related to release conditions were easier to understand and could be used by managers to make translocation decisions under different circumstances. PMID:25737134

  9. Analyzing kinesin motor domain translocation in cultured hippocampal neurons

    PubMed Central

    Huang, Chung-Fang; Banker, Gary

    2016-01-01

    Neuronal microtubules are subject to extensive posttranslational modifications and are bound by MAPs, tip-binding proteins, and other accessory proteins. All of these features, which are difficult to replicate in vitro, are likely to influence the translocation of kinesin motors. Here we describe assays for evaluating the translocation of a population of fluorescently labeled kinesin motor domains, based on their accumulation in regions of the cell enriched in microtubule plus ends. Neurons lend themselves to these experiments because of their microtubule organization. In axons, microtubules are oriented with their plus ends out; dendrites contain a mixed population of microtubules, but those near the tips are also plus end out. The assays involve the expression of constitutively active kinesins that can walk processively, but that lack the autoinhibitory domain in the tail that normally prevents their binding to microtubules until they attach to vesicles. The degree to which such motor domains accumulate at neurite tips serves as a measure of the efficiency of their translocation. Although these assays cannot provide the kind of quantitative kinetic information obtained from in vitro assays, they offer a simple way to examine kinesin translocation in living neurons. They can be used to compare the translocation efficiency of different kinesin motors and to evaluate how mutations or posttranslational modifications within the motor domain influence kinesin translocation. Changes to motor domain accumulation in these assays can also serve as readout for changes in the microtubule cytoskeleton that affect kinesin translocation. PMID:26794516

  10. Forced Translocation of Polymer through Nanopore: Deterministic Model and Simulations

    NASA Astrophysics Data System (ADS)

    Wang, Yanqian; Panyukov, Sergey; Liao, Qi; Rubinstein, Michael

    2012-02-01

    We propose a new theoretical model of forced translocation of a polymer chain through a nanopore. We assume that DNA translocation at high fields proceeds too fast for the chain to relax, and thus the chain unravels loop by loop in an almost deterministic way. So the distribution of translocation times of a given monomer is controlled by the initial conformation of the chain (the distribution of its loops). Our model predicts the translocation time of each monomer as an explicit function of initial polymer conformation. We refer to this concept as ``fingerprinting''. The width of the translocation time distribution is determined by the loop distribution in initial conformation as well as by the thermal fluctuations of the polymer chain during the translocation process. We show that the conformational broadening δt of translocation times of m-th monomer δtm^1.5 is stronger than the thermal broadening δtm^1.25 The predictions of our deterministic model were verified by extensive molecular dynamics simulations

  11. Does translocation influence physiological stress in the desert tortoise?

    USGS Publications Warehouse

    Drake, K.K.; Nussear, K.E.; Esque, T.C.; Barber, A.M.; Vittum, K.M.; Medica, P.A.; Tracy, C.R.; Hunter, K.W.

    2012-01-01

    Wildlife translocation is increasingly used to mitigate disturbances to animals or habitat due to human activities, yet little is known about the extent to which translocating animals causes stress. To understand the relationship between physiological stress and translocation, we conducted a multiyear study (2007–2009) using a population of desert tortoises (Gopherus agassizii) near Fort Irwin, California. Blood samples were collected from adult tortoises in three treatment groups (resident, translocated and control) for 1 year prior to and 2 years after translocation. Samples were analyzed by radioimmunoassay for plasma total corticosterone (CORT), a glucocorticoid hormone commonly associated with stress responses in reptiles. CORT values were analyzed in relation to potential covariates (animal sex, date, behavior, treatment, handling time, air temperature, home-range size, precipitation and annual plant production) among seasons and years. CORT values in males were higher than in females, and values for both varied monthly throughout the activity season and among years. Year and sex were strong predictors of CORT, and translocation explained little in terms of CORT. Based on these results, we conclude that translocation does not elicit a physiological stress response in desert tortoises.

  12. Reciprocal translocations in Saccharomyces cerevisiae formed by nonhomologous end joining.

    PubMed

    Yu, Xin; Gabriel, Abram

    2004-02-01

    Reciprocal translocations are common in cancer cells, but their creation is poorly understood. We have developed an assay system in Saccharomyces cerevisiae to study reciprocal translocation formation in the absence of homology. We induce two specific double-strand breaks (DSBs) simultaneously on separate chromosomes with HO endonuclease and analyze the subsequent chromosomal rearrangements among surviving cells. Under these conditions, reciprocal translocations via nonhomologous end joining (NHEJ) occur at frequencies of approximately 2-7 x 10(-5)/cell exposed to the DSBs. Yku80p is a component of the cell's NHEJ machinery. In its absence, reciprocal translocations still occur, but the junctions are associated with deletions and extended overlapping sequences. After induction of a single DSB, translocations and inversions are recovered in wild-type and rad52 strains. In these rearrangements, a nonrandom assortment of sites have fused to the DSB, and their junctions show typical signs of NHEJ. The sites tend to be between open reading frames or within Ty1 LTRs. In some cases the translocation partner is formed by a break at a cryptic HO recognition site. Our results demonstrate that NHEJ-mediated reciprocal translocations can form in S. cerevisiae as a consequence of DSB repair. PMID:15020464

  13. Translocation of threatened plants as a conservation measure in China.

    PubMed

    Liu, Hong; Ren, Hai; Liu, Qiang; Wen, XiangYing; Maunder, Michael; Gao, JiangYun

    2015-12-01

    We assessed the current status of plant conservation translocation efforts in China, a topic poorly reported in recent scientific literature. We identified 222 conservation translocation cases involving 154 species, of these 87 were Chinese endemic species and 101 (78%) were listed as threatened on the Chinese Species Red List. We categorized the life form of each species and, when possible, determined for each case the translocation type, propagule source, propagule type, and survival and reproductive parameters. A surprisingly large proportion (26%) of the conservation translocations in China were conservation introductions, largely implemented in response to large-scale habitat destruction caused by the Three-Gorge Dam and another hydropower project. Documentation and management of the translocations varied greatly. Less than half the cases had plant survival records. Statistical analyses showed that survival percentages were significantly correlated with plant life form and the type of planting materials. Thirty percent of the cases had records on whether or not individuals flowered or fruited. Results of information theoretic model selection indicated that plant life form, translocation type, propagule type, propagule source, and time since planting significantly influenced the likelihood of flowering and fruiting on the project level. We suggest that the scientific-based application of species conservation translocations should be promoted as part of a commitment to species recovery management. In addition, we recommend that the common practice of within and out of range introductions in nature reserves to be regulated more carefully due to its potential ecological risks. We recommend the establishment of a national office and database to coordinate conservation translocations in China. Our review effort is timely considering the need for a comprehensive national guideline for the newly announced nation-wide conservation program on species with extremely

  14. Can hunting of translocated nuisance Canada geese reduce local conflicts?

    USGS Publications Warehouse

    Holevinski, R.A.; Malecki, R.A.; Curtis, P.D.

    2006-01-01

    Resident Canada geese (Branta canadensis) nest or reside in the temperate latitudes of North America. In past years, translocation-the capture and subsequent release of geese at distant locations-has been used to establish resident goose populations and to reduce nuisance problems. However, with new special hunting seasons designed to target resident Canada geese, we can now evaluate translocation as a management tool when hunting is allowed at release sites. We selected 2 study sites, representative of urban and suburban locations with nuisance resident geese, in central and western New York, USA. In June 2003, we translocated 80 neck-banded adult geese, 14 radiomarked adult females, and 83 juveniles 150 km east and southwest from urban and suburban problem sites in western New York to state-owned Wildlife Management Areas. At these same capture sites, we used 151 neck-banded adult geese, 12 radiomarked females, and 100 juveniles as controls to compare dispersal movements and harvest vulnerability to translocated geese. All observations (n = 45) of translocated radiomarked geese were <20 km from release sites, in areas where hunting was permitted. Only 25 of 538 observations (4.6%) of radiomarked geese at control sites were in areas open to hunting. The remainder of observations occurred at nonhunting locations within 10 km of control sites. More translocated adult geese (23.8%) were harvested than control geese (6.6%; ??2 = 72.98, P = 0.0009). More translocated juvenile geese were harvested (22.9%) than juvenile controls (5.0%; ??2 = 72.30, P = 0.0005). Only 7 (8.8%) translocated adult geese returned to the original capture sites during Canada goose hunting seasons. Translocation of adult and juvenile geese in family groups may alleviate nuisance problems at conflict sites through increased harvest, reducing the number of birds returning in subsequent years.

  15. Mode of ATM-dependent suppression of chromosome translocation

    SciTech Connect

    Yamauchi, Motohiro; Suzuki, Keiji; Oka, Yasuyoshi; Suzuki, Masatoshi; Kondo, Hisayoshi; Yamashita, Shunichi

    2011-12-09

    Highlights: Black-Right-Pointing-Pointer We addressed how ATM suppresses frequency of chromosome translocation. Black-Right-Pointing-Pointer We found ATM/p53-dependent G1 checkpoint suppresses translocation frequency. Black-Right-Pointing-Pointer We found ATM and DNA-PKcs function in a common pathway to suppress translocation. -- Abstract: It is well documented that deficiency in ataxia telangiectasia mutated (ATM) protein leads to elevated frequency of chromosome translocation, however, it remains poorly understood how ATM suppresses translocation frequency. In the present study, we addressed the mechanism of ATM-dependent suppression of translocation frequency. To know frequency of translocation events in a whole genome at once, we performed centromere/telomere FISH and scored dicentric chromosomes, because dicentric and translocation occur with equal frequency and by identical mechanism. By centromere/telomere FISH analysis, we confirmed that chemical inhibition or RNAi-mediated knockdown of ATM causes 2 to 2.5-fold increase in dicentric frequency at first mitosis after 2 Gy of gamma-irradiation in G0/G1. The FISH analysis revealed that ATM/p53-dependent G1 checkpoint suppresses dicentric frequency, since RNAi-mediated knockdown of p53 elevated dicentric frequency by 1.5-fold. We found ATM also suppresses dicentric occurrence independently of its checkpoint role, as ATM inhibitor showed additional effect on dicentric frequency in the context of p53 depletion and Chk1/2 inactivation. Epistasis analysis using chemical inhibitors revealed that ATM kinase functions in the same pathway that requires kinase activity of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to suppress dicentric frequency. From the results in the present study, we conclude that ATM minimizes translocation frequency through its commitment to G1 checkpoint and DNA double-strand break repair pathway that requires kinase activity of DNA-PKcs.

  16. Within-Range Translocations and Their Consequences in European Larch

    PubMed Central

    Wagner, Stefanie; Liepelt, Sascha; Gerber, Sophie; Petit, Rémy J.

    2015-01-01

    In contrast to biological invasions, translocations of individuals within a species range are understudied, due to difficulties in systematically detecting them. This results in limited knowledge about the corresponding processes and uncertainties regarding the status of extant populations. European larch, a forest tree whose fragmented native distribution is restricted to the Alps and to other Central European mountains, has been massively planted for at least 300 years. Here we focus on the genetic characterization of translocations having taken place within its native range. Microsatellite variation at 13 nuclear loci and sequence data of two mitochondrial DNA fragments were analyzed on the basis of a comprehensive range-wide population sample. Two complementary methods (Geneclass and Structure) were used to infer translocation events based on nuclear data whereas mitochondrial data were used for validation of these inferences. Using Geneclass, we found translocation events in a majority of populations. Additional cases of translocation and many instances of admixture were identified using Structure, thanks to the clear-cut ancestral genetic structure detected in this species. In particular, a strong divide between Alpine and Central European populations, also apparent at mitochondrial markers, helped uncover details on translocation events and related processes. Translocations and associated admixture events were found to be heterogeneously distributed across the species range, with a particularly high frequency in Central Europe. Furthermore, translocations frequently involved multiple geographic sources, some of which were over-represented. Our study illustrates the importance of range-wide investigations for tracing translocations back to their origins and for revealing some of their consequences. It provides some first clues for developing suitable conservation and management strategies. PMID:26000791

  17. Slowing DNA Translocation through a Nanopore Using a Functionalized Electrode

    PubMed Central

    Krishnakumar, Padmini; Gyarfas, Brett; Song, Weisi; Sen, Suman; Zhang, Peiming; Krstić, Predrag; Lindsay, Stuart

    2013-01-01

    Nanopores were fabricated with an integrated microscale Pd electrode coated with either a hydrogen-bonding, or hydrophobic monolayer. Bare pores, or those coated with octane thiol, translocated single-stranded DNA with times of a few microseconds per base. Pores functionalized with 4(5)-(2-mercaptoethyl)-1H-imidazole-2-carboxamide slowed average translocation times, calculated as the duration of the event divided by the number of bases translocated, to about 100 microseconds per base at biases in the range of 50 to 80 mV. PMID:24161197

  18. Ribosomal Translocation: One Step Closer to the Molecular Mechanism

    PubMed Central

    Shoji, Shinichiro; Walker, Sarah E.; Fredrick, Kurt

    2010-01-01

    Protein synthesis occurs in ribosomes, the targets of numerous antibiotics. How these large and complex machines read and move along mRNA have proven to be challenging questions. In this Review, we focus on translocation, the last step of the elongation cycle in which movement of tRNA and mRNA is catalyzed by elongation factor G. Translocation entails large-scale movements of the tRNAs and conformational changes in the ribosome that require numerous tertiary contacts to be disrupted and reformed. We highlight recent progress toward elucidating the molecular basis of translocation and how various antibiotics influence tRNA–mRNA movement. PMID:19173642

  19. De Novo microdeletion on an inherited Robertsonian translocation chromosome: A cause for dysmorphism in the apparently balanced translocation carrier

    SciTech Connect

    Bonthron, D.T.; Smith, S.J.L.; Fantes, J.; Gosden, C.M.

    1993-09-01

    Robertsonian translocations are usually ascertained through abnormal children, making proposed phenotypic effects of apparently balanced translocations difficult to study in an unbiased way. From molecular genetic studies, though, some apparently balanced rearrangments are now known to be associated with phenotypic abnormalities resulting from uniparental disomy. Molecular explanations for other cases in which abnormality is seen in a balanced translocation carrier are being sought. In the present paper, an infant is described who has retarded growth, developmental delay, gross muscular hypotonia, slender habitus, frontal bossing, micrognathia, hooked nose, abundant wispy hair, and blue sclerae. Cytogenetically, she appeared to be a carrier of a balanced, paternally derived 14;21 Robertsonian translocation. Analysis of DNA polymorphisms showed that she had no paternal allele at the D14S13 locus (14q32). Study of additional DNA markers within 14q32 revealed that her previously undescribed phenotype results from an interstitial microdeletion within 14q32. Fluorescent in situ hybridization was used to show that this microdeletion had occurred de novo on the Robertsonian translocation chromosome. These observations may reactivate old suspicions of a causal association between Robertsonian translocations and de novo rearrangements in offspring; a systematic search for similar subcytogentic rearrangements in other families, in which there are phenotypically abnormal children with apparently balanced translocations, may be fruitful. The clinical and molecular genetic data presented also define a new contiguous gene syndrome due to interstitial 14q32 deletion. 42 refs., 4 figs., 1 tab.

  20. Multiscale model of platelet translocation and collision

    NASA Astrophysics Data System (ADS)

    Wang, Weiwei; Mody, Nipa A.; King, Michael R.

    2013-07-01

    The tethering of platelets on the injured vessel surface mediated by glycoprotein Ibα (GPIbα) - Von Willebrand factor (vWF) bonds, as well as the interaction between flowing platelets and adherent platelets, are two key events that take place immediately following blood vessel injury. This early-stage platelet deposition and accumulation triggers the initiation of hemostasis, a self-defensive mechanism to prevent the body from excessive blood loss. To understand and predict this complex process, one must integrate experimentally determined information on the mechanics and biochemical kinetics of participating receptors over very small time frames (1-1000 μs) and length scales (10-100 nm), to collective phenomena occurring over seconds and tens of microns. In the present study, a unique three dimensional multiscale computational model, Platelet Adhesive Dynamics (PAD), was applied to elucidate the unique physics of (i) a non-spherical, disk-shaped platelet interacting and tethering onto the damaged vessel wall followed by (ii) collisional interactions between a flowing platelet with a downstream adherent platelet. By analyzing numerous simulations under different physiological conditions, we conclude that the platelet's unique spheroid-shape provides heterogeneous, orientation-dependent translocation (rolling) behavior which enhances cell-wall interactions. We also conclude that platelet-platelet near field interactions are critical for cell-cell communication during the initiation of microthrombi. The PAD model described here helps to identify the physical factors that control the initial stages of platelet capture during this process.

  1. Biphasic translocation of Bax to mitochondria.

    PubMed Central

    Capano, Michela; Crompton, Martin

    2002-01-01

    Using green fluorescent protein-tagged Bax, we demonstrate that Bax is sequestered from the cytosol of cardiomyocytes in two distinct phases following the induction of apoptosis with staurosporine. In the first phase, lasting several hours, Bax removal from the cytosol was relatively small. In the second phase, Bax was very largely removed from the cytosol and sequestered into large aggregates associated with the mitochondria. To test which of the phases involved cytochrome c release, cells were transfected with a red fluorescent protein-cytochrome c fusion. The cytochrome c fusion protein was accumulated by mitochondria of healthy cells and was released by staurosporine in phase 1. When green fluorescent protein-Bax was immunoprecipitated from extracts of cells in phase 1 and phase 2, the voltage-dependent anion channel (mitochondrial outer membrane) and the adenine nucleotide translocase (mitochondrial inner membrane) were also precipitated. These data support a two-phase model of Bax translocation in which Bax targets the mitochondrial intermembrane contact sites and releases cytochrome c in the first phase, and is then packaged into large aggregates on mitochondria in the second. PMID:12097139

  2. DNA Translocations through Solid-State Plasmonic Nanopores

    PubMed Central

    2015-01-01

    Nanopores enable label-free detection and analysis of single biomolecules. Here, we investigate DNA translocations through a novel type of plasmonic nanopore based on a gold bowtie nanoantenna with a solid-state nanopore at the plasmonic hot spot. Plasmonic excitation of the nanopore is found to influence both the sensor signal (nanopore ionic conductance blockade during DNA translocation) and the process that captures DNA into the nanopore, without affecting the duration time of the translocations. Most striking is a strong plasmon-induced enhancement of the rate of DNA translocation events in lithium chloride (LiCl, already 10-fold enhancement at a few mW of laser power). This provides a means to utilize the excellent spatiotemporal resolution of DNA interrogations with nanopores in LiCl buffers, which is known to suffer from low event rates. We propose a mechanism based on plasmon-induced local heating and thermophoresis as explanation of our observations. PMID:25347403

  3. Translocation of α-Synuclein Expressed in Escherichia coli▿

    PubMed Central

    Ren, Guoping; Wang, Xi; Hao, Shufeng; Hu, Hongyu; Wang, Chih-chen

    2007-01-01

    α-Synuclein is a major component of Lewy bodies in Parkinson's disease. Although no signal sequence is apparent, α-synuclein expressed in Escherichia coli is mostly located in the periplasm. The possibilities that α-synuclein translocated into the periplasm across the inner membrane by the SecA or the Tat targeting route identified in bacteria and that α-synuclein was released through MscL were excluded. The signal recognition particle-dependent pathway is involved in the translocation of α-synuclein. The C-terminal 99-to-140 portion of the α-synuclein molecule plays a signal-like role for its translocation into the periplasm, cooperating with the central 61-to-95 section. The N-terminal 1-to-60 region is not required for this translocation. PMID:17277073

  4. Translocation of an Incompressible Vesicle through a Pore.

    PubMed

    Shojaei, Hamid R; Muthukumar, Murugappan

    2016-07-01

    We have derived the free energy landscape for the translocation of a single vesicle through a narrow pore by accounting for bending and stretching of the vesicle, and the deformation of the vesicle by the pore. Emergence of a free energy barrier for translocation is a general result, and the magnitude of the barrier is calculated in terms of the various material parameters. The extent of the reduction in the barrier by the presence of an external constant force is calculated. Using the Fokker-Planck formalism, we have calculated the average translocation time corresponding to the various free energy landscapes representing different parameter sets. The dependencies of the average translocation time on the strength of the external force, vesicle size, bending and stretching moduli of the vesicle, and radius and length of the pore are derived, and the computed results are discussed. PMID:27089012

  5. Translocation of an Incompressible Vesicle through a Pore

    PubMed Central

    Shojaei, Hamid R.; Muthukumar, Murugappan

    2016-01-01

    We have derived the free energy landscape for the translocation of a single vesicle through a narrow pore by accounting for bending and stretching of the vesicle, and the deformation of the vesicle by the pore. Emergence of a free energy barrier for translocation is a general result, and the magnitude of the barrier is calculated in terms of the various material parameters. The extent of the reduction in the barrier by the presence of an external constant force is calculated. Using the Fokker–Planck formalism, we have calculated the average translocation time corresponding to the various free energy landscapes representing different parameter sets. The dependencies of the average translocation time on the strength of the external force, vesicle size, bending and stretching moduli of the vesicle, and radius and length of the pore are derived, and the computed results are discussed. PMID:27089012

  6. Translocation of flexible polymersomes across pores at the nanoscale.

    PubMed

    Pegoraro, Carla; Cecchin, Denis; Madsen, Jeppe; Warren, Nicholas; Armes, Steven P; MacNeil, Sheila; Lewis, Andrew; Battaglia, Giuseppe

    2014-04-01

    Hierarchical biological systems such as tissues and organs are often characterised by highly crowded and packed environments with nanoscopic interconnections between them. Engineering nanovectors that can penetrate and diffuse across these is critical to ensure enhanced delivery and targeting. Here we demonstrate that flexible polymeric vesicles, known as polymersomes, enable the translocation of large macromolecules across both synthetic and biological porous systems. We compare the translocation across narrow pores of different polymersome formulations. We demonstrate that effective translocation depends on the right combination of mechanical properties and surface lubrication. We prove that with the effect of external gradients (e.g. osmotic pressure, capillarity, hydration, etc.) polymersomes can translocate across pores with diameters one order of magnitude smaller without breaking. We demonstrate that these properties are essential to develop effective tissue penetration and show polymersome mediated transdermal delivery of large macromolecules such as dextran and antibodies using human ex vivo skin. PMID:26828800

  7. Light-regulated translocation of signaling proteins in Drosophila photoreceptors

    PubMed Central

    Frechter, Shahar; Minke, Baruch

    2007-01-01

    Illumination of Drosophila photoreceptor cells induces multi-facet responses, which include generation of the photoreceptor potential, screening pigment migration and translocation of signaling proteins which is the focus of recent extensive research. Translocation of three signaling molecules is covered in this review: (1) Light-dependent translocation of arrestin from the cytosol to the signaling membrane, the rhabdomere, determines the lifetime of activated rhodopsin. Arrestin translocates in PIP3 and NINAC myosin III dependent manner, and specific mutations which disrupt the interaction between arrestin and PIP3 or NINAC also impair the light-dependant translocation of arrestin and the termination of the response to light. (2) Activation of Drosophila visual G protein, DGq, causes a massive and reversible, translocation of the α subunit from the signaling membrane to the cytosol, accompanied by activity-dependent architectural changes. Analysis of the translocation and the recovery kinetics of DGqα in wild-type flies and specific visual mutants indicated that DGqα is necessary but not sufficient for the architectural changes. (3) The TRP-like (TRPL) but not TRP channels translocate in a light-dependent manner between the rhabdomere and the cell body. As a physiological consequence of this light-dependent modulation of the TRP/TRPL ratio, the photoreceptors of dark-adapted flies operate at a wider dynamic range, which allows the photoreceptors enriched with TRPL to function better in darkness and dim background illumination. Altogether, signal-dependent movement of signaling proteins plays a major role in the maintenance and function of photoreceptor cells. PMID:16458490

  8. Slowing DNA Translocation in a Nanofluidic Field-Effect Transistor.

    PubMed

    Liu, Yifan; Yobas, Levent

    2016-04-26

    Here, we present an experimental demonstration of slowing DNA translocation across a nanochannel by modulating the channel surface charge through an externally applied gate bias. The experiments were performed on a nanofluidic field-effect transistor, which is a monolithic integrated platform featuring a 50 nm-diameter in-plane alumina nanocapillary whose entire length is surrounded by a gate electrode. The field-effect transistor behavior was validated on the gating of ionic conductance and protein transport. The gating of DNA translocation was subsequently studied by measuring discrete current dips associated with single λ-DNA translocation events under a source-to-drain bias of 1 V. The translocation speeds under various gate bias conditions were extracted by fitting event histograms of the measured translocation time to the first passage time distributions obtained from a simple 1D biased diffusion model. A positive gate bias was observed to slow the translocation of single λ-DNA chains markedly; the translocation speed was reduced by an order of magnitude from 18.4 mm/s obtained under a floating gate down to 1.33 mm/s under a positive gate bias of 9 V. Therefore, a dynamic and flexible regulation of the DNA translocation speed, which is vital for single-molecule sequencing, can be achieved on this device by simply tuning the gate bias. The device is realized in a conventional semiconductor microfabrication process without the requirement of advanced lithography, and can be potentially further developed into a compact electronic single-molecule sequencer. PMID:27019102

  9. Elongation factor G initiates translocation through a power stroke.

    PubMed

    Chen, Chunlai; Cui, Xiaonan; Beausang, John F; Zhang, Haibo; Farrell, Ian; Cooperman, Barry S; Goldman, Yale E

    2016-07-01

    During the translocation step of prokaryotic protein synthesis, elongation factor G (EF-G), a guanosine triphosphatase (GTPase), binds to the ribosomal PRE-translocation (PRE) complex and facilitates movement of transfer RNAs (tRNAs) and messenger RNA (mRNA) by one codon. Energy liberated by EF-G's GTPase activity is necessary for EF-G to catalyze rapid and precise translocation. Whether this energy is used mainly to drive movements of the tRNAs and mRNA or to foster EF-G dissociation from the ribosome after translocation has been a long-lasting debate. Free EF-G, not bound to the ribosome, adopts quite different structures in its GTP and GDP forms. Structures of EF-G on the ribosome have been visualized at various intermediate steps along the translocation pathway, using antibiotics and nonhydolyzable GTP analogs to block translocation and to prolong the dwell time of EF-G on the ribosome. However, the structural dynamics of EF-G bound to the ribosome have not yet been described during normal, uninhibited translocation. Here, we report the rotational motions of EF-G domains during normal translocation detected by single-molecule polarized total internal reflection fluorescence (polTIRF) microscopy. Our study shows that EF-G has a small (∼10°) global rotational motion relative to the ribosome after GTP hydrolysis that exerts a force to unlock the ribosome. This is followed by a larger rotation within domain III of EF-G before its dissociation from the ribosome. PMID:27313204

  10. Molecular studies of translocations and trisomy involving chromosome 13

    SciTech Connect

    Robinson, W.P.; Bernasconi, F.; Dutly, F.; Schinzel, A.A.

    1996-01-11

    Twenty-four cases of trisomy 13 and one case with disomy 13, but a de novo dic(13,13)(p12p12) chromosome, were examined with molecular markers to determine the origin of the extra (or rearranged) chromosome. Twenty-one of 23 informative patients were consistent with a maternal origin of the extra chromosome. Lack of a third allele at any locus in both paternal origin cases indicate a somatic duplication of the paternal chromosome occurred. Five cases had translocation trisomy. The patient with a paternal rob(13q14q) had a maternal meiotic origin of the trisomy; thus, the paternal inheritance of the translocation chromosome was purely coincidental. Since there is not a significantly increased risk for unbalanced offspring of a t(13q14q) carrier and most trisomies are maternal in origin, this result should not be surprising; however, it illustrates that one cannot infer the origin of translocation trisomy based on parental origin of the translocation. Lack of a third allele at any locus in one of the three t(13q13q) cases indicates that it was most likely an isochromosome of postmeiotic origin, whereas the other two cases showed evidence of recombination. One balanced (nontrisomic) case with a nonmosaic 45, -13, -13, +t(13;13) karyotype was also investigated and was determined to be a somatic Robertsonian translocation between the maternal and paternal homologues, as has been found for all balanced homologous Robertsonian translocations so far investigated. Thus, it is also incorrect to assume in de novo translocation cases that the two involved chromosomes are even from the same parent. Despite a maternal origin of the trisomy, we cannot therefore infer anything about the parental origin of the chromosomes 13 and 14 involved in the translocation in the de novo t(13q14q) case nor for the two t(13;13) chromosomes showing a meiotic origin of the trisomy. 30 refs., 1 fig., 2 tabs.

  11. Survival of mountain quail translocated from two distinct source populations

    USGS Publications Warehouse

    Troy, Ronald J.; Coates, Peter S.; Connelly, John W.; Gillette, Gifford; Delehanty, David J.

    2013-01-01

    Translocation of mountain quail (Oreortyx pictus) to restore viable populations to their former range has become a common practice. Because differences in post-release vital rates between animals from multiple source populations has not been well studied, wildlife and land managers may arbitrarily choose the source population or base the source population on immediate availability when planning translocation projects. Similarly, an understanding of the optimal proportion of individuals from different age and sex classes for translocation would benefit translocation planning. During 2006 and 2007, we captured and translocated 125 mountain quail from 2 ecologically distinct areas: 38 from southern California and 87 from southwestern Oregon. We released mountain quail in the Bennett Hills of south-central Idaho. We radio-marked and monitored a subsample of 58 quail and used them for a 2-part survival analysis. Cumulative survival probability was 0.23 ± 0.05 (SE) at 150 days post-release. We first examined an a priori hypothesis (model) that survival varied between the 2 distinct source populations. We found that source population did not explain variation in survival. This result suggests that wildlife managers have flexibility in selecting source populations for mountain quail translocation efforts. In a post hoc examination, we pooled the quail across source populations and evaluated differences in survival probabilities between sex and age classes. The most parsimonious model indicated that adult male survival was substantially less than survival rates of other mountain quail age and sex classes (i.e., interaction between sex and age). This result suggests that translocation success could benefit by translocating yearling males rather than adult males, perhaps because adult male breeding behavior results in vulnerability to predators

  12. Surface modification of graphene nanopores for protein translocation

    PubMed Central

    Shan, Y. P.; Tiwari, P. B.; Krishnakumar, P.; Vlassiouk, I.; Li, W.Z.; Wang, X.W.; Darici, Y.; Lindsay, S.M.; Wang, H. D.; Smirnov, S.; He, J.

    2014-01-01

    Studies of DNA translocation through graphene nanopores have revealed their potential for DNA sequencing. Here we report a study of protein translocation through chemically modified graphene nanopores. A transmission electron microscope (TEM) was used to cut nanopores with diameters between 5-20 nm in multilayer graphene prepared by chemical vapor deposition (CVD). After oxygen plasma treatment, the dependence of the measured ionic current on salt concentration and pH was consistent with a small surface charge induced by the formation of carboxyl groups. While translocation of gold nanoparticles (10 nm) was readily detected through such treated pores of a larger diameter, translocation of protein ferritin was not observed either for oxygen plasma treated pores, or for pores modified with mercaptohexadecanoic acid. Ferritin translocation events were reliably observed after the pores were modified with the phospholipid-PEG (DPPE-PEG750) amphiphile. The ion current signature of translocation events was complex, suggesting that a series of interactions between the protein and pore occur during the process. PMID:24231385

  13. Translocation of α-helix chains through a nanopore

    NASA Astrophysics Data System (ADS)

    Yang, Zhiyong; Li, Shiben; Zhang, Linxi; ur Rehman, Ateeq; Liang, Haojun

    2010-10-01

    The translocation of α-helix chains through a nanopore is studied through Langevin dynamics simulations. The α-helix chains exhibit several different characteristics about their average translocation times and the α-helix structures when they transport through the nanopores under the driving forces. First, the relationship between average translocation times τ and the chain length N satisfies the scaling law, τ ˜Nα, and the scaling exponent α depends on the driving force f for the small forces while it is close to the Flory exponent (ν) in the other force regions. For the chains with given chain lengths, it is observed that the dependence of the average translocation times can be expressed as τ ˜f-1/2 for the small forces while can be described as τ ˜f in the large force regions. Second, for the large driving force, the average number of α-helix structures Nh decreases first and then increases in the translocation process. The average waiting time of each bead, especially of the first bead, is also dependent on the driving forces. Furthermore, an elasticity spring model is presented to reasonably explain the change of the α-helix number during the translocation and its elasticity can be locally damaged by the large driving forces. Our results demonstrate the unique behaviors of α-helix chains transporting through the pores, which can enrich our insights into and knowledge on biopolymers transporting through membranes.

  14. Atomic structure of anthrax PA pore elucidates toxin translocation

    PubMed Central

    Jiang, Jiansen; Pentelute, Bradley L.; Collier, R. John; Zhou, Z. Hong

    2015-01-01

    Summary Anthrax toxin, comprising protective antigen (PA), lethal factor (LF) and edema factor (EF), is the major virulence factor of Bacillus anthracis, an agent that causes high mortality in human and animals. PA forms oligomeric prepores that undergo conversion to membrane-spanning pores by endosomal acidification, and these pores translocate the enzymes LF and EF into the cytosol of target cells1. PA is not only a vaccine component and therapeutic target for anthrax infections but also an excellent model system for understanding the mechanism of protein translocation. Based on biochemical and electrophysiological results, researchers have proposed that a Φ-clamp composed of Phe427 residues of PA catalyzes protein translocation via a charge-state dependent Brownian ratchet2–9. Although atomic structures of PA prepores are available10–14, how PA senses low pH, converts to active pore and translocates LF and EF are not well defined without an atomic model of the PA pore. Here, by cryo electron microscopy (cryoEM) with direct electron counting, we have determined the PA pore structure at 2.9-Å resolution. The structure reveals the long-sought-after catalytic Φ-clamp and the membrane-spanning translocation channel, and supports the Brownian ratchet model for protein translocation. Comparisons of four structures reveal conformational changes in prepore to pore conversion that support a multi-step mechanism by which low-pH is sensed and the membrane-spanning channel is formed. PMID:25778700

  15. Protein kinase C translocation in human blood platelets

    SciTech Connect

    Wang, Hoauyan; Friedman, E. )

    1990-01-01

    Protein kinase C (PKC) activity and translocation in response to the phorbol ester, phorbol 12-myristate, 13-acetate (PMA), serotonin (5-HT) and thrombin was assessed in human platelets. Stimulation with PMA and 5-HT for 10 minutes or thrombin for 1 minute elicited platelet PKC translocation from cytosol to membrane. The catecholamines, norepinephrine or epinephrine at 10 {mu}M concentrations did not induce redistribution of platelet PKC. Serotonin and the specific 5-HT{sub 2} receptor agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane (DOI) but not the 5-HT{sub 1A} or 5-HT{sub 1B} agonists, ({plus minus}) 8-hydroxy-dipropylamino-tetralin (8-OH-DPAT) or 5-methoxy-3-3-(1,2,3,6-tetrahydro-4-pyridin) 1H-indole succinate (RU 24969) induced dose-dependent PKC translocations. Serotonin-evoked PKC translocation was blocked by selective 5-HT{sub 2} receptor antagonists, ketanserin and spiroperidol. These results suggest that, in human platelets, PMA, thrombin and 5-HT can elicit PKC translocation from cytosol to membrane. Serotonin-induced PKC translocation in platelets is mediated via 5-HT{sub 2} receptors.

  16. Atomic structure of anthrax protective antigen pore elucidates toxin translocation.

    PubMed

    Jiang, Jiansen; Pentelute, Bradley L; Collier, R John; Zhou, Z Hong

    2015-05-28

    Anthrax toxin, comprising protective antigen, lethal factor, and oedema factor, is the major virulence factor of Bacillus anthracis, an agent that causes high mortality in humans and animals. Protective antigen forms oligomeric prepores that undergo conversion to membrane-spanning pores by endosomal acidification, and these pores translocate the enzymes lethal factor and oedema factor into the cytosol of target cells. Protective antigen is not only a vaccine component and therapeutic target for anthrax infections but also an excellent model system for understanding the mechanism of protein translocation. On the basis of biochemical and electrophysiological results, researchers have proposed that a phi (Φ)-clamp composed of phenylalanine (Phe)427 residues of protective antigen catalyses protein translocation via a charge-state-dependent Brownian ratchet. Although atomic structures of protective antigen prepores are available, how protective antigen senses low pH, converts to active pore, and translocates lethal factor and oedema factor are not well defined without an atomic model of its pore. Here, by cryo-electron microscopy with direct electron counting, we determine the protective antigen pore structure at 2.9-Å resolution. The structure reveals the long-sought-after catalytic Φ-clamp and the membrane-spanning translocation channel, and supports the Brownian ratchet model for protein translocation. Comparisons of four structures reveal conformational changes in prepore to pore conversion that support a multi-step mechanism by which low pH is sensed and the membrane-spanning channel is formed. PMID:25778700

  17. Surface modification of graphene nanopores for protein translocation.

    PubMed

    Shan, Y P; Tiwari, P B; Krishnakumar, P; Vlassiouk, I; Li, W Z; Wang, X W; Darici, Y; Lindsay, S M; Wang, H D; Smirnov, S; He, J

    2013-12-13

    Studies of DNA translocation through graphene nanopores have revealed their potential for DNA sequencing. Here we report a study of protein translocation through chemically modified graphene nanopores. A transmission electron microscope (TEM) was used to cut nanopores with diameters between 5 and 20 nm in multilayer graphene prepared by chemical vapor deposition (CVD). After oxygen plasma treatment, the dependence of the measured ionic current on salt concentration and pH was consistent with a small surface charge induced by the formation of carboxyl groups. While translocation of gold nanoparticles (10 nm) was readily detected through such treated pores of a larger diameter, translocation of the protein ferritin was not observed either for oxygen plasma treated pores, or for pores modified with mercaptohexadecanoic acid. Ferritin translocation events were reliably observed after the pores were modified with the phospholipid-PEG (DPPE-PEG750) amphiphile. The ion current signature of translocation events was complex, suggesting that a series of interactions between the protein and pores occurs during the process. PMID:24231385

  18. Carbon translocation in zooanthaellae-coelenterate symbioses

    SciTech Connect

    Battey, J.F.

    1985-01-01

    When host and algal triglycerides synthesized in the symbiotic sea anemone Condylactis gigantea during light and dark incubations in /sup 14/C-bicarbonate and /sup 14/C-acetate were deacylated, more then 80% of the radioactivity was found in the fatty acid moiety. In contrast, triglycerides isolated from zooxanthellae and host incubated in /sup 14/C-glycerol in the dark were found to have more then 95% of their radioactivity in the glycerol moiety. During /sup 14/C-glycerol incubations in the light, radioactivity in the fatty acid moiety of zooxanthellae triglyceride fatty acid moiety stayed below 5% during /sup 14/C-glycerol incubations in the light. These results show neither the zooxanthellae nor host can rapidly convert glycerol to fatty acid. Radioactivity from /sup 14/C-glycerol that does eventually appear in host lipid may have been respired to /sup 14/CO/sub 2/ then photosynthetically fixed by the zooxanthellae and synthesized into lipid fatty acid. The isolated zooxanthellae of C. gigantea contained 3.62 +/- 0.33 mM glycerol, which was 26x the 0.141 +/- 0.02 mM found in the coelenterate tissue. Aposymbiotic coelenterate tissue contained 0.169 +/- 0.05 mM glycerol. The metabolic inhibitors, sodium cyanide, aminooxyacetic acid and cerulenin were used to try and uncouple the production of glycerol by the zooxanthellae from its utilization by the coelenterate host. 10/sup -5/ M NaCN increased the ratio of cross photosynthesis to respiration in both intact tentacles and isolated zooxanthellae, increased translocation from 17.7 +/- 3.5% of total fixed carbon in controls to 43.5 +/- 5.79%, and doubled the amount of photosynthetically fixed carbon accumulating in the coelenterate host over that in controls.

  19. Using survival analysis to study translocation success in the Gila topminnow (Poeciliopsis occidentalis).

    PubMed

    Sheller, Frances J; Fagan, William F; Unmack, Peter J

    2006-10-01

    Translocation, the intentional release of captive-propagated and/or wild-caught animals into the wild in an attempt to establish, reestablish, or augment a population, is a commonly used approach to species conservation. Despite the frequent mention of translocation as an aid in threatened or endangered species recovery plans, translocations have resulted in the establishment of few sustainable populations. To improve the effectiveness of translocation efforts, it is essential to identify and adopt features that contribute to successful translocations. This study analyzed 148 translocations of the endangered Gila topminnow (Poeciliopsis occidentalis) to identify various factors that have significantly influenced translocation success. We quantified success as the "persistence time" of translocated populations and used survival analysis to interpret the role of several factors. The following factors affected persistence times of translocated populations: season in which the fish were translocated, habitat type of the translocation site, and genetic origin of the fish stocked. In general, factors associated with stocking, the population stocked, and the site of translocation can significantly affect the persistence of translocated populations and thus increase the probability of translocation success. For Gila topminnow, future translocations should be undertaken in late summer or fall (not early summer), should occur into ponds (not streams, wells, or tanks), and should generally utilize individuals from genetic lineages other than Monkey Spring. For other species, a key lesson emerging from this work is that life history attributes for each translocated species need to be considered carefully. PMID:17069370

  20. Conflict Bear Translocation: Investigating Population Genetics and Fate of Bear Translocation in Dachigam National Park, Jammu and Kashmir, India

    PubMed Central

    Mukesh; Sharma, Lalit Kumar; Charoo, Samina Amin; Sathyakumar, Sambandam

    2015-01-01

    The Asiatic black bear population in Dachigam landscape, Jammu and Kashmir is well recognized as one of the highest density bear populations in India. Increasing incidences of bear-human interactions and the resultant retaliatory killings by locals have become a serious threat to the survivorship of black bears in the Dachigam landscape. The Department of Wildlife Protection in Jammu and Kashmir has been translocating bears involved in conflicts, henceforth ‘conflict bears’ from different sites in Dachigam landscape to Dachigam National Park as a flagship activity to mitigate conflicts. We undertook this study to investigate the population genetics and the fate of bear translocation in Dachigam National Park. We identified 109 unique genotypes in an area of ca. 650 km2 and observed bear population under panmixia that showed sound genetic variability. Molecular tracking of translocated bears revealed that mostly bears (7 out of 11 bears) returned to their capture sites, possibly due to homing instincts or habituation to the high quality food available in agricultural croplands and orchards, while only four bears remained in Dachigam National Park after translocation. Results indicated that translocation success was most likely to be season dependent as bears translocated during spring and late autumn returned to their capture sites, perhaps due to the scarcity of food inside Dachigam National Park while bears translocated in summer remained in Dachigam National Park due to availability of surplus food resources. Thus, the current management practices of translocating conflict bears, without taking into account spatio-temporal variability of food resources in Dachigam landscape seemed to be ineffective in mitigating conflicts on a long-term basis. However, the study highlighted the importance of molecular tracking of bears to understand their movement patterns and socio-biology in tough terrains like Dachigam landscape. PMID:26267280

  1. Conflict bear translocation: investigating population genetics and fate of bear translocation in Dachigam National Park, Jammu and Kashmir, India.

    PubMed

    Mukesh; Sharma, Lalit Kumar; Charoo, Samina Amin; Sathyakumar, Sambandam

    2015-01-01

    The Asiatic black bear population in Dachigam landscape, Jammu and Kashmir is well recognized as one of the highest density bear populations in India. Increasing incidences of bear-human interactions and the resultant retaliatory killings by locals have become a serious threat to the survivorship of black bears in the Dachigam landscape. The Department of Wildlife Protection in Jammu and Kashmir has been translocating bears involved in conflicts, henceforth 'conflict bears' from different sites in Dachigam landscape to Dachigam National Park as a flagship activity to mitigate conflicts. We undertook this study to investigate the population genetics and the fate of bear translocation in Dachigam National Park. We identified 109 unique genotypes in an area of ca. 650 km2 and observed bear population under panmixia that showed sound genetic variability. Molecular tracking of translocated bears revealed that mostly bears (7 out of 11 bears) returned to their capture sites, possibly due to homing instincts or habituation to the high quality food available in agricultural croplands and orchards, while only four bears remained in Dachigam National Park after translocation. Results indicated that translocation success was most likely to be season dependent as bears translocated during spring and late autumn returned to their capture sites, perhaps due to the scarcity of food inside Dachigam National Park while bears translocated in summer remained in Dachigam National Park due to availability of surplus food resources. Thus, the current management practices of translocating conflict bears, without taking into account spatio-temporal variability of food resources in Dachigam landscape seemed to be ineffective in mitigating conflicts on a long-term basis. However, the study highlighted the importance of molecular tracking of bears to understand their movement patterns and socio-biology in tough terrains like Dachigam landscape. PMID:26267280

  2. Computer simulation of viral-assembly and translocation

    NASA Astrophysics Data System (ADS)

    Mahalik, Jyoti Prakash

    We investigated four different problems using coarse grained computational models : self-assembly of single stranded (ss) DNA virus, ejection dynamics of double stranded(ds) DNA from phages, translocation of ssDNA through MspA protein pore, and segmental dynamics of a polymer translocating through a synthetic nanopore. In the first part of the project, we investigated the self-assembly of a virus with and without its genome. A coarse-grained model was proposed for the viral subunit proteins and its genome (ssDNA). Langevin dynamics simulation, and replica exchange method were used to determine the kinetics and energetics of the self-assembly process, respectively. The self-assembly follows a nucleation-growth kind of mechanism. The ssDNA plays a crucial role in the self-assembly by acting as a template and enhancing the local concentration of the subunits. The presence of the genome does not changes the mechanism of the self-assembly but it reduces the nucleation time and enhances the growth rate by almost an order of magnitude. The second part of the project involves the investigation of the dynamics of the ejection of dsDNA from phages. A coarse-grained model was used for the phage and dsDNA. Langevin dynamics simulation was used to investigate the kinetics of the ejection. The ejection is a stochastic process and a slow intermediate rate kinetics was observed for most ejection trajectories. We discovered that the jamming of the DNA at the pore mouth at high packing fraction and for a disordered system is the reason for the intermediate slow kinetics. The third part of the project involves translocation of ssDNA through MspA protein pore. MspA protein pore has the potential for genome sequencing because of its ability to clearly distinguish the four different nucleotides based on their blockade current, but it is a challenge to use this pore for any practical application because of the very fast traslocation time. We resolved the state of DNA translocation

  3. High-speed detection of DNA translocation in nanopipettes

    NASA Astrophysics Data System (ADS)

    Fraccari, Raquel L.; Ciccarella, Pietro; Bahrami, Azadeh; Carminati, Marco; Ferrari, Giorgio; Albrecht, Tim

    2016-03-01

    We present a high-speed electrical detection scheme based on a custom-designed CMOS amplifier which allows the analysis of DNA translocation in glass nanopipettes on a microsecond timescale. Translocation of different DNA lengths in KCl electrolyte provides a scaling factor of the DNA translocation time equal to p = 1.22, which is different from values observed previously with nanopipettes in LiCl electrolyte or with nanopores. Based on a theoretical model involving electrophoresis, hydrodynamics and surface friction, we show that the experimentally observed range of p-values may be the result of, or at least be affected by DNA adsorption and friction between the DNA and the substrate surface.We present a high-speed electrical detection scheme based on a custom-designed CMOS amplifier which allows the analysis of DNA translocation in glass nanopipettes on a microsecond timescale. Translocation of different DNA lengths in KCl electrolyte provides a scaling factor of the DNA translocation time equal to p = 1.22, which is different from values observed previously with nanopipettes in LiCl electrolyte or with nanopores. Based on a theoretical model involving electrophoresis, hydrodynamics and surface friction, we show that the experimentally observed range of p-values may be the result of, or at least be affected by DNA adsorption and friction between the DNA and the substrate surface. Electronic supplementary information (ESI) available: Gel electrophoresis confirming lengths and purity of DNA samples, comparison between Axopatch 200B and custom-built setup, comprehensive low-noise amplifier characterization, representative I-V curves of nanopipettes used, typical scatter plots of τ vs. peak amplitude for the four LDNA's used, table of most probable τ values, a comparison between different fitting models for the DNA translocation time distribution, further details on the stochastic numerical simulation of the scaling statistics and the derivation of the extended

  4. Strandwise translocation of a DNA glycosylase on undamaged DNA.

    PubMed

    Qi, Yan; Nam, Kwangho; Spong, Marie C; Banerjee, Anirban; Sung, Rou-Jia; Zhang, Michael; Karplus, Martin; Verdine, Gregory L

    2012-01-24

    Base excision repair of genotoxic nucleobase lesions in the genome is critically dependent upon the ability of DNA glycosylases to locate rare sites of damage embedded in a vast excess of undamaged DNA, using only thermal energy to fuel the search process. Considerable interest surrounds the question of how DNA glycosylases translocate efficiently along DNA while maintaining their vigilance for target damaged sites. Here, we report the observation of strandwise translocation of 8-oxoguanine DNA glycosylase, MutM, along undamaged DNA. In these complexes, the protein is observed to translocate by one nucleotide on one strand while remaining untranslocated on the complementary strand. We further report that alterations of single base-pairs or a single amino acid substitution (R112A) can induce strandwise translocation. Molecular dynamics simulations confirm that MutM can translocate along DNA in a strandwise fashion. These observations reveal a previously unobserved mode of movement for a DNA-binding protein along the surface of DNA. PMID:22219368

  5. Criteria for minimal model of driven polymer translocation.

    PubMed

    Suhonen, P M; Kaski, K; Linna, R P

    2014-10-01

    While the characteristics of the driven translocation for asymptotically long polymers are well understood, this is not the case for finite-sized polymers, which are relevant for real-world experiments and simulation studies. Most notably, the behavior of the exponent α, which describes the scaling of the translocation time with polymer length, when the driving force fp in the pore is changed, is under debate. By Langevin dynamics simulations of regular and modified translocation models using the freely jointed-chain polymer model we find that a previously reported incomplete model, where the trans side and fluctuations were excluded, gives rise to characteristics that are in stark contradiction with those of the complete model, for which α increases with fp. Our results suggest that contribution due to fluctuations is important. We construct a minimal model where dynamics is completely excluded to show that close alignment with a full translocation model can be achieved. Our findings set very stringent requirements for a minimal model that is supposed to describe the driven polymer translocation correctly. PMID:25375518

  6. Temperature dependence of DNA translocations through solid-state nanopores

    PubMed Central

    Verschueren, Daniel V.; Jonsson, Magnus P.; Dekker, Cees

    2015-01-01

    In order to gain a better physical understanding of DNA translocations through solid-state nanopores, we study the temperature dependence of λ-DNA translocations through 10 nm-in-diameter silicon-nitride nanopores, both experimentally and theoretically. The measured ionic conductance G, the DNA-induced ionic-conductance blockades ΔG and the event frequency Γ all increase with increasing temperature while the DNA translocation time τ decreases. G and ΔG are accurately described when bulk and surface conductances of the nanopore are considered and access resistance is incorporated appropriately. Viscous drag on the untranslocated part of the DNA coil is found to dominate the temperature dependence of the translocation times and the event rate is well described by a balance between diffusion and electrophoretic motion. The good fit between modeled and measured properties of DNA translocations through solid-state nanopores in this first comprehensive temperature study, suggest that our model captures the relevant physics of the process. PMID:25994084

  7. Translocation and Endocytosis for Cell-penetrating Peptide Internalization

    PubMed Central

    Jiao, Chen-Yu; Delaroche, Diane; Burlina, Fabienne; Alves, Isabel D.; Chassaing, Gérard; Sagan, Sandrine

    2009-01-01

    Cell-penetrating peptides (CPPs) share the property of cellular internalization. The question of how these peptides reach the cytoplasm of cells is still widely debated. Herein, we have used a mass spectrometry-based method that enables quantification of internalized and membrane-bound peptides. Internalization of the most used CPP was studied at 37 °C (endocytosis and translocation) and 4 °C (translocation) in wild type and proteoglycan-deficient Chinese hamster ovary cells. Both translocation and endocytosis are internalization pathways used by CPP. The choice of one pathway versus the other depends on the peptide sequence (not the number of positive changes), the extracellular peptide concentration, and the membrane components. There is no relationship between the high affinity of these peptides for the cell membrane and their internalization efficacy. Translocation occurs at low extracellular peptide concentration, whereas endocytosis, a saturable and cooperative phenomenon, is activated at higher concentrations. Translocation operates in a narrow time window, which implies a specific lipid/peptide co-import in cells. PMID:19833724

  8. Some Factors Regulating Auxin Translocation in Intact Bean Seedlings 1

    PubMed Central

    Long, John; Basler, Eddie

    1973-01-01

    Several factors which influence the translocation patterns of stem-injected indoleacetic acid, 2,4-dichlorophenoxyacetic acid, and 2,4,5-trichlorophenoxyacetic acid in bean seedlings (Phaseolus vulgaris L. cv. Stringless Greenpod) were characterized. The acropetal translocation of auxin from the site of injection is markedly sensitive to concentration in the range of 1.0 to 5.0 micrograms per plant. The antiauxin p-chlorophenoxyisobutyric acid enhanced translocation of 2,4,5-trichlorophenoxyacetic acid to the growing shoots and primary leaves. Translocation to the roots was unaffected by p-chlorophenoxyisobutyric acid while leaching of 2,4,5-trichlorophenoxyacetic acid into the nutrient solution was enhanced slightly. Steam girdling experiments revealed that translocation to the primary leaves was in the xylem. The protein synthesis inhibitor, cycloheximide, inhibited accumulation of 2,4,5-trichlorophenoxyacetic acid in young shoots, epicotyls, and roots and enhanced accumulation in the primary leaves. The relative exchangeability of auxin between xylem and phloem is discussed in terms of regulation of auxin movements in intact bean seedlings. Images PMID:16658273

  9. Sulfur Dioxide Inhibition of Translocation in Bean Plants 1

    PubMed Central

    Teh, Kwang Ho; Swanson, Carroll A.

    1982-01-01

    Exposure of the source leaf of bean (Phaseolus vulgaris L. cv. Black Valentine) for 2 hours to 2.9 microliters per liter SO2 inhibited the net photosynthetic rate an average of 75% and, simultaneously, the translocation rate an average of 45%. Calculations indicated that the experimentally determined translocation rates from SO2-stressed leaves were lower than were the rates expected on the basis of the observed reductions in photosynthesis. It is inferred that, under SO2 stress, the phloem-loading system becomes a major limiting step in controlling the translocation rate. Following removal of SO2, photosynthesis recovered quite rapidly (to about 60% of its preexposure rate within 2 hours), but the translocation rate failed to increase during this time interval. This delayed response of translocation to removal of SO2 does not appear to be due to an injury effect of SO2, inasmuch as a similar effect was obtained by exposing the source leaf to a short (2-hour) interval of dark. PMID:16662191

  10. Meiotic behaviour of evolutionary sex-autosome translocations in Bovidae.

    PubMed

    Vozdova, Miluse; Ruiz-Herrera, Aurora; Fernandez, Jonathan; Cernohorska, Halina; Frohlich, Jan; Sebestova, Hana; Kubickova, Svatava; Rubes, Jiri

    2016-09-01

    The recurrent occurrence of sex-autosome translocations during mammalian evolution suggests common mechanisms enabling a precise control of meiotic synapsis, recombination and inactivation of sex chromosomes. We used immunofluorescence and FISH to study the meiotic behaviour of sex chromosomes in six species of Bovidae with evolutionary sex-autosome translocations (Tragelaphus strepsiceros, Taurotragus oryx, Tragelaphus imberbis, Tragelaphus spekii, Gazella leptoceros and Nanger dama ruficollis). The autosomal regions of fused sex chromosomes showed normal synapsis with their homologous counterparts. Synapsis in the pseudoautosomal region (PAR) leads to the formation of characteristic bivalent (in T. imberbis and T. spekii with X;BTA13/Y;BTA13), trivalent (in T. strepsiceros and T. oryx with X/Y;BTA13 and G. leptoceros with X;BTA5/Y) and quadrivalent (in N. dama ruficollis with X;BTA5/Y;BTA16) structures at pachynema. However, when compared with other mammals, the number of pachynema lacking MLH1 foci in the PAR was relatively high, especially in T. imberbis and T. spekii, species with both sex chromosomes involved in sex autosome translocations. Meiotic transcriptional inactivation of the sex-autosome translocations assessed by γH2AX staining was restricted to their gonosomal regions. Despite intraspecies differences, the evolutionary fixation of sex-autosome translocations among bovids appears to involve general mechanisms ensuring sex chromosome pairing, synapsis, recombination and inactivation. PMID:27136937

  11. Electrostatics of polymer translocation events in electrolyte solutions

    NASA Astrophysics Data System (ADS)

    Buyukdagli, Sahin; Ala-Nissila, T.

    2016-07-01

    We develop an analytical theory that accounts for the image and surface charge interactions between a charged dielectric membrane and a DNA molecule translocating through the membrane. Translocation events through neutral carbon-based membranes are driven by a competition between the repulsive DNA-image-charge interactions and the attractive coupling between the DNA segments on the trans and the cis sides of the membrane. The latter effect is induced by the reduction of the coupling by the dielectric membrane. In strong salt solutions where the repulsive image-charge effects dominate the attractive trans-cis coupling, the DNA molecule encounters a translocation barrier of ≈10 kBT. In dilute electrolytes, the trans-cis coupling takes over image-charge forces and the membrane becomes a metastable attraction point that can trap translocating polymers over long time intervals. This mechanism can be used in translocation experiments in order to control DNA motion by tuning the salt concentration of the solution.

  12. Electrostatics of polymer translocation events in electrolyte solutions.

    PubMed

    Buyukdagli, Sahin; Ala-Nissila, T

    2016-07-01

    We develop an analytical theory that accounts for the image and surface charge interactions between a charged dielectric membrane and a DNA molecule translocating through the membrane. Translocation events through neutral carbon-based membranes are driven by a competition between the repulsive DNA-image-charge interactions and the attractive coupling between the DNA segments on the trans and the cis sides of the membrane. The latter effect is induced by the reduction of the coupling by the dielectric membrane. In strong salt solutions where the repulsive image-charge effects dominate the attractive trans-cis coupling, the DNA molecule encounters a translocation barrier of ≈10 kBT. In dilute electrolytes, the trans-cis coupling takes over image-charge forces and the membrane becomes a metastable attraction point that can trap translocating polymers over long time intervals. This mechanism can be used in translocation experiments in order to control DNA motion by tuning the salt concentration of the solution. PMID:27394120

  13. Low processivity for DNA translocation by the ISWI molecular motor.

    PubMed

    Eastlund, Allen; Al-Ani, Gada; Fischer, Christopher J

    2015-10-01

    The motor protein ISWI (Imitation SWItch) is the conserved catalytic ATPase domain of the ISWI family of chromatin remodelers. Members of the ISWI family are involved in regulating the structure of cellular chromatin during times of transcription, translation, and repair. Current models for the nucleosome repositioning activity of ISWI and other chromatin remodelers require the translocation of the remodeling protein along double-stranded DNA through an ATP-dependent mechanism. Here we report results from spectrofluorometric stopped-flow experiments which demonstrate that ISWI displays very low processivity for free DNA translocation. By combining these results with those from experiments monitoring the DNA stimulated ATPase activity of ISWI we further demonstrate that the DNA translocation by ISWI is tightly coupled to ATP hydrolysis. The calculated coupling efficiency of 0.067±0.018 ATP/ISWI/bp is seemingly quite low in comparison to similar DNA translocases and we present potential models to account for this. Nevertheless, the tight coupling of ATP hydrolysis to DNA translocation suggests that DNA translocation is not energetically rate limiting for nucleosome repositioning by ISWI. PMID:26116984

  14. Uptake and translocation of hexachlorobenzene: Oilpumpkin and sunflower

    SciTech Connect

    1993-10-01

    The uptake of hexachlorobenzene (HCB) and its translocation to seeds were studied with oil pumpkin and sunflower plants. Open air pot experiments were conducted with soil treated with different amounts of HCB. 14C-labelled HCB was used in solution culture experiments with young plants to investigate the distribution of HCB within the plants. During the experiments the contaminant was taken up by the root system of pumkin plant and translocated intensity to the reproductive organs. Autoradiographic pictures of crossections of stems and young fruits confirm this. Such translocation mechanism was not found in sunflower. Nevertheless it can be assumed that under field conditions the uptake of vaporized HCB from contamination soil by foliage and fruits of oil pumpkin is the main pathway of contamination.

  15. Resistance to glyphosate from altered herbicide translocation patterns.

    PubMed

    Preston, Christopher; Wakelin, Angela M

    2008-04-01

    Glyphosate-resistant weeds have evolved as a result of the intensive use of glyphosate for weed control. An alteration in the way glyphosate is translocated within the plant has been identified as a mechanism of glyphosate resistance in populations of Lolium rigidum Gaud., L. multiflorum Lam. and Conyza canadensis (L.) Cronq. In these resistant plants, glyphosate becomes concentrated in the leaves rather than being translocating throughout the plant. This type of resistance is inherited as a single dominant or semi-dominant allele. Resistance due to reduced translocation appears to be a common mechanism of resistance in L. rigidum and C. canadensis, probably because it provides a greater level of resistance than other mechanisms. This type of glyphosate resistance also appears to reduce the fitness of plants that carry it. This may influence how glyphosate resistance can be managed. PMID:18080284

  16. Translocation of polymers into crowded media with dynamic attractive nanoparticles.

    PubMed

    Cao, Wei-Ping; Ren, Qing-Bao; Luo, Meng-Bo

    2015-07-01

    The translocation of polymers through a small pore into crowded media with dynamic attractive nanoparticles is simulated. Results show that the nanoparticles at the trans side can affect the translocation by influencing the free-energy landscape and the diffusion of polymers. Thus the translocation time τ is dependent on the polymer-nanoparticle attraction strength ɛ and the mobility of nanoparticles V. We observe a power-law relation of τ with V, but the exponent is dependent on ɛ and nanoparticle concentration. In addition, we find that the effect of attractive dynamic nanoparticles on the dynamics of polymers is dependent on the time scale. At a short time scale, subnormal diffusion is observed at strong attraction and the diffusion is slowed down by the dynamic nanoparticles. However, the diffusion of polymers is normal at a long time scale and the diffusion constant increases with the increase in V. PMID:26274196

  17. High-speed detection of DNA translocation in nanopipettes.

    PubMed

    Fraccari, Raquel L; Ciccarella, Pietro; Bahrami, Azadeh; Carminati, Marco; Ferrari, Giorgio; Albrecht, Tim

    2016-04-14

    We present a high-speed electrical detection scheme based on a custom-designed CMOS amplifier which allows the analysis of DNA translocation in glass nanopipettes on a microsecond timescale. Translocation of different DNA lengths in KCl electrolyte provides a scaling factor of the DNA translocation time equal to p = 1.22, which is different from values observed previously with nanopipettes in LiCl electrolyte or with nanopores. Based on a theoretical model involving electrophoresis, hydrodynamics and surface friction, we show that the experimentally observed range of p-values may be the result of, or at least be affected by DNA adsorption and friction between the DNA and the substrate surface. PMID:26985713

  18. Crystallographic snapshot of cellulose synthesis and membrane translocation

    PubMed Central

    Morgan, Jacob L.W.; Strumillo, Joanna; Zimmer, Jochen

    2012-01-01

    Cellulose, the most abundant biological macromolecule, is an extracellular, linear polymer of glucose molecules. It represents an essential component of plant cell walls but is also found in algae and bacteria. In bacteria, cellulose production frequently correlates with the formation of biofilms, a sessile, multicellular growth form. Cellulose synthesis and transport across the inner bacterial membrane is mediated by a complex of the multi-spanning catalytic BcsA subunit and the membrane-anchored, periplasmic BcsB protein. Here we present the crystal structure of a complex of BcsA and BcsB from Rhodobacter sphaeroides containing a translocating polysaccharide. The structure of the BcsA-B translocation intermediate reveals the architecture of the cellulose synthase, demonstrates how BcsA forms a cellulose-conducting channel, and suggests a model for the coupling of cellulose synthesis and translocation in which the nascent polysaccharide is extended by one glucose molecule at a time. PMID:23222542

  19. Insights into Buforin II Membrane Translocation from Molecular Dynamics Simulations

    PubMed Central

    Elmore, Donald E.

    2012-01-01

    Buforin II is a histone-derived antimicrobial peptide that readily translocates across lipid membranes without causing significant membrane permeabilization. Previous studies showed that mutating the sole proline of buforin II dramatically decreases its translocation. As well, researchers have proposed that the peptide crosses membranes in a cooperative manner through forming transient toroidal pores. This paper reports molecular dynamics simulations designed to investigate the structure of buforin II upon membrane entry and evaluate whether the peptide is able to form toroidal pore structures. These simulations showed a relationship between protein-lipid interactions and increased structural deformations of the buforin N-terminal region promoted by proline. Moreover, simulations with multiple peptides show how buforin II can embed deeply into membranes and potentially form toroidal pores. Together, these simulations provide structural insight into the translocation process for buforin II in addition to providing more general insight into the role proline can play in antimicrobial peptides. PMID:23022591

  20. The role of phospholipase D in Glut-4 translocation.

    PubMed

    Huang, Ping; Frohman, Michael A

    2003-01-01

    Insulin-stimulated Glut-4 translocation is regulated through a complex pathway. Increasing attention is being paid to the role undertaken in this process by Phospholipase D, a signal transduction-activated enzyme that generates the lipid second-messenger phosphatidic acid. Phospholipase D facilitates Glut-4 translocation at potentially multiple steps in its outward movement. Current investigation is centered on Phospholipase D promotion of Glut-4-containing membrane vesicle trafficking and vesicle fusion into the plasma membrane, in part through activation of atypical protein kinase C isoforms. PMID:14648804

  1. Habitat drives dispersal and survival of translocated juvenile desert tortoises

    USGS Publications Warehouse

    Nafus, Melia G.; Esque, Todd; Averill-Murray, Roy C.; Nussear, Kenneth E.; Swaisgood, Ronald R.

    2016-01-01

    5.Synthesis and applications. Resource managers using translocations as a conservation tool should prioritize acquiring data linking habitat to fitness. In particular, for species that depend on avoiding detection, refuges such as burrows and habitat that improved concealment had notable ability to improve survival and dispersal. Our study on juvenile Mojave desert tortoises showed that refuge availability or the distributions of habitat appropriate for concealment are important considerations for identifying translocation sites for species highly dependent on crypsis, camouflage, or other forms of habitat matching.

  2. Free energy evaluation in polymer translocation via Jarzynski equality

    NASA Astrophysics Data System (ADS)

    Mondaini, Felipe; Moriconi, L.

    2014-05-01

    We perform, with the help of cloud computing resources, extensive Langevin simulations, which provide free energy estimates for unbiased three-dimensional polymer translocation. We employ the Jarzynski equality in its rigorous setting, to compute the variation of the free energy in single monomer translocation events. In our three-dimensional Langevin simulations, the excluded-volume and van der Waals interactions between beads (monomers and membrane atoms) are modeled through a repulsive Lennard-Jones (LJ) potential and consecutive monomers are subject to the Finite-Extension Nonlinear Elastic (FENE) potential. Analysing data for polymers with different lengths, the free energy profile is noted to have interesting finite-size scaling properties.

  3. Resistive Pulse Analysis of Microgel Deformation During Nanopore Translocation

    PubMed Central

    Holden, Deric A.; Hendrickson, Grant; Lyon, L. Andrew; White, Henry S.

    2012-01-01

    Deformation of 570-nm radius poly(N-isopropylacrylamide-co-acrylic acid) microgels passing through individual 375- to 915-nm radius nanopores in glass has been investigated by the resistive-pulse method. Particle translocation through nanopores of dimensions smaller than the microgel yields electrical signatures reflecting the dynamics of microgel deformation. Translocation rates, and event duration and peak shape, are functions of the conductivities of microgel and electrolyte. Our results demonstrate that nanopore resistive-pulse methods provide new fundamental insights into microgel permeation through porous membranes.

  4. Pore translocation of polymer chains with physical knots

    NASA Astrophysics Data System (ADS)

    Suma, Antonio; Rosa, Angelo; Micheletti, Cristian

    The driven traslocation of knotted chains through narrow pores has important implications for single-molecule manipulation contexts. Its complex phenomenology is, however, still largely unexplored, both as a function of knot complexity and the magnitude of the driving, translocating force. We accordingly report on a systematic theoretical and computational investigation of both aspects. In particular we consider the case of flexible chains accommodating a large repertoire of knots that are driven through pores too narrow to allow for their passage. We show that the observed rich translocation phenomenology can be rationalised in a transparent mechanical framework that can further be used for predictive purposes.

  5. Genomewide Search for Type 2 Diabetes–Susceptibility Genes in French Whites: Evidence for a Novel Susceptibility Locus for Early-Onset Diabetes on Chromosome 3q27-qter and Independent Replication of a Type 2–Diabetes Locus on Chromosome 1q21–q24

    PubMed Central

    Vionnet, Nathalie; Hani, El Habib; Dupont, Sophie; Gallina, Sophie; Francke, Stephan; Dotte, Sébastien; De Matos, Frédérique; Durand, Emmanuelle; Leprêtre, Frédéric; Lecoeur, Cécile; Gallina, Philippe; Zekiri, Lirije; Dina, Christian; Froguel, Philippe

    2000-01-01

    Despite recent advances in the molecular genetics of type 2 diabetes, the majority of susceptibility genes in humans remain to be identified. We therefore conducted a 10-cM genomewide search (401 microsatellite markers) for type 2 diabetes–related traits in 637 members of 143 French pedigrees ascertained through multiple diabetic siblings, to map such genes in the white population. Nonparametric two-point and multipoint linkage analyzes—using the MAPMAKER-SIBS (MLS) and MAXIMUM-BINOMIAL-LIKELIHOOD (MLB) programs for autosomal markers and the ASPEX program for chromosome X markers—were performed with six diabetic phenotypes: diabetes and diabetes or glucose intolerance (GI), as well as with each of the two phenotypes associated with normal body weight (body-mass index<27 kg/m2) or early age at diagnosis (<45 years). In a second step, high-resolution genetic mapping (∼2 cM) was performed in regions on chromosomes 1 and 3 loci showing the strongest linkage to diabetic traits. We found evidence for linkage with diabetes or GI diagnosed at age <45 years in 92 affected sib pairs from 55 families at the D3S1580 locus on chromosome 3q27-qter using MAPMAKER-SIBS (MLS = 4.67, P=.000004), supported by the MLB statistic (MLB-LOD=3.43, P=.00003). We also found suggestive linkage between the lean diabetic status and markers APOA2–D1S484 (MLS = 3.04, P=.00018; MLB-LOD=2.99, P=.00010) on chromosome 1q21-q24. Several other chromosomal regions showed indication of linkage with diabetic traits, including markers on chromosome 2p21-p16, 10q26, 20p, and 20q. These results (a) showed evidence for a novel susceptibility locus for type 2 diabetes in French whites on chromosome 3q27-qter and (b) confirmed the previously reported diabetes-susceptibility locus on chromosome 1q21-q24. Saturation on both chromosomes narrowed the regions of interest down to an interval of <7 cM. PMID:11067779

  6. Distribution and survival of Escherichia coli translocating from the intestine after thermal injury.

    PubMed Central

    Alexander, J W; Gianotti, L; Pyles, T; Carey, M A; Babcock, G F

    1991-01-01

    The present investigation was performed to study the kinetics of tissue distribution and deposition of Escherichia coli and endotoxin translocating from the intestine after thermal injury. Escherichia coli was grown in the presence of 14C glucose and both labeled bacteria and endotoxin prepared from the labeled bacteria were used as translocation probes. Escherichia coli (10(8) to 10(10) bacteria) and E. coli endotoxin (100 micrograms per animal) were gavaged into the stomach immediately before a 30% burn injury was inflicted in mice. Animals were killed 1, 4 and 24 hours after burn injury. Translocation occurred extensively within 1 hour after burn injury. Expressed as amount of radioactivity per gram of tissue, translocation was greatest in the mesenteric lymph node (MLN) followed by spleen, lung, and liver. Translocation of endotoxin was similar to translocation of intact bacteria, with the exception that less radioactivity could be found in the peritoneal cavity and more in the liver. Both intact E. coli and endotoxin translocated directly through the intact bowel wall. Killing of bacteria was greatest in the MLN and spleen, approximating 95% to more than 99% of translocating bacteria. Killing efficiency was lowest in the lungs. It is concluded that estimation of translocation by viable bacterial counts in tissues grossly underestimates the extent of translocation of bacteria and ignores the extent of translocation of endotoxin. Translocation of endotoxin may have biologic significance that is independent of and in addition to translocation of intact bacteria. PMID:2039286

  7. Translocation as a conservation tool for Agassiz's desert tortoises: survivorship, reproduction, and movements

    USGS Publications Warehouse

    Nussear, K.E.; Tracy, C.R.; Medica, P.A.; Wilson, D.S.; Marlow, R.W.; Corn, P.S.

    2012-01-01

    We translocated 120 Agassiz's desert tortoises to 5 sites in Nevada and Utah to evaluate the effects of translocation on tortoise survivorship, reproduction, and habitat use. Translocation sites included several elevations, and extended to sites with vegetation assemblages not typically associated with desert tortoises in order to explore the possibility of moving animals to upper elevation areas. We measured survivorship, reproduction, and movements of translocated and resident animals at each site. Survivorship was not significantly different between translocated and resident animals within and among sites, and survivorship was greater overall during non-drought years. The number of eggs produced by tortoises was similar for translocated and resident females, but differed among sites. Animals translocated to atypical habitat generally moved until they reached vegetation communities more typical of desert tortoise habitat. Even within typical tortoise habitat, tortoises tended to move greater distances in the first year after translocation than did residents, but their movements in the second or third year after translocation were indistinguishable from those of resident tortoises. Our data show that tortoises translocated into typical Mojave desert scrub habitats perform well; however, the large first-year movements of translocated tortoises have important management implications. Projects that employ translocations must consider how much area will be needed to contain translocated tortoises and whether roads need fencing to prevent the loss of animals.

  8. Robertsonian Translocations: An Overview of 872 Robertsonian Translocations Identified in a Diagnostic Laboratory in China

    PubMed Central

    Chen, Fan; Jiang, Shuai; Su, Hui; Liang, Jianfen; Deng, Chunhua; Hu, Chaohui; Yu, Shihui

    2015-01-01

    Robertsonian translocations (ROBs) have an estimated incidence rate of 1/1000 births, making this type of rearrangement the most common structural chromosomal abnormalities seen in the general population. In this study, we reports 872 cases of ROBs from 205,001 specimens karyotyped postnatally in a single accredited laboratory in China, including 583 balanced ROBs, 264 unbalanced ROBs, 9 mosaic ROBs, and 18 complex ROBs. Ninety-three percent of the balanced ROBs observed were adults with infertility, miscarriage, or offspring(s) with known chromosomal abnormalities. Significant excess of females were found to be carriers of balanced ROBs with an adjusted male/female ratio of 0.77. Ninety-eight percent of the unbalanced ROBs observed were children with variable referral reasons. Almost all of the unbalanced ROBs involved chromosome 21 except a single ROB with [46,XX,der(13;14),+13] identified in a newborn girl with multiple congenital anomalies. Multiple novel ROB karyotypes were reported in this report. This study represents the largest collections of ROBs in Chinese population. PMID:25932913

  9. Yeast Pol4 Promotes Tel1-Regulated Chromosomal Translocations

    PubMed Central

    Sastre-Moreno, Guillermo; Aguilera, Andrés; Blanco, Luis

    2013-01-01

    DNA double-strand breaks (DSBs) are one of the most dangerous DNA lesions, since their erroneous repair by nonhomologous end-joining (NHEJ) can generate harmful chromosomal rearrangements. PolX DNA polymerases are well suited to extend DSB ends that cannot be directly ligated due to their particular ability to bind to and insert nucleotides at the imperfect template-primer structures formed during NHEJ. Herein, we have devised genetic assays in yeast to induce simultaneous DSBs in different chromosomes in vivo. The repair of these breaks in trans could result in reciprocal chromosomal translocations that were dependent on classical Ku-dependent NHEJ. End-joining events leading to translocations were mainly based on the formation of short base pairing between 3′-overhanging DNA ends coupled to gap-filling DNA synthesis. A major proportion of these events were specifically dependent on yeast DNA polymerase Pol4 activity. In addition, we have discovered that Pol4-Thr540 amino acid residue can be phosphorylated by Tel1/ATM kinase, which could modulate Pol4 activity during NHEJ. Our data suggest that the role of Tel1 in preventing break-induced chromosomal translocations can, to some extent, be due to its stimulating effect on gap-filling activity of Pol4 to repair DSBs in cis. Overall, this work provides further insight to the molecular mechanisms of DSB repair by NHEJ and presents a new perspective to the understanding of how chromosomal translocations are formed in eukaryotic cells. PMID:23874240

  10. Bacterial translocation in the rat model of lectin induced diarrhoea.

    PubMed

    Shoda, R; Mahalanabis, D; Wahed, M A; Albert, M J

    1995-03-01

    Red kidney beans were fed to weanling Long-Evans rats to cause diarrhoea (mean (SD) faecal wet weight: 2.66 (0.73) g/day in six rats fed beans v 1.12 (0.47) g/day in six control rats, p < 0.01) and increased faecal energy loss (4.87 (0.41) v 2.14 (0.23) kcal/day, p < 0.01). In addition, the rats fed beans had heavier small intestines (80.6 (4.6) v 51.9 (8.4) g/kg body weight, p < 0.01), heavier mesenteric lymph nodes (0.72 (0.27) v 0.08 (0.08) g/kg body weight, p < 0.05), and translocation of indigenous intestinal bacteria, Citrobacter Spp and Escherichia coli, to the mesenteric lymph nodes. (Translocation positive, that is, > 100 colonies per g of nodal tissue: 75% v 0%, p < 0.005.) These data suggest that diarrhoea induced by red kidney beans is a suitable model for studies of an important cause of persistent diarrhoea--that is, systemic complications. This rat model of lectin induced diarrhoea with translocation of intraluminal enteric bacteria into mesenteric lymph nodes should be useful in understanding the well known septicaemic complications associated with prolonged diarrhoea in infants and small children and in studies on factors that may modify or prevent bacterial translocation. PMID:7698696

  11. Congenital nystagmus cosegregating with a balanced 7;15 translocation.

    PubMed Central

    Patton, M A; Jeffery, S; Lee, N; Hogg, C

    1993-01-01

    We report a family in which autosomal dominant congenital nystagmus cosegregates with a balanced 7;15 translocation. Ophthalmic investigation showed predominantly horizontal nystagmus with a small rotatory component and no significant loss of visual function. This finding suggests a possible localisation for autosomal dominant congenital nystagmus (McKusick 164100). Images PMID:8326501

  12. An intergenomic reciprocal translocation associated with oat winterhardiness

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The reciprocal intergenomic translocation between hexaploid oat (Avena sp.) chromosomes 7C and 17 (T7C-17) has been associated with the division of cultivated oat into A. sativa (L.) and A. byzantina (C. Koch) species as well as fall and spring growth habit. The objective of this experiment was to ...

  13. 3D view of chromosomes, DNA damage, and translocations.

    PubMed

    Schwartz, Michal; Hakim, Ofir

    2014-04-01

    The cell nucleus is a busy and organized organelle. In this megalopolis made of billions of nucleotides, protein factors find their target loci to exert nuclear functions such as transcription and replication. Remarkably, despite the lack of internal membrane barrier, the interlinked and tightly regulated nuclear processes occur in spatially organized fashion. These processes can lead to double-strand breaks (DSBs) that compromise the integrity of the genome. Moreover, in some cells like lymphocytes, DNA damage is also targeted within the context of immunoglobulin gene recombination. If not repaired correctly, DSBs can cause chromosomal rearrangements, including translocations which are etiological in numerous tumors. Therefore, the chromosomal locations of DSBs, as well as their spatial positioning, are important contributors to formation of chromosomal translocations at specific genomic loci. To obtain a mechanistic understanding of chromosomal translocations these parameters should be accounted for in a global and integrative fashion. In this review we will discuss recent findings addressing how genome architecture, DNA damage, and repair contribute to the genesis of chromosomal translocations. PMID:24632298

  14. DNA translocation across planar bilayers containing Bacillus subtilis ion channels.

    PubMed

    Szabò, I; Bàthori, G; Tombola, F; Brini, M; Coppola, A; Zoratti, M

    1997-10-01

    The mechanisms by which genetic material crosses prokaryotic membranes are incompletely understood. We have developed a new methodology to study the translocation of genetic material via pores in a reconstituted system, using techniques from electrophysiology and molecular biology. We report here that planar bilayer membranes become permeable to double-stranded DNA (kilobase range) if Bacillus subtilis membrane vesicles containing high conductance channels have been fused into them. The translocation is an electrophoretic process, since it does not occur if a transmembrane electrical field opposing the movement of DNA, a polyanion, is applied. It is not an aspecific permeation through the phospholipid bilayer, since it does not take place if no proteins have been incorporated into the membrane. The transport is also not due simply to the presence of polypeptides in the membrane, since it does not occur if the latter contains gramicidin A or a eukaryotic, multi-protein vesicle fraction exhibiting 30-picosiemens anion-selective channel activity. The presence of DNA alters the behavior of the bacterial channels, indicating that it interacts with the pores and may travel through their lumen. These results support the idea that DNA translocation may take place through proteic pores and suggest that some of the high conductance bacterial channels observed in electrophysiological experiments may be constituents of the DNA translocating machinery in these organisms. PMID:9312144

  15. The human minisatellite consensus at breakpoints of oncogene translocations.

    PubMed Central

    Krowczynska, A M; Rudders, R A; Krontiris, T G

    1990-01-01

    A reexamination of human minisatellite (hypervariable) regions following the cloning and sequencing of the new minisatellite, VTR1.1, revealed that many of these structures possessed a strongly conserved copy of the chi-like octamer, GC[A/T]GG[A/T]GG. In oncogene translocations apparently created by aberrant VDJ recombinase activity, this VTR octamer was often found within a few bases of the breakpoint (p less than 10(-10)). Three bcl2 rearrangements which occurred within 2 bp of one another were located precisely adjacent to this consensus; it defined the 5' border of that oncogene's major breakpoint cluster. Several c-myc translocations also occurred within 2 bp of this sequence. While the appearance of a chi-like element in polymorphic minisatellite sequences is consistent with a role promoting either recombination or replication slippage, the existence of such elements at sites of somatic translocations suggests chi function in site-specific recombination, perhaps as a subsidiary recognition signal in immunoglobulin gene rearrangement. We discuss the implications of these observations for mechanisms by which oncogene translocations and minisatellite sequences are generated. Images PMID:1969618

  16. Soil translocation estimates calibrated for moldboard plow depth

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Over the past century, one of the biggest culprits of tillage-induced soil erosion and translocation has been the moldboard plow. The distance soil will move by moldboard plow tillage has been shown to be correlated with slope gradient. Lindstrom et al. (1992) developed regression equations describi...

  17. Autosomal Translocation Patient Who Experienced Premature Menopause: A Case Report.

    PubMed

    Kim, Tae-Hee; Kim, Yesol; Jeong, Do-Won; Lee, Eun-Gyeong; Jeon, Dong-Su; Kim, Jun-Mo

    2015-08-01

    Premature ovarian failure (POF) is a condition in which the ovarian functions of hormone production and oocyte development become impaired before the typical age for menopause. POF and early menopause are present in a broad spectrum of gonad dysgenesis, from a complete cessation of ovarian function to an intermittent follicle maturation failure. Actually POF has been identified as a genetic entity (especially chromosome X), but data on genetic factors of premature menopause are limited. Until now, several cases revealed that inactivation of X chromosomes has an effect on ages of premature menopause and females with balanced or unbalanced X-autosome translocations can have several reproductive problems. On the other hand, there have been a few data that was caused by autosome-autosome translocation can lead. Therefore we report a relevant case of POF with translocation between chromosomes 1 and 4. She had her first menstrual period at the age of 12, and after 7 years she stopped menstruation. Chromosomal analysis showed 46, XX, t (1;4) (p22.3;q31.3). While evaluating this rare case, we could review various causes (especially genetic factors) of POF. To remind clinicians about this disease, we report a case of POF caused by autosome-autosome translocation with a literature review. PMID:26356509

  18. Unassisted translocation of large polypeptide domains across phospholipid bilayers

    PubMed Central

    Brambillasca, Silvia; Yabal, Monica; Makarow, Marja; Borgese, Nica

    2006-01-01

    Although transmembrane proteins generally require membrane-embedded machinery for integration, a few can insert spontaneously into liposomes. Previously, we established that the tail-anchored (TA) protein cytochrome b(5) (b5) can posttranslationally translocate 28 residues downstream to its transmembrane domain (TMD) across protein-free bilayers (Brambillasca, S., M. Yabal, P. Soffientini, S. Stefanovic, M. Makarow, R.S. Hegde, and N. Borgese. 2005. EMBO J. 24:2533–2542). In the present study, we investigated the limits of this unassisted translocation and report that surprisingly long (85 residues) domains of different sequence and charge placed downstream of b5's TMD can posttranslationally translocate into mammalian microsomes and liposomes at nanomolar nucleotide concentrations. Furthermore, integration of these constructs occurred in vivo in translocon-defective yeast strains. Unassisted translocation was not unique to b5 but was also observed for another TA protein (protein tyrosine phosphatase 1B) whose TMD, like the one of b5, is only moderately hydrophobic. In contrast, more hydrophobic TMDs, like synaptobrevin's, were incapable of supporting unassisted integration, possibly because of their tendency to aggregate in aqueous solution. Our data resolve long-standing discrepancies on TA protein insertion and are relevant to membrane evolution, biogenesis, and physiology. PMID:17130291

  19. Polymer translocation into and out of an ellipsoidal cavity.

    PubMed

    Polson, James M

    2015-05-01

    Monte Carlo simulations are used to study the translocation of a polymer into and out of an ellipsoidal cavity through a narrow pore. We measure the polymer free energy F as a function of a translocation coordinate, s, defined to be the number of bonds that have entered the cavity. To study polymer insertion, we consider the case of a driving force acting on monomers inside the pore, as well as monomer attraction to the cavity wall. We examine the changes to F(s) upon variation in the shape anisometry and volume of the cavity, the polymer length, and the strength of the interactions driving the insertion. For athermal systems, the free energy functions are analyzed using a scaling approach, where we treat the confined portion of the polymer to be in the semi-dilute regime. The free energy functions are used with the Fokker-Planck (FP) equation to calculate mean translocation times, as well as translocation time distributions. We find that both polymer ejection and insertion are faster for ellipsoidal cavities than for spherical cavities. The results are in qualitative agreement with those of a Langevin dynamics study in the case of ejection but not for insertion. The discrepancy is likely due to out-of-equilibrium conformational behaviour that is not accounted for in the FP approach. PMID:25956116

  20. UPTAKE, TRANSLOCATION AND RELEASE OF PHOSPHORUS BY 'ELODEA DENSA'

    EPA Science Inventory

    Short-term (16h) laboratory studies of 32p uptake by Elodea densa rooted in sediment demonstrated both foliar and root uptake, and that translocation occurred acropetally and basipetally. Root absorption is projected to provide 83-85% of total phosphorus uptake during 12-16th pho...

  1. Nuclear translocation of urokinase-type plasminogen activator.

    PubMed

    Stepanova, Victoria; Lebedeva, Tatiana; Kuo, Alice; Yarovoi, Serge; Tkachuk, Sergei; Zaitsev, Sergei; Bdeir, Khalil; Dumler, Inna; Marks, Michael S; Parfyonova, Yelena; Tkachuk, Vsevolod A; Higazi, Abd Al-Roof; Cines, Douglas B

    2008-07-01

    Urokinase-type plasminogen activator (uPA) participates in diverse (patho)physiological processes through intracellular signaling events that affect cell adhesion, migration, and proliferation, although the mechanisms by which these occur are only partially understood. Here we report that upon cell binding and internalization, single-chain uPA (scuPA) translocates to the nucleus within minutes. Nuclear translocation does not involve proteolytic activation or degradation of scuPA. Neither the urokinase receptor (uPAR) nor the low-density lipoprotein-related receptor (LRP) is required for nuclear targeting. Rather, translocation involves the binding of scuPA to the nucleocytoplasmic shuttle protein nucleolin through a region containing the kringle domain. RNA interference and mutational analysis demonstrate that nucleolin is required for the nuclear transport of scuPA. Furthermore, nucleolin is required for the induction smooth muscle alpha-actin (alpha-SMA) by scuPA. These data reveal a novel pathway by which uPA is rapidly translocated to the nucleus where it might participate in regulating gene expression. PMID:18337556

  2. Functional nanoparticles translocation into cell and adhesion force curve analysis.

    PubMed

    Lee, Haisung; Veerapandian, Murugan; Kim, Byung Tae; Yun, Kyusik; Seo, Soo-Won

    2012-10-01

    The aim of this research is to investigate the cell translocation of two functional nanoparticles (barium sulfate (BaSO4NPs), europium (III) doped gadolinium oxide nanoparticles (Gd2O3@EuNPs)) into A549 cells by Bio-Atomic Force Microscopy (Bio-AFM). Successful cell translocation of these two nanoparticles are ensured from the measurement of changes in the cell surface roughness and interaction (extension), retraction forces from the vertical deflection of tip towards substrate surfaces through force-distance curve slope analysis. Measurement of typical adhesion forces (i.e., extension and retraction) between the tip-substrate (0.0963 and 1.155 nN), tip-A549 cell substrate (0.1177 and 2.468 nN), tip-Gd2O3@EuNPs/A549 substrate (0.0785 and 0.4276 nN) and tip-BaSO4NPs/A549 substrate (0.518 and 6.838 nN) confirms the successful cell translocation of functional nanoparticles into A549 cells. Further the nanoscale resolution of topographical height and 3D images evinces the surface characteristics of normal A549 cells and nanoparticles translocated A549 cells. PMID:23421137

  3. Observing cellulose biosynthesis and membrane translocation in crystallo.

    PubMed

    Morgan, Jacob L W; McNamara, Joshua T; Fischer, Michael; Rich, Jamie; Chen, Hong-Ming; Withers, Stephen G; Zimmer, Jochen

    2016-03-17

    Many biopolymers, including polysaccharides, must be translocated across at least one membrane to reach their site of biological function. Cellulose is a linear glucose polymer synthesized and secreted by a membrane-integrated cellulose synthase. Here, in crystallo enzymology with the catalytically active bacterial cellulose synthase BcsA-BcsB complex reveals structural snapshots of a complete cellulose biosynthesis cycle, from substrate binding to polymer translocation. Substrate- and product-bound structures of BcsA provide the basis for substrate recognition and demonstrate the stepwise elongation of cellulose. Furthermore, the structural snapshots show that BcsA translocates cellulose via a ratcheting mechanism involving a 'finger helix' that contacts the polymer's terminal glucose. Cooperating with BcsA's gating loop, the finger helix moves 'up' and 'down' in response to substrate binding and polymer elongation, respectively, thereby pushing the elongated polymer into BcsA's transmembrane channel. This mechanism is validated experimentally by tethering BcsA's finger helix, which inhibits polymer translocation but not elongation. PMID:26958837

  4. Successive Translocation of the Rings in a [3]Rotaxane.

    PubMed

    Jagesar, Dhiredj C; Wiering, Piet G; Kay, Euan R; Leigh, David A; Brouwer, Albert M

    2016-06-17

    A [2]rotaxane, a [3]rotaxane and the corresponding thread containing two succinamide (succ) binding stations and a central redox-active pyromellitimide (pmi) station were studied. Infrared spectroelectrochemical experiments revealed the translocation of the macrocycle between the succinamide station and the electrochemically reduced pmi station (radical anion and dianion). Remarkably, in the [3]rotaxane, the rings can be selectively translocated. One-electron reduction leads to the translocation of one of the two macrocycles from the succinamide to the pyromellitimide station, whereas activation of the shuttle through two-electron reduction results in the translocation of both macrocycles: the dianion, due to its higher electron density and hence greater hydrogen-bond accepting affinity, is hydrogen bonded to both macrocycles. Systems with such an on-command contraction are known as molecular muscles. The relative strengths of the binding between the macrocycle and the imide anions could be estimated from the hydrogen-bond-induced shifts in the C=O stretching frequencies of hydrogen-bond accepting amide groups of the macrocycle. PMID:26918870

  5. Cold-inhibited phloem translocation in sugar beet

    SciTech Connect

    Grusak, M.A.

    1985-01-01

    Experimental studies were undertaken on a simplified single source leaf-single sink leaf, or single source leaf-double sink leaf sugar beet system to investigate the responsive nature of the long-distance phloem translocation system to localized cooling perturbations on the source leaf petiole. Experiments were performed by using a steady state (/sup 14/C)-labelling system for the source leaf, and translocation into the sink leaf (leaves) was monitored with a Geiger-Mueller system. A specially designed Peltier apparatus enabled cooling of the source petiole to 1/sup 0/C (or other desired temperatures) at various positions on the petiole, over different lengths, and at different rates of cooling. Initial experiment were designed to test the predictions of a mathematical recovery model of translocation inhibited by cold. The results did not support the mathematical model, but did suggest that vascular anastomoses may be involved in the recovery response. Selective petiolar incision/excision experiments showed that anastomoses were capable of re-establishing translocation following a disruption of flow. Studies with two monitored sink levels suggested that the inhibition to slow-coolings was not due to reduced translocation through the cooled source petiole region, but rather, was due to a repartitioning of flow among the terminal sinks (sink leaves and hypocotyl/crown region above the heat-girdled root). This repartitioning occurred via a redirection of flow through the vascular connections in the crown region of the plant, and appeared to be promoted by rapid, physical signals originating from the cooled region of the petiole.

  6. RNase A Does Not Translocate the Alpha-Hemolysin Pore

    PubMed Central

    Krasniqi, Besnik; Lee, Jeremy S.

    2014-01-01

    The application of nanopore sensing utilizing the α-hemolysin pore to probe proteins at single-molecule resolution has expanded rapidly. In some studies protein translocation through the α-hemolysin has been reported. However, there is no direct evidence, as yet, that proteins can translocate the α-hemolysin pore. The biggest challenge to obtaining direct evidence is the lack of a highly sensitive assay to detect very low numbers of protein molecules. Furthermore, if an activity based assay is applied then the proteins translocating by unfolding should refold back to an active confirmation for the assay technique to work. To overcome these challenges we selected a model enzyme, ribonuclease A, that readily refolds to an active conformation even after unfolding it with denaturants. In addition we have developed a highly sensitive reverse transcription polymerase chain reaction based activity assay for ribonuclease A. Initially, ribonuclease A, a protein with a positive net charge and dimensions larger than the smallest diameter of the pore, was subjected to nanopore analysis under different experimental conditions. Surprisingly, although the protein was added to the cis chamber (grounded) and a positive potential was applied, the interaction of ribonuclease A with α-hemolysin pore induced small and large blockade events in the presence and the absence of a reducing and/or denaturing agent. Upon measuring the zeta potential, it was found that the protein undergoes a charge reversal under the experimental conditions used for nanopore sensing. From the investigation of the effect of voltage on the interaction of ribonuclease A with the α-hemolysin pore, it was impossible to conclude if the events observed were translocations. However, upon testing for ribonuclease A activity on the trans chamber it was found that ribonuclease A does not translocate the α-hemolysin pore. PMID:24505349

  7. Complex Y-linked translocations in Delia antiqua produced by irradiation of a fertile Y-linked translocation.

    PubMed

    Robinson, A S; van Heemert, K

    1981-02-01

    In the onion fly, Delia antiqua, a fertile, Y-linked translocation involving chromosomes Y and 2 was irradiated with fast neutrons to induce new complexes involving the Y-chromosome. This chromosome is male determining in the onion fly. Such complexes can be used for the development of genetic sexing systems and also for the introduction of sterility into field populations following release. Irradiation reduced egg fertility by 54 per cent and significantly reduced larval survival but it had no effect on the F1 sex ratio. By measuring the fertility of 807 F1 males following outcrossing, 112 semi-sterile progenies were isolated of which 11 were lost, 29 showed no inheritance of the semi-sterility, 59 were new autosomal translocations and 13 were new complex Y-linked translocations. This classification was accomplished by checking the fertilities of outcrossed F2 males and females. Following cytological observation it was revealed that one of these new complexes involved four chromosome pairs, the remainder involved three. There appeared to be no correlation between the fertility of the translocation and the complexity of the rearrangement. The utilization of these rearrangements in the development of the genetic sexing technique for the onion fly is discussed, together with an assessment of their use for fertility reduction in natural populations. PMID:7263278

  8. A gatekeeper chaperone complex directs translocator secretion during Type Three Secretion

    SciTech Connect

    Archuleta, Tara L.; Spiller, Benjamin W.; Kubori, Tomoko

    2014-11-06

    Many Gram-negative bacteria use Type Three Secretion Systems (T3SS) to deliver effector proteins into host cells. These protein delivery machines are composed of cytosolic components that recognize substrates and generate the force needed for translocation, the secretion conduit, formed by a needle complex and associated membrane spanning basal body, and translocators that form the pore in the target cell. A defined order of secretion in which needle component proteins are secreted first, followed by translocators, and finally effectors, is necessary for this system to be effective. While the secreted effectors vary significantly between organisms, the ~20 individual protein components that form the T3SS are conserved in many pathogenic bacteria. One such conserved protein, referred to as either a plug or gatekeeper, is necessary to prevent unregulated effector release and to allow efficient translocator secretion. The mechanism by which translocator secretion is promoted while effector release is inhibited by gatekeepers is unknown. We present the structure of the Chlamydial gatekeeper, CopN, bound to a translocator-specific chaperone. The structure identifies a previously unknown interface between gatekeepers and translocator chaperones and reveals that in the gatekeeper-chaperone complex the canonical translocator-binding groove is free to bind translocators. Thus, structure-based mutagenesis of the homologous complex in Shigella reveals that the gatekeeper-chaperone-translocator complex is essential for translocator secretion and for the ordered secretion of translocators prior to effectors.

  9. A gatekeeper chaperone complex directs translocator secretion during Type Three Secretion

    DOE PAGESBeta

    Archuleta, Tara L.; Spiller, Benjamin W.; Kubori, Tomoko

    2014-11-06

    Many Gram-negative bacteria use Type Three Secretion Systems (T3SS) to deliver effector proteins into host cells. These protein delivery machines are composed of cytosolic components that recognize substrates and generate the force needed for translocation, the secretion conduit, formed by a needle complex and associated membrane spanning basal body, and translocators that form the pore in the target cell. A defined order of secretion in which needle component proteins are secreted first, followed by translocators, and finally effectors, is necessary for this system to be effective. While the secreted effectors vary significantly between organisms, the ~20 individual protein components thatmore » form the T3SS are conserved in many pathogenic bacteria. One such conserved protein, referred to as either a plug or gatekeeper, is necessary to prevent unregulated effector release and to allow efficient translocator secretion. The mechanism by which translocator secretion is promoted while effector release is inhibited by gatekeepers is unknown. We present the structure of the Chlamydial gatekeeper, CopN, bound to a translocator-specific chaperone. The structure identifies a previously unknown interface between gatekeepers and translocator chaperones and reveals that in the gatekeeper-chaperone complex the canonical translocator-binding groove is free to bind translocators. Thus, structure-based mutagenesis of the homologous complex in Shigella reveals that the gatekeeper-chaperone-translocator complex is essential for translocator secretion and for the ordered secretion of translocators prior to effectors.« less

  10. Two cases of Y; autosome translocations: A 45,X male and a clinically trisomy 18 patient

    SciTech Connect

    Farah, S.B.; Ramos, C.F.; Mello, M.P. de; Sartorato, E.L.; Lopes, V.L.G.S.; Cavalcanti, D.P.; Hackel, C.; Horeilli-Kuitunen, N.

    1994-02-15

    The authors report on 2 cases of Y; autosome translocations. One is a male with normal external genitalia and 45,X karyotype without evidence of mosaicism or apparent translocation on cytogenetic analysis. In situ hybridization showed that the euchromatic portion of the Y-chromosome is translocated to chromosome 15. The other case is a clinically trisomy 18 male patient, with modal number of 46, a small metacentric marker with appearance of an i(18p) and cytogenic and molecular evidence of Y;18 translocation. The occurrence of Y;18 translocation associated with clinical signs of trisomy 18 is reported here for the first time. 32 refs., 2 figs., 1 tab.

  11. Phosphatidylserine-binding protein lactadherin inhibits protein translocation across the ER membrane.

    PubMed

    Yamamoto, Hitoshi; Kida, Yuichiro; Sakaguchi, Masao

    2013-05-10

    Secretory and membrane proteins are translocated across and inserted into the endoplasmic reticulum membrane via translocon channels. To investigate the effect of the negatively-charged phospholipid phosphatidylserine on the translocation of nascent polypeptide chains through the translocon, we used the phosphatidylserine-binding protein lactadherin C2-domain. Lactadherin inhibited targeting of nascent chain to the translocon by signal sequence and the initiation of translocation. Moreover, lactadherin inhibited the movement of the translocating polypeptide chain regardless of the presence or absence of positively-charged residues. Phosphatidylserine might be critically involved in translocon function, but it is not a major determinant for translocation arrest of positively-charged residues. PMID:23583395

  12. Diversity of Specificity and Function of Phosphate Translocators in Various Plastids

    PubMed Central

    Heldt, Hans W.; Flügge, Ulf-Ingo; Borchert, Sieglinde

    1991-01-01

    This report gives a comparison of the specificity of phosphate translocators in various plastids. Whereas the phosphate translocator of the C3 plant spinach mediates a counter exchange between inorganic phosphate, dihydroxyacetone phosphate, and 3-phosphoglycerate, the phosphate translocators in chloroplasts from C4 and CAM plants transport phosphoenolpyruvate in addition to the above mentioned metabolites. In plastids from pea roots the phosphate translocator also transports glucose 6-phosphate. This diversity of phosphate translocators is discussed in view of the special functions of the various plastids. PMID:16667988

  13. Microfold Cells Actively Translocate Mycobacterium tuberculosis to Initiate Infection.

    PubMed

    Nair, Vidhya R; Franco, Luis H; Zacharia, Vineetha M; Khan, Haaris S; Stamm, Chelsea E; You, Wu; Marciano, Denise K; Yagita, Hideo; Levine, Beth; Shiloh, Michael U

    2016-08-01

    The prevailing paradigm is that tuberculosis infection is initiated when patrolling alveolar macrophages and dendritic cells within the terminal alveolus ingest inhaled Mycobacterium tuberculosis (Mtb). However, definitive data for this model are lacking. Among the epithelial cells of the upper airway, a specialized epithelial cell known as a microfold cell (M cell) overlies various components of mucosa-associated lymphatic tissue. Here, using multiple mouse models, we show that Mtb invades via M cells to initiate infection. Intranasal Mtb infection in mice lacking M cells either genetically or by antibody depletion resulted in reduced invasion and dissemination to draining lymph nodes. M cell-depleted mice infected via aerosol also had delayed dissemination to lymph nodes and reduced mortality. Translocation of Mtb across two M cell transwell models was rapid and transcellular. Thus, M cell translocation is a vital entry mechanism that contributes to the pathogenesis of Mtb. PMID:27452467

  14. Intermediate States During mRNA-tRNA Translocation

    PubMed Central

    Frank, Joachim

    2012-01-01

    Recent studies support the notion that the pre-translocation (PRE) ribosomal complex functions, at least in part, as a Brownian machine, stochastically fluctuating among multiple conformations and transfer RNA (tRNA) binding configurations. Apart from the relatively more energetically stable conformational states of the PRE complex, termed macrostate I (MS I) and macrostate II (MS II), several additional intermediate states have been recently discovered. Structural and kinetic analyses of these states, made possible by cryogenic electron microscopy (cryo-EM), X-ray crystallography, and single-molecule fluorescence resonance energy transfer (smFRET), have provided important insights into the translocation process, which is now understood to proceed, at least in the first step of the process, as a Brownian machine that is transiently stabilized in the “productive” MS II conformation by the binding of the translocase elongation factor G (EF-G). PMID:22906732

  15. A Novel Mode of Translocation for Cytolethal Distending Toxin

    PubMed Central

    Guerra, Lina; Nemec, Kathleen N.; Massey, Shane; Tatulian, Suren A.; Thelestam, Monica; Frisan, Teresa; Teter, Ken

    2008-01-01

    Summary Thermal instability in the toxin catalytic subunit may be a common property of toxins that exit the endoplasmic reticulum (ER) by exploiting the mechanism of ER-associated degradation (ERAD). The Haemophilus ducreyi cytolethal distending toxin (HdCDT) does not utilize ERAD to exit the ER, so we predicted the structural properties of its catalytic subunit (HdCdtB) would differ from other ER-translocating toxins. Here, we document the heat-stable properties of HdCdtB which distinguish it from other ER-translocating toxins. Cell-based assays further suggested that HdCdtB does not unfold before exiting the ER and that it may move directly from the ER lumen to the nucleoplasm. These observations suggest a novel mode of ER exit for HdCdtB. PMID:19118582

  16. Accumulation and translocation of 198Hg in four crop species.

    PubMed

    Cui, Liwei; Feng, Xinbin; Lin, Che-Jen; Wang, Xinming; Meng, Bo; Wang, Xun; Wang, Heng

    2014-02-01

    The uptake and transport of mercury (Hg) through vegetation play an important role in the biogeochemical cycling of Hg. However, quantitative information regarding Hg translocation in plants is poorly understood. In the present study, Hg uptake, accumulation, and translocation in 4 crops-rice (Oryza.sativa L.), wheat (Triticum L.), corn (Zea mays L.), and oilseed rape (Brassica campestris L.)-grown in Hoagland solution were investigated using a stable isotope ((198)Hg) tracing technique. The distribution of (198)Hg in root, stem, and leaf after uptake was quantified, and the release of (198)Hg into the air from crop leaf was investigated. It was found that the concentration of Hg accumulated in the root, stem, and leaf of rice increased linearly with the spiked (198)Hg concentration. The uptake equilibrium constant was estimated to be 2.35 mol Hg/g dry weight in rice root per mol/L Hg remaining in the Hoagland solution. More than 94% of (198)Hg uptake was accumulated in the roots for all 4 crops examined. The translocation to stem and leaf was not significant because of the absence of Hg(2+) complexes that facilitate Hg transport in plants. The accumulated (198)Hg in stem and leaf was not released from the plant at air Hg(0) concentration ranging from 0 ng/m(3) to 10 ng/m(3). Transfer factor data analysis showed that Hg translocation from stems to leaves was more efficient than that from roots to stems. PMID:24173818

  17. Child with Sotos phenotype and a 5:15 translocation

    SciTech Connect

    Maround, C.; Schmerler, S.; Hutcheon, R.G.

    1994-04-15

    The authors report on a 4-year-old girl with Sotos phenotype and a de novo balanced translocation between the long arms of chromosome 5 and chromosome 15 [46,XX,t(5,15)(q35;q22)]. They suggest a relationship between genetic material at 5q35 or 15q22 and the expression of an autosomal dominant gene. 18 refs., 2 figs.

  18. Translocation and clustering of endosomes and lysosomes depends on microtubules.

    PubMed

    Matteoni, R; Kreis, T E

    1987-09-01

    Indirect immunofluorescence labeling of normal rat kidney (NRK) cells with antibodies recognizing a lysosomal glycoprotein (LGP 120; Lewis, V., S.A. Green, M. Marsh, P. Vihko, A. Helenius, and I. Mellman, 1985, J. Cell Biol., 100:1839-1847) reveals that lysosomes accumulate in the region around the microtubule-organizing center (MTOC). This clustering of lysosomes depends on microtubules. When the interphase microtubules are depolymerized by treatment of the cells with nocodazole or during mitosis, the lysosomes disperse throughout the cytoplasm. Lysosomes recluster rapidly (within 30-60 min) in the region of the centrosomes either upon removal of the drug, or, in telophase, when repolymerization of interphase microtubules has occurred. During this translocation process the lysosomes can be found aligned along centrosomal microtubules. Endosomes and lysosomes can be visualized by incubating living cells with acridine orange. We have analyzed the movement of these labeled endocytic organelles in vivo by video-enhanced fluorescence microscopy. Translocation of endosomes and lysosomes occurs along linear tracks (up to 10 microns long) by discontinuous saltations (with velocities of up to 2.5 microns/s). Organelles move bidirectionally with respect to the MTOC. This movement ceases when microtubules are depolymerized by treatment of the cells with nocodazole. After nocodazole washout and microtubule repolymerization, the translocation and reclustering of fluorescent organelles predominantly occurs in a unidirectional manner towards the area of the MTOC. Organelle movement remains unaffected when cells are treated with cytochalasin D, or when the collapse of intermediate filaments is induced by microinjected monoclonal antivimentin antibodies. It can be concluded that translocation of endosomes and lysosomes occurs along microtubules and is independent of the intermediate filament and microfilament networks. PMID:3308906

  19. Importin-mediated nuclear translocation of galectin-3.

    PubMed

    Nakahara, Susumu; Hogan, Victor; Inohara, Hidenori; Raz, Avraham

    2006-12-22

    Galectin-3 (Gal-3), a member of a beta-galactoside-binding protein family, is involved in RNA processing and cell cycle regulation through activation of transcription factors when translocated to the nucleus. We have previously shown that Gal-3 can import into the nucleus through at least two pathways; via passive diffusion and/or active transport (Nakahara, S., Oka, N., Wang, Y., Hogan, V., Inohara, H, and Raz, A. (2006) Cancer Res. 66, 9995-10006). Here, we investigated the process mediated by the active nuclear transport of Gal-3 and have identified a nuclear localization signal (NLS)-like motif in its protein sequence, (223)HRVKKL(228), that resembles p53 and c-Myc NLSs ((378)SRHKKL(383), (322)AKRVKL(327)), respectively. Moreover, trimers of enhanced green fluorescence protein (3xGFP) fused with this NLS-like sequence, which is too large to passively diffuse through the nuclear pores, accumulated in the cell nuclei. To gain insights into this newly identified nuclear import mechanism, the interaction between Gal-3 and importins (importins alpha and beta) that carry the NLS harboring nuclear proteins into the nucleus, was investigated. Pull-down assays and bimolecular fluorescence complementation (BiFC) analysis revealed that wild-type Gal-3, but not mutant Gal-3 (R224A), binds to importin-alpha. Down-regulation of importin-beta by RNA interference (RNAi) efficiently abrogates its nuclear accumulation. Furthermore, we provide evidence that impaired nuclear translocation of mutant Gal-3 protein (R224A) results in accelerated degradation compared with the wild-type protein. Thus, these results suggest that Gal-3 is translocated to the nucleus, in part, via the importin-alpha/beta route and that Arg(224) amino acid residue of human Gal-3 is essential for its active nuclear translocation and its molecular stability. PMID:17056590

  20. Subcellular distribution and translocation of radionuclides in plants

    SciTech Connect

    Gouthu, S.; Weginwar, R.; Arie, Tsutomu; Ambe, Shizuko; Ozaki, Takuo; Enomoto, Shuichi; Ambe, Fumitoshi; Yamaguchi, Isamu

    1999-09-01

    The subcellular distribution of radionuclides in Glycine max Merr. (soybean) and Cucumis sativus L. (cucumber) and translocation of plant absorbed radionuclides with growth in soybean were studied. More than 60% of cellular incorporated Rb{sup {minus}83}, Sr{sup {minus}85}, Mn{sup {minus}54}, Nb{sup {minus}95}, and Se{sup {minus}75} remained in the supernatant fraction; 55% and 20% of Cr{sup {minus}51} was bound to soybean and cucumber cell wall fractions, respectively; 70% or more of Be{sup {minus}7}, Y{sup {minus}88}, and Fe{sup {minus}59} was fixed in the chloroplast fraction; and approx. 10% of Sc{sup {minus}46}, Fe{sup {minus}59}, V{sup {minus}48}, and As were fixed in the mitochondrial fraction. Translocation of nuclides within the soybean plant at different stages of growth has been determined. Vanadium, Y{sup {minus}88}, Be{sup {minus}7}, Se{sup {minus}75}, Nb{sup {minus}95}, Sc{sup {minus}46}, Cr{sup {minus}51}, and Zr{sup {minus}88} were predominantly accumulated in the root. Although the total percentage of plant uptake of Sc{sup {minus}46}, Zr{sup {minus}88}, Nb{sup {minus}95}, Sc{sup {minus}46}, and Cr{sup {minus}51} was high, because of low mobility and translocation to shoot, their accumulation in the fruit fraction was negligible. The translocation of mobile nuclides in plants was demonstrated clearly by Rb{sup {minus}83}, Zn{sup {minus}65}, and Fe{sup {minus}59}. Data on the nuclide fraction mobilized from vegetative parts into edible parts was used to assess the percentage of accumulated radionuclides in plants that may reach humans through beans.

  1. Controlling polymer translocation and ion transport via charge correlations.

    PubMed

    Buyukdagli, Sahin; Ala-Nissila, T

    2014-11-01

    We develop a correlation-corrected transport theory in order to predict ionic and polymer transport properties of membrane nanopores under physical conditions where mean-field electrostatics breaks down. The experimentally observed low KCl conductivity of open α-hemolysin pores is quantitatively explained by the presence of surface polarization effects. Upon the penetration of a DNA molecule into the pore, these polarization forces combined with the electroneutrality of DNA sets a lower boundary for the ionic current, explaining the weak salt dependence of blocked pore conductivities at dilute ion concentrations. The addition of multivalent counterions to the solution results in the reversal of the polymer charge and the direction of the electroosmotic flow. With trivalent spermidine or quadrivalent spermine molecules, the charge inversion is strong enough to stop the translocation of the polymer and to reverse its motion. This mechanism can be used efficiently in translocation experiments in order to improve the accuracy of DNA sequencing by minimizing the translocation velocity of the polymer. PMID:25310861

  2. Dominant-lethal mutations and heritable translocations in mice

    SciTech Connect

    Generoso, W.M.

    1983-01-01

    Chromosome aberrations are a major component of radiation or chemically induced genetic damage in mammalian germ cells. The types of aberration produced are dependent upon the mutagen used and the germ-cell stage treated. For example, in male meiotic and postmeiotic germ cells certain alkylating chemicals induce both dominant-lethal mutations and heritable translocations while others induce primarily dominant-lethal mutations. Production of these two endpoints appears to be determined by the stability of alkylation products with the chromosomes. If the reaction products are intact in the male chromosomes at the time of sperm entry, they may be repaired in fertilized eggs. If repair is not effected and the alkylation products persist to the time of pronuclear chromosome replication, they lead to chromatid-type aberrations and eventually to dominant-lethality. The production of heritable translocations, on the other hand, requires a transformation of unstable alkylation products into suitable intermediate lesions. The process by which these lesions are converted into chromosome exchange within the male genome takes place after sperm enters the egg but prior to the time of pronuclear chromosome replication (i.e., chromosome-type). Thus, dominant-lethal mutations result from both chromatid- and chromosome-type aberrations while heritable translocations result primarily from the latter type. DNA target sites associated with the production of these two endpoints are discussed.

  3. Flow-induced translocation of star polymers through a nanopore.

    PubMed

    Ding, Mingming; Duan, Xiaozheng; Shi, Tongfei

    2016-03-01

    We study the flow-induced translocation of the star polymers through a nanopore using a hybrid simulation method that incorporates a lattice-Boltzmann approach for the fluid into a molecular dynamics model for the polymer. Our simulation demonstrates the existence of an optimal forward arm number of the star polymers captured by the nanopore, and illustrates its significance in determining the critical velocity flux of the star polymer translocation through the nanopore. Importantly, we find that the critical velocity flux of the star polymers is independent of the arm polymerization degree, but exhibits a linear dependence on the arm number. Based on previous scaling arguments and our simulation results, we conclude a linear dependence of the critical velocity flux on the arm number of the star polymers, which can successfully describe the dynamics of the star polymer translocation. Our simulation results rationalize the experimental results for the dependence of the critical velocity flux on the arm polymerization degree and the arm number of the star polymers, which provide new insights for the characterization and the purification of the star polymers. PMID:26879130

  4. Coliphage HK022 Nun protein inhibits RNA polymerase translocation.

    PubMed

    Vitiello, Christal L; Kireeva, Maria L; Lubkowska, Lucyna; Kashlev, Mikhail; Gottesman, Max

    2014-06-10

    The Nun protein of coliphage HK022 arrests RNA polymerase (RNAP) in vivo and in vitro at pause sites distal to phage λ N-Utilization (nut) site RNA sequences. We tested the activity of Nun on ternary elongation complexes (TECs) assembled with templates lacking the λ nut sequence. We report that Nun stabilizes both translocation states of RNAP by restricting lateral movement of TEC along the DNA register. When Nun stabilized TEC in a pretranslocated register, immediately after NMP incorporation, it prevented binding of the next NTP and stimulated pyrophosphorolysis of the nascent transcript. In contrast, stabilization of TEC by Nun in a posttranslocated register allowed NTP binding and nucleotidyl transfer but inhibited pyrophosphorolysis and the next round of forward translocation. Nun binding to and action on the TEC requires a 9-bp RNA-DNA hybrid. We observed a Nun-dependent toe print upstream to the TEC. In addition, mutations in the RNAP β' subunit near the upstream end of the transcription bubble suppress Nun binding and arrest. These results suggest that Nun interacts with RNAP near the 5' edge of the RNA-DNA hybrid. By stabilizing translocation states through restriction of TEC lateral mobility, Nun represents a novel class of transcription arrest factors. PMID:24853501

  5. Aminoglycoside activity observed on single pre-translocation ribosome complexes

    PubMed Central

    Feldman, Michael B; Terry, Daniel S; Altman, Roger B; Blanchard, Scott C

    2010-01-01

    Aminoglycoside-class antibiotics bind directly to ribosomal RNA, imparting pleiotropic effects on ribosome function. Despite in-depth structural investigations of aminoglycoside–RNA oligonucleotide and aminoglycoside-ribosome interactions, mechanisms explaining the unique ribosome inhibition profiles of chemically similar aminoglycosides remain elusive. Here, using single-molecule fluorescence resonance energy transfer (smFRET) methods, we show that high-affinity aminoglycoside binding to the conserved decoding site region of the functional pre-translocation ribosome complex specifically remodels the nature of intrinsic dynamic processes within the particle. The extents of these effects, which are distinct for each member of the aminoglycoside class, strongly correlate with their inhibition of EF-G–catalyzed translocation. Neomycin, a 4,5-linked amino-glycoside, binds with lower affinity to one or more secondary binding sites, mediating distinct structural and dynamic perturbations that further enhance translocation inhibition. These new insights help explain why closely related aminoglycosides elicit pleiotropic translation activities and demonstrate the potential utility of smFRET as a tool for dissecting the mechanisms of antibiotic action. PMID:19946275

  6. A WRKY Transcription Factor Regulates Fe Translocation under Fe Deficiency.

    PubMed

    Yan, Jing Ying; Li, Chun Xiao; Sun, Li; Ren, Jiang Yuan; Li, Gui Xin; Ding, Zhong Jie; Zheng, Shao Jian

    2016-07-01

    Iron (Fe) deficiency affects plant growth and development, leading to reduction of crop yields and quality. Although the regulation of Fe uptake under Fe deficiency has been well studied in the past decade, the regulatory mechanism of Fe translocation inside the plants remains unknown. Here, we show that a WRKY transcription factor WRKY46 is involved in response to Fe deficiency. Lack of WRKY46 (wrky46-1 and wrky46-2 loss-of-function mutants) significantly affects Fe translocation from root to shoot and thus causes obvious chlorosis on the new leaves under Fe deficiency. Gene expression analysis reveals that expression of a nodulin-like gene (VACUOLAR IRON TRANSPORTER1-LIKE1 [VITL1]) is dramatically increased in wrky46-1 mutant. VITL1 expression is inhibited by Fe deficiency, while the expression of WRKY46 is induced in the root stele. Moreover, down-regulation of VITL1 expression can restore the chlorosis phenotype on wrky46-1 under Fe deficiency. Further yeast one-hybrid and chromatin immunoprecipitation experiments indicate that WRKY46 is capable of binding to the specific W-boxes present in the VITL1 promoter. In summary, our results demonstrate that WRKY46 plays an important role in the control of root-to-shoot Fe translocation under Fe deficiency condition via direct regulation of VITL1 transcript levels. PMID:27208259

  7. DegP Chaperone Suppresses Toxic Inner Membrane Translocation Intermediates.

    PubMed

    Braselmann, Esther; Chaney, Julie L; Champion, Matthew M; Clark, Patricia L

    2016-01-01

    The periplasm of Gram-negative bacteria includes a variety of molecular chaperones that shepherd the folding and targeting of secreted proteins. A central player of this quality control network is DegP, a protease also suggested to have a chaperone function. We serendipitously discovered that production of the Bordetella pertussis autotransporter virulence protein pertactin is lethal in Escherichia coli ΔdegP strains. We investigated specific contributions of DegP to secretion of pertactin as a model system to test the functions of DegP in vivo. The DegP chaperone activity was sufficient to restore growth during pertactin production. This chaperone dependency could be relieved by changing the pertactin signal sequence: an E. coli signal sequence leading to co-translational inner membrane (IM) translocation was sufficient to suppress lethality in the absence of DegP, whereas an E. coli post-translational signal sequence was sufficient to recapitulate the lethal phenotype. These results identify a novel connection between the DegP chaperone and the mechanism used to translocate a protein across the IM. Lethality coincided with loss of periplasmic proteins, soluble σE, and proteins regulated by this essential stress response. These results suggest post-translational IM translocation can lead to the formation of toxic periplasmic folding intermediates, which DegP can suppress. PMID:27626276

  8. Translocation of Sulfate in Soybean (Glycine max L. Merr) 1

    PubMed Central

    Smith, Ivan K.; Lang, A. Lee

    1988-01-01

    Sulfate translocation in soybean (Glycine max L. Merr) was investigated. More than 90% of the sulfate entering the shoot system was recoverable in one or two developing trifoliate leaves. In young plants, the first trifoliate leaf contained between 10 to 20 times as much sulfate as the primary leaves, even though both types of leaf had similar rates of transpiration and photosynthesis. We conclude that most of the sulfate entering mature leaves is rapidly loaded into the phloem and translocated to sinks elsewhere in the plant. This loading was inhibited by carbonylcyanide m-chlorophenylhydrazone and selenate. At sulfate concentrations below 0.1 millimolar, more than 95% of the sulfate entering primary leaves was exported. At higher concentrations the rate of export increased but so did the amount of sulfate remaining in the leaves. Removal of the first trifoliate leaf increased two-fold the transport of sulfate to the apex, indicating that these are competing sinks for sulfate translocated from the primary leaves. The small amount of sulfate transported into the mesophyll cells of primary leaves is a result of feedback regulation by the intracellular sulfate pool, not a consequence of their metabolic inactivity. For example, treatment of plants with 2 millimolar aminotriazole caused a 700 nanomoles per gram fresh weight increase in the glutathione content of primary leaves, but had no effect on sulfate aquisition. PMID:16665991

  9. Black bears in Arkansas: Characteristics of a successful translocation

    USGS Publications Warehouse

    Smith, Kimberly G.; Clark, Joseph D.

    1994-01-01

    In 1958, the Arkansas Game and Fish Commission began translocating black bears (Ursus americanus) from Minnesota to the Interior Highlands (Ozark and Ouachita mountains) of Arkansas where bears had been extirpated early in this century. This project continued for 11 years with little public imput, during which time an estimated 254 bears were released. We estimate there are now >2,500 bears in the Interior Highlands of Arkansas, Missouri, and Oklahoma, making it one of the most successful translocations of a Carnivora. Factors that contributed to the success include use of wild-captured animals, elimination of major factors associated with extirpation, release into prime habitats within the former range, multiple release sites, release of 20–40 animals/year for eight years, and release of mostly males prior to release of mostly females. Studies on two allopatric populations demonstrate that they are now diverging in some demographic characteristics, including litter size, cub survivorship, and adult sex-ratio. Translocation of black bears to the Interior Highlands is successful in terms of numbers of animals, but it will not be truly successful until people accept black bears as part of the regional fauna. To that end, those associated with management and research of bears in Arkansas are now focussing on public education and control of nuisance bears.

  10. Elevated chromosome translocation frequencies in New Zealand nuclear test veterans.

    PubMed

    Wahab, M A; Nickless, E M; Najar-M'kacher, R; Parmentier, C; Podd, J V; Rowland, R E

    2008-01-01

    In 1957/58 the British Government conducted a series of nuclear tests in the mid-Pacific codenamed Operation Grapple, which involved several naval vessels from Britain and New Zealand. Two New Zealand frigates with 551 personnel onboard were stationed at various distances between 20 and 150 nautical miles from ground zero. In the present study we applied the cytomolecular technique mFISH (multicolour fluorescent in situ hybridisation) to investigate a potential link between chromosome abnormalities and possible past radiation exposure in New Zealand nuclear test veterans who participated in Operation Grapple. Compared to age matched controls, the veterans showed significantly higher (P < 0.0001) frequencies of chromosomal abnormalities (275 translocations and 12 dicentrics in 9,360 cells vs. 96 translocations and 1 dicentric in 9,548 cells in the controls), in addition to a significant excess of CCRs (complex chromosomal rearrangements) in the veterans. A Kolmogorov-Smirnoff test showed that the distributions of translocations for the two groups were significantly different. PMID:18544930

  11. Single Nanoparticle Translocation Through Chemically Modified Solid Nanopore.

    PubMed

    Tan, Shengwei; Wang, Lei; Liu, Hang; Wu, Hongwen; Liu, Quanjun

    2016-12-01

    The nanopore sensor as a high-throughput and low-cost technology can detect single nanoparticle in solution. In the present study, the silicon nitride nanopores were fabricated by focused Ga ion beam (FIB), and the surface was functionalized with 3-aminopropyltriethoxysilane to change its surface charge density. The positively charged nanopore surface attracted negatively charged nanoparticles when they were in the vicinity of the nanopore. And, nanoparticle translocation speed was slowed down to obtain a clear and deterministic signal. Compared with previous studied small nanoparticles, the electrophoretic translocation of negatively charged polystyrene (PS) nanoparticles (diameter ~100 nm) was investigated in solution using the Coulter counter principle in which the time-dependent nanopore current was recorded as the nanoparticles were driven across the nanopore. A linear dependence was found between current drop and biased voltage. An exponentially decaying function (t d   ~ e (-v/v0) ) was found between the duration time and biased voltage. The interaction between the amine-functionalized nanopore wall and PS microspheres was discussed while translating PS microspheres. We explored also translocations of PS microspheres through amine-functionalized solid-state nanopores by varying the solution pH (5.4, 7.0, and 10.0) with 0.02 M potassium chloride (KCl). Surface functionalization showed to provide a useful step to fine-tune the surface property, which can selectively transport molecules or particles. This approach is likely to be applied to gene sequencing. PMID:26831688

  12. Covalently dimerized SecA is functional in protein translocation.

    PubMed

    de Keyzer, Jeanine; van der Sluis, Eli O; Spelbrink, Robin E J; Nijstad, Niels; de Kruijff, Ben; Nouwen, Nico; van der Does, Chris; Driessen, Arnold J M

    2005-10-21

    The ATPase SecA provides the driving force for the transport of secretory proteins across the cytoplasmic membrane of Escherichia coli. SecA exists as a dimer in solution, but the exact oligomeric state of SecA during membrane binding and preprotein translocation is a topic of debate. To study the requirements of oligomeric changes in SecA during protein translocation, a non-dissociable SecA dimer was formed by oxidation of the carboxyl-terminal cysteines. The cross-linked SecA dimer interacts with the SecYEG complex with a similar stoichiometry as non-cross-linked SecA. Cross-linking reversibly disrupts the SecB binding site on SecA. However, in the absence of SecB, the activity of the disulfide-bonded SecA dimer is indistinguishable from wild-type SecA. Moreover, SecYEG binding stabilizes a cold sodium dodecylsulfate-resistant dimeric state of SecA. The results demonstrate that dissociation of the SecA dimer is not an essential feature of the protein translocation reaction. PMID:16115882

  13. Dieldrin uptake and translocation in plants growing in hydroponic medium.

    PubMed

    Murano, Hirotatsu; Otani, Takashi; Seike, Nobuyasu; Sakai, Mizuki

    2010-01-01

    It has been known that the Cucurbitaceae family takes up a large amount of persistent organic pollutants from soils and that the translocation of those compounds in cucurbits is higher than those in non-cucurbits. To understand the persistent organic pollutant uptake mechanisms of plant species, we compared the dieldrin absorption and transportation potentials of several plants in hydroponic medium. Sorghum (Sorghum vulgare Moench), sunflower (Helianthus annuus L.), soybean (Glycine max), komatsuna (Brassica rapa var. peruviridis), white-flowered gourd (Lagenaria siceraria var. hispida), cucumber (Cucumis sativus L.), and zucchini (Cucurbita pepo L.) were grown in a dieldrin-added hydroponic medium for 10 d, and then the amount of dieldrin in their shoots and roots was measured. All of the roots contained dieldrin, whereas only the cucurbits (white-flowered gourd, cucumber, and zucchini) contained considerable amounts of dieldrin in their shoots. The dieldrin uptake to the roots depended on the concentration of the n-hexane soluble components in the roots, regardless of whether the dieldrin in the roots was translocated to shoots or not. The dieldrin uptake from the solution to the roots was thought to be due to a passive response, such as adsorption on the roots. The translocation of dieldrin from the roots to the shoots was probably through the xylems. The amounts of dieldrin in the shoots per transpiration rates were higher for cucurbits than for non-cucurbits. It seems likely that cucurbits have uptake mechanisms for hydrophobic organic chemicals. PMID:20821429

  14. Single Nanoparticle Translocation Through Chemically Modified Solid Nanopore

    NASA Astrophysics Data System (ADS)

    Tan, Shengwei; Wang, Lei; Liu, Hang; Wu, Hongwen; Liu, Quanjun

    2016-02-01

    The nanopore sensor as a high-throughput and low-cost technology can detect single nanoparticle in solution. In the present study, the silicon nitride nanopores were fabricated by focused Ga ion beam (FIB), and the surface was functionalized with 3-aminopropyltriethoxysilane to change its surface charge density. The positively charged nanopore surface attracted negatively charged nanoparticles when they were in the vicinity of the nanopore. And, nanoparticle translocation speed was slowed down to obtain a clear and deterministic signal. Compared with previous studied small nanoparticles, the electrophoretic translocation of negatively charged polystyrene (PS) nanoparticles (diameter ~100 nm) was investigated in solution using the Coulter counter principle in which the time-dependent nanopore current was recorded as the nanoparticles were driven across the nanopore. A linear dependence was found between current drop and biased voltage. An exponentially decaying function ( t d ~ e -v/v0 ) was found between the duration time and biased voltage. The interaction between the amine-functionalized nanopore wall and PS microspheres was discussed while translating PS microspheres. We explored also translocations of PS microspheres through amine-functionalized solid-state nanopores by varying the solution pH (5.4, 7.0, and 10.0) with 0.02 M potassium chloride (KCl). Surface functionalization showed to provide a useful step to fine-tune the surface property, which can selectively transport molecules or particles. This approach is likely to be applied to gene sequencing.

  15. Genome-wide and fine-mapping linkage studies of type 2 diabetes and glucose traits in the Old Order Amish: evidence for a new diabetes locus on chromosome 14q11 and confirmation of a locus on chromosome 1q21-q24.

    PubMed

    Hsueh, Wen-Chi; St Jean, Pamela L; Mitchell, Braxton D; Pollin, Toni I; Knowler, William C; Ehm, Margaret G; Bell, Callum J; Sakul, Hakan; Wagner, Michael J; Burns, Daniel K; Shuldiner, Alan R

    2003-02-01

    We conducted a genome scan using a 10-cM map to search for genes linked to type 2 diabetes in 691 individuals from a founder population, the Old Order Amish. We then saturated two regions on chromosomes 1 and 14 showing promising linkage signals with additional markers to produce a approximately 2-cM map for fine mapping. Analyses of both discrete traits (type 2 diabetes and the composite trait of type 2 diabetes and/or impaired glucose homeostasis [IGH]), and quantitative traits (glucose levels during a 75-g oral glucose challenge, designated glucose 0-180 and HbA(1c)) were performed. We obtained significant evidence for linkage to type 2 diabetes in a novel region on chromosome 14q11 (logarithm of odds [LOD] for diabetes = 3.48, P = 0.00005). Furthermore, we observed evidence for the existence of a diabetes-related locus on chromosome 1q21-q24 (LOD for type 2 diabetes/IGH = 2.35, P = 0.0008), a region shown to be linked to diabetes in several other studies. Suggestive evidence for linkage to glucose traits was observed on three other regions: 14q11-q13 (telomeric to that above with LOD = 1.82-1.85 for glucose 150 and 180), 1p31 (LOD = 1.28-2.30 for type 2 diabetes and glucose 120-180), and 18p (LOD = 3.07, P = 0.000085 for HbA(1c) and LOD = 1.50 for glucose 0). In conclusion, our findings provide evidence that type 2 diabetes susceptibility genes reside on chromosomes 1, 14, and 18. PMID:12540634

  16. Unbalanced translocation in a mother and her son in one of two 5;10 translocation families

    SciTech Connect

    John, C.K.; Barber, I.; Collinson, M.N.

    1996-03-01

    We present two families with different distal long arm 5;10 translocations. In one family the propositus and his mother inherited the same derived chromosome 10 from the maternal grandfather who has a balanced t(5;10)(q35.3;q26.13). The phenotype of both the affected patients is milder and only partially overlaps with that of previous cases of distal 10q deletion. Other previously reported cases of transmitted imbalance are also remarkable for mild phenotype, occurrence of deletions rather than duplications and a strong bias toward maternal as opposed to paternal transmission. In the second family, the propositus inherited a derived chromosome 10 from his mother who carries a balanced t(5;10)(q35.1;q26.3) translocation; his clinical manifestations are consistent with an emerging phenotype for distal 5q duplications. 30 refs., 6 figs., 2 tabs.

  17. Isolation and analysis of the 21q+ chromosome in the acute myelogenous leukemia 8; 21 translocation: evidence that c-mos is not translocated

    SciTech Connect

    Drabkin, H.A.; Diaz, M.; Bradley, C.M.; Le Beau, M.M.; Rowley, J.D.; Patterson, D.

    1985-01-01

    Acute myelogenous leukemia (AML), subgroup M2, is associated with a nonrandom chromosomal translocation, t(8;21)(q22,q22). The oncogene c-mos also has been localized to the q22 band on chromosome 8. There is also evidence that genes on chromosome 21 may be important in the development of leukemia. To determine whether the c-mos oncogene has been translocated in AML-M2 with this translocation and to isolate DNA sequences and genes from these two chromosomes that may be important in malignancy, the authors constructed somatic cell hybrids between a Chinese hamster ovary cell (CHO) mutant defective in glycine metabolism and myeloblasts with an 8;21 translocation from a patient with AML. The authors isolated the 21q+ chromosome of this translocation in a somatic cell hybrid and showed that the c-mos oncogene had not been translocated to chromosome 21, ruling out the possibility that translocation of c-mos to chromosome 21 is necessary for development of AML-M2. In addition, there was no detectable rearrangement of the c-mos locus within a 12.4-kilobase region surrounding the gene, indicating that rearrangement of the coding region of the gene itself or alteration of proximal 5' or 3' flanking sequences is not involved. The authors used this hybrid to determine whether specific DNA sequences and biochemical markers from chromosomes 8 and 21 had been translocated in this case.

  18. Fitness costs of neighborhood disruption in translocations of a solitary mammal.

    PubMed

    Shier, Debra M; Swaisgood, Ronald R

    2012-02-01

    Translocation is used to reestablish wild populations of animals, but translocation projects often do not meet their objectives because postrelease mortality of animals is high. One reason for translocation failure is that the behavioral or ecological requirements of released animals are unmet. Maintaining founder-group social relationships during release can affect reestablishment of social species. Solitary territorial species with stable neighbors (restricted dispersal and lifetime occupation of a home range) of the same species may also benefit from the maintenance of these social relationships during translocation. We translocated Stephens' kangaroo rats (Dipodomys stephensi), a solitary species listed as endangered under the U.S. Endangered Species Act, with and without neighboring kangaroo rats. We compared the settlement (establishment of a stable home range) decisions and fitness of kangaroo rats between the 2 treatments. Kangaroo rats translocated with neighbors traveled shorter distances before establishing territories, had higher survival rates, and had significantly higher reproductive success than kangaroo rats translocated without neighbors. Number of offspring was 24-fold higher for kangaroo rats translocated with neighbors than those translocated without neighbors. Differences in behavior following release may partially explain differences in survival between the 2 groups. Immediately following release, animals translocated with neighbors fought less and spent significantly more time foraging and digging burrows than animals translocated without neighbors. Our results indicate that even for solitary species, maintaining relationships among members of a translocated group of animals can influence translocation success. This study is the first empirical demonstration of the fitness consequences of disrupting social relationships among territorial neighbors. PMID:21978094

  19. Stable Translocation Intermediates Jam Global Protein Export in Plasmodium falciparum Parasites and Link the PTEX Component EXP2 with Translocation Activity

    PubMed Central

    Mesén-Ramírez, Paolo; Reinsch, Ferdinand; Blancke Soares, Alexandra; Bergmann, Bärbel; Ullrich, Ann-Katrin; Tenzer, Stefan

    2016-01-01

    Protein export is central for the survival and virulence of intracellular P. falciparum blood stage parasites. To reach the host cell, exported proteins cross the parasite plasma membrane (PPM) and the parasite-enclosing parasitophorous vacuole membrane (PVM), a process that requires unfolding, suggestive of protein translocation. Components of a proposed translocon at the PVM termed PTEX are essential in this phase of export but translocation activity has not been shown for the complex and questions have been raised about its proposed membrane pore component EXP2 for which no functional data is available in P. falciparum. It is also unclear how PTEX mediates trafficking of both, soluble as well as transmembrane proteins. Taking advantage of conditionally foldable domains, we here dissected the translocation events in the parasite periphery, showing that two successive translocation steps are needed for the export of transmembrane proteins, one at the PPM and one at the PVM. Our data provide evidence that, depending on the length of the C-terminus of the exported substrate, these steps occur by transient interaction of the PPM and PVM translocon, similar to the situation for protein transport across the mitochondrial membranes. Remarkably, we obtained constructs of exported proteins that remained arrested in the process of being translocated across the PVM. This clogged the translocation pore, prevented the export of all types of exported proteins and, as a result, inhibited parasite growth. The substrates stuck in translocation were found in a complex with the proposed PTEX membrane pore component EXP2, suggesting a role of this protein in translocation. These data for the first time provide evidence for EXP2 to be part of a translocating entity, suggesting that PTEX has translocation activity and provide a mechanistic framework for the transport of soluble as well as transmembrane proteins from the parasite boundary into the host cell. PMID:27168322

  20. Simulation studies of DNA translocation through a nanopore (^)

    NASA Astrophysics Data System (ADS)

    Bhattacharya, Aniket

    2009-03-01

    The experimental studies of voltage driven translocation of a single stranded DNA through a α-hemolysin pore, have stimulated a lot of activities as the phenomenon is rich in fundamental science involved and its prospective technical applications for detecting DNA/RNA sequences. While it is the attributes of heteropolymer translocation that are the key ingredients for prospective new sequencing methods, these experiments have generated stimulating theoretical and numerical studies directed toward a seemingly much simpler problem of homopolymer translocation through a nanopore. The earlier theoretical work of Muthukumar, Sung and Park, and by Kardar and his collaboartors^2 have been supplemented by more recent theoretical work by Dubbledam et. al and Panja et. al^3. During this talk I will show results from Langevin dynamics simulation carried out on a coarse-garined bead-spring model of DNA-polymer both for the unbiased and driven translocation^4. During the first part of the talk, after a brief review of the current theories of DNA translocation, specifically mentioning the underlying assumptions, I will compare simulation results with those predicted by different theories. Particularly, I will show numerical results for the translocation exponent α defined as <τ>˜N^α and the exponent for the s-coordinate β defined as ˜&βcirc;, and discuss how the numerical values differ as one chooses slightly different pore width and geometry. In the second part of my talk I show how a model attractive nanopore can distinguish the sequence of a heteropolymer^4 and discuss possibility of making a device based on this idea. ^work done in collaboration with Kaifu Luo, Tapio Ala-Nissila, See-chen Yin, Andrey Milchev and Kurt Binder^1J. J. Kasianowiczs, E. Brandin, D. Branton and D. W. Deamer, Proc. Natl. Acad. Sci. U.S.A. 93, 13770 (1996).^2W. Sung and P. J. Park, Phys. Rev. Lett. 77, 783 (1996); M. Muthukumar, J. Chem. Phys. 111, 10371 (1999); J. Chuang, Y. Kantor

  1. Biopersistence and brain translocation of aluminum adjuvants of vaccines.

    PubMed

    Gherardi, Romain Kroum; Eidi, Housam; Crépeaux, Guillemette; Authier, François Jerome; Cadusseau, Josette

    2015-01-01

    Aluminum oxyhydroxide (alum) is a crystalline compound widely used as an immunological adjuvant of vaccines. Concerns linked to the use of alum particles emerged following recognition of their causative role in the so-called macrophagic myofasciitis (MMF) lesion detected in patients with myalgic encephalomyelitis/chronic fatigue/syndrome. MMF revealed an unexpectedly long-lasting biopersistence of alum within immune cells in presumably susceptible individuals, stressing the previous fundamental misconception of its biodisposition. We previously showed that poorly biodegradable aluminum-coated particles injected into muscle are promptly phagocytosed in muscle and the draining lymph nodes, and can disseminate within phagocytic cells throughout the body and slowly accumulate in brain. This strongly suggests that long-term adjuvant biopersistence within phagocytic cells is a prerequisite for slow brain translocation and delayed neurotoxicity. The understanding of basic mechanisms of particle biopersistence and brain translocation represents a major health challenge, since it could help to define susceptibility factors to develop chronic neurotoxic damage. Biopersistence of alum may be linked to its lysosome-destabilizing effect, which is likely due to direct crystal-induced rupture of phagolysosomal membranes. Macrophages that continuously perceive foreign particles in their cytosol will likely reiterate, with variable interindividual efficiency, a dedicated form of autophagy (xenophagy) until they dispose of alien materials. Successful compartmentalization of particles within double membrane autophagosomes and subsequent fusion with repaired and re-acidified lysosomes will expose alum to lysosomal acidic pH, the sole factor that can solubilize alum particles. Brain translocation of alum particles is linked to a Trojan horse mechanism previously described for infectious particles (HIV, HCV), that obeys to CCL2, signaling the major inflammatory monocyte chemoattractant

  2. Modeling the mechanochemistry of the ϕ29 DNA translocation motor

    NASA Astrophysics Data System (ADS)

    Perez-Carrasco, R.; Fiasconaro, A.; Falo, F.; Sancho, J. M.

    2013-03-01

    We present a study of the DNA translocation of the bacteriophage ϕ29 packaging molecular motor. From the available experimental information we present a model system based on a stochastic flashing potential, which reproduces the experimental observations such as detailed trajectories, steps and substeps, spatial correlation, and velocity. Moreover, the model allows the evaluation of the power and efficiency of this motor. We have found that the maximum power regime does not correspond with that of the maximum efficiency. This information can stimulate further experiments.

  3. Unbalanced translocation (1;7) in childhood myelodysplasia.

    PubMed

    Horsman, D E; Massing, B G; Chan, K W; Kalousek, D K

    1988-03-01

    We have identified an unusual pediatric patient among twelve patients with myelodysplasia and an unbalanced translocation involving chromosomes 1 and 7: -7, +der(1)t(1;7)(p11;p11). This 16-year-old male patient developed myelodysplasia and evolving acute leukemia, which were preceded by a 7-year history of marrow hypoplasia. The remaining patients were adults with clinical and hematologic findings similar to other reported cases with this chromosomal abnormality. The late appearance of this unbalanced clonal abnormality in this patient with marrow hypoplasia documents the importance of close cytogenetic follow-up of all patients with suspected bone marrow injury. PMID:3348202

  4. Rotational streaming in fiber cells and its role in translocation.

    PubMed

    Worley, J F

    1968-10-01

    All visible protoplasmic streaming in sections of various plant stems was reversibly stopped by 2,4-dinitrophenol (DNP). Sections contained epidermal, cortical, and fiber cell types. Cells treated with DNP retained their semipermeability as evidenced by their plasmolysis in sucrose solutions. Washing out the DNP resulted in the rapid resumption of protoplasmic streaming in all 3 cell types. Both the rate of movement of sodium fluorescein and the shape of the advancing dye front were greatly altered by DNP treatment. Dye transport was decreased in the fibers and little affected in cortical cells. The results suggest that rotational streaming accelerates the translocation of soluble substances in fiber cells. PMID:16656950

  5. Inhibitors of Protein Translocation Across the ER Membrane.

    PubMed

    Kalies, Kai-Uwe; Römisch, Karin

    2015-10-01

    Protein translocation into the endoplasmic reticulum (ER) constitutes the first step of protein secretion. ER protein import is essential in all eukaryotic cells and is particularly critical in fast-growing tumour cells. Thus, the process can serve as target both for potential cancer drugs and for bacterial virulence factors. Inhibitors of protein transport across the ER membrane range from broad-spectrum to highly substrate-specific and can interfere with virtually any stage of this multistep process, and even with transport of endocytosed antigens into the cytosol for cross-presentation. PMID:26122014

  6. Use of chromosome translocations for measuring prior environment exposures in humans

    SciTech Connect

    Tucker, J. D.

    1997-05-01

    Recent advances in cytogenetic methodology are beginning to have a major impact upon our ability to provide assessments of environmental exposure in humans. The advent of fluorescent-based techniques for `painting` whole chromosomes has made the analysis of chromosome translocations rapid, specific, sensitive and routine. Chromosome painting has been used to address a wide variety of scientific questions, resulting in an increased understanding of the biological consequences of adverse environmental exposure. This paper describes the use of chromosome translocations as a biological marker of exposure and effect in humans. The relevance of translocations is discussed, as are the advantages and disadvantages of painting compared to classical cytogenetic methods for translocation evaluation. The factors to consider in the use of translocations as a retrospective indicator of exposure are then described. Several theoretical parameters that are important to the use of translocations are provided, and the paper concludes with a vision for the future of cytogenetic methodology.

  7. Akt phosphorylation is essential for nuclear translocation and retention in NGF-stimulated PC12 cells

    SciTech Connect

    Truong Le Xuan Nguyen; Choi, Joung Woo; Lee, Sang Bae; Ye, Keqiang; Woo, Soo-Dong; Lee, Kyung-Hoon; Ahn, Jee-Yin . E-mail: jyahn@med.skku.ac.kr

    2006-10-20

    Nerve growth factor (NGF) elicits Akt translocation into the nucleus, where it phosphorylates nuclear targets. Here, we describe that Akt phosphorylation can promote the nuclear translocation of Akt and is necessary for its nuclear retention. Overexpression of Akt-K179A, T308A, S473A-mutant failed to show either nuclear translocation or nuclear Akt phosphorylation, whereas expression of wild-type counterpart elicited profound Akt phosphorylation and induced nuclear translocation under NGF stimulation. Employing the PI3K inhibitor and a variety of mutants PI3K, we showed that nuclear translocation of Akt was mediated by activation of PI3K, and Akt phosphorylation status in the nucleus required PI3K activity. Thus the activity of PI3K might contribute to the nuclear translocation of Akt, and that Akt phosphorylation is essential for its nuclear retention under NGF stimulation conditions.

  8. Induction of site-specific chromosomal translocations in embryonic stem cells by CRISPR/Cas9

    PubMed Central

    Jiang, Junfeng; Zhang, Li; Zhou, Xingliang; Chen, Xi; Huang, Guanyi; Li, Fengsheng; Wang, Ruizhe; Wu, Nancy; Yan, Youzhen; Tong, Chang; Srivastava, Sankalp; Wang, Yue; Liu, Houqi; Ying, Qi-Long

    2016-01-01

    Chromosomal translocation is the most common form of chromosomal abnormality and is often associated with congenital genetic disorders, infertility, and cancers. The lack of cellular and animal models for chromosomal translocations, however, has hampered our ability to understand the underlying disease mechanisms and to develop new therapies. Here, we show that site-specific chromosomal translocations can be generated in mouse embryonic stem cells (mESCs) via CRISPR/Cas9. Mouse ESCs carrying translocated chromosomes can be isolated and expanded to establish stable cell lines. Furthermore, chimeric mice can be generated by injecting these mESCs into host blastocysts. The establishment of ESC-based cellular and animal models of chromosomal translocation by CRISPR/Cas9 provides a powerful platform for understanding the effect of chromosomal translocation and for the development of new therapeutic strategies. PMID:26898344

  9. Salt dependence of DNA translocation dynamics through silicon nanopores detected by ultraviolet excitation

    NASA Astrophysics Data System (ADS)

    Ito, Shintaro; Yamazaki, Hirohito; Tsukahara, Mutsumi; Esashika, Keiko; Saiki, Toshiharu

    2016-04-01

    DNA translocation through nanopores was observed using ultraviolet excitation to investigate the effect of salt concentration and counterion species on the translocation speed. The translocation of 9.6-kbp DNA molecules was measured in an aqueous solvent containing KCl, NaCl, or LiCl. An increase in the KCl concentration from 0.5 to 2 M increased the DNA translocation time. Maintaining the salt concentration at 1.0 M but replacing KCl with NaCl or LiCl also increased the translocation time. These results suggest that the effective charge on the DNA changed due to the binding of counterions, decreasing the DNA electrophoretic mobility. Significant correlation was observed between the translocation time and the dwell time in the observation volume (time needed to move out of the observation volume), and a possible explanation for this observation is provided.

  10. Conversion of graded phosphorylation into switch-like nuclear translocation via autoregulatory mechanisms in ERK signalling

    PubMed Central

    Shindo, Yuki; Iwamoto, Kazunari; Mouri, Kazunari; Hibino, Kayo; Tomita, Masaru; Kosako, Hidetaka; Sako, Yasushi; Takahashi, Koichi

    2016-01-01

    The phosphorylation cascade in the extracellular signal-regulated kinase (ERK) pathway is a versatile reaction network motif that can potentially act as a switch, oscillator or memory. Nevertheless, there is accumulating evidence that the phosphorylation response is mostly linear to extracellular signals in mammalian cells. Here we find that subsequent nuclear translocation gives rise to a switch-like increase in nuclear ERK concentration in response to signal input. The switch-like response disappears in the presence of ERK inhibitor, suggesting the existence of autoregulatory mechanisms for ERK nuclear translocation involved in conversion from a graded to a switch-like response. In vitro reconstruction of ERK nuclear translocation indicates that ERK-mediated phosphorylation of nucleoporins regulates ERK translocation. A mathematical model and knockdown experiments suggest a contribution of nucleoporins to regulation of the ERK nuclear translocation response. Taken together, this study provides evidence that nuclear translocation with autoregulatory mechanisms acts as a switch in ERK signalling. PMID:26786866

  11. Conformation-dependent translocation of a star polymer through a nanochannel

    PubMed Central

    Liu, Zhu; Liu, Jiannan; Xiao, Mengying; Wang, Rong; Chen, Yeng-Long

    2014-01-01

    The translocation process of star polymers through a nanochannel is investigated by dissipative particle dynamics simulations. The translocation process is strongly influenced by the star arm arrangement as the polymer enters the channel, and a scaling relation between the translocation time τ and the total number of beads Ntot is obtained. Qualitative agreements are found with predictions of the nucleation and growth model for linear block co-polymer translocation. In the intermediate stage where the center of the star polymer is at the channel entrance, the translocation time is found to have power law-dependence on the number of arms outside the channel and very weakly dependent on the number of arms in the channel. Increasing the total number of star arms also increases the star translocation time. PMID:25332744

  12. Hyperthermia increases gamma-ray and fission neutron-induced translocations in Drosophila

    SciTech Connect

    Mittler, S.

    1984-01-01

    Hyperthermia has been reported in Drosophila melanogaster to increase radiation-induced chromosome rearrangements, chromosome loss, recessive and dominant lethals. To determine whether hyperthermia would also affect high linear energy transfer (LET)-induced genetic damage such as translocations, which involve breakage and reunion of chromosomes, a genetic system was employed not only allowing detection of ordinary 2;3 translocations, but also permitting a more accurate measure of Y-autosome translocations.

  13. Translocation of a Polymer Chain across a Nanopore: A Brownian Dynamics Simulation Study

    NASA Technical Reports Server (NTRS)

    Tian, Pu; Smith, Grant D.

    2003-01-01

    We carried out Brownian dynamics simulation studies of the translocation of single polymer chains across a nanosized pore under the driving of an applied field (chemical potential gradient). The translocation process can be either dominated by the entropic barrier resulted from restricted motion of flexible polymer chains or by applied forces (or chemical gradient across the wall), we focused on the latter case in our studies. Calculation of radius of gyrations at the two opposite sides of the wall shows that the polymer chains are not in equilibrium during the translocation process. Despite this fact, our results show that the one-dimensional diffusion and the nucleation model provide an excellent description of the dependence of average translocation time on the chemical potential gradients, the polymer chain length and the solvent viscosity. In good agreement with experimental results and theoretical predictions, the translocation time distribution of our simple model shows strong non-Gaussian characteristics. It is observed that even for this simple tubelike pore geometry, more than one peak of translocation time distribution can be generated for proper pore diameter and applied field strengths. Both repulsive Weeks-Chandler-Anderson and attractive Lennard-Jones polymer-nanopore interaction were studied, attraction facilitates the translocation process by shortening the total translocation time and dramatically improve the capturing of polymer chain. The width of the translocation time distribution was found to decrease with increasing temperature, increasing field strength, and decreasing pore diameter.

  14. A G-protein subunit translocation embedded network motif underlies GPCR regulation of calcium oscillations.

    PubMed

    Giri, Lopamudra; Patel, Anilkumar K; Karunarathne, W K Ajith; Kalyanaraman, Vani; Venkatesh, K V; Gautam, N

    2014-07-01

    G-protein βγ subunits translocate reversibly from the plasma membrane to internal membranes on receptor activation. Translocation rates differ depending on the γ subunit type. There is limited understanding of the role of the differential rates of Gβγ translocation in modulating signaling dynamics in a cell. Bifurcation analysis of the calcium oscillatory network structure predicts that the translocation rate of a signaling protein can regulate the damping of system oscillation. Here, we examined whether the Gβγ translocation rate regulates calcium oscillations induced by G-protein-coupled receptor activation. Oscillations in HeLa cells expressing γ subunit types with different translocation rates were imaged and quantitated. The results show that differential Gβγ translocation rates can underlie the diversity in damping characteristics of calcium oscillations among cells. Mathematical modeling shows that a translocation embedded motif regulates damping of G-protein-mediated calcium oscillations consistent with experimental data. The current study indicates that such a motif may act as a tuning mechanism to design oscillations with varying damping patterns by using intracellular translocation of a signaling component. PMID:24988358

  15. Detection and Identification of Translocations by Increased Specific Nondisjunction in ASPERGILLUS NIDULANS

    PubMed Central

    Upshall, Alan; Käfer, Etta

    1974-01-01

    A meiotic technique for visual detection of translocations has been applied to ten mitotically identified interchanges, and three new translocations were discovered using this method. Testcrosses between "standard" strains and potential translocation strains—e.g. strains with newly induced mutants or descendants from translocation crosses—are inspected for the frequency of abnormal-looking colonies. In all heterozygous translocation crosses "abnormals" are increased at least tenfold compared to the average control level of 0.15%. Most of these are disomics, and can be recognized by their characteristic phenotypes. Each translocation produces a few specific types, since nondisjunction is increased mainly in the linkage groups involved in the translocation (50–100-fold over control values). Therefore, translocations were not only detected but often tentatively assigned to linkage groups from the analysis of the disomic progeny in crosses. In addition, this technique allows reciprocal and nonreciprocal translocations to be distinguished, since only the latter produce one-third phenotypically abnormal duplication progeny. While results are clearcut in most cases, occasionally problems are encountered, e.g. when morphological mutants segregate in crosses, or when other genetic factors which increase or reduce the frequency of nondisjunction are present in certain strains. PMID:4594334

  16. Protein translocation without specific quality control in a computational model of the Tat system

    NASA Astrophysics Data System (ADS)

    Nayak, Chitra R.; Brown, Aidan I.; Rutenberg, Andrew D.

    2014-10-01

    The twin-arginine translocation (Tat) system transports folded proteins of various sizes across both bacterial and plant thylakoid membranes. The membrane-associated TatA protein is an essential component of the Tat translocon, and a broad distribution of different sized TatA-clusters is observed in bacterial membranes. We assume that the size dynamics of TatA clusters are affected by substrate binding, unbinding, and translocation to associated TatBC clusters, where clusters with bound translocation substrates favour growth and those without associated substrates favour shrinkage. With a stochastic model of substrate binding and cluster dynamics, we numerically determine the TatA cluster size distribution. We include a proportion of targeted but non-translocatable (NT) substrates, with the simplifying hypothesis that the substrate translocatability does not directly affect cluster dynamical rate constants or substrate binding or unbinding rates. This amounts to a translocation model without specific quality control. Nevertheless, NT substrates will remain associated with TatA clusters until unbound and so will affect cluster sizes and translocation rates. We find that the number of larger TatA clusters depends on the NT fraction f. The translocation rate can be optimized by tuning the rate of spontaneous substrate unbinding, {{\\Gamma }_{U}}. We present an analytically solvable three-state model of substrate translocation without cluster size dynamics that follows our computed translocation rates, and that is consistent with in vitro Tat-translocation data in the presence of NT substrates.

  17. [Identification of 1AL/1RS translocation in winter common wheat varieties of Ukrainian selection].

    PubMed

    Kozub, N O; Sozinov, I O; Koliuchyĭ, V T; Vlasenko, V A; Sobko, T O; Sozinov, O O

    2005-01-01

    Analysis of alcohol-soluble protein (gliadin) patterns of a group of winter common wheat varieties from different breeding centers of Ukraine resulted in identification of six varieties with the rye 1AL/1RS translocation. The line 7086 AR also carries this translocation. The identified 1AL/1RS translocation is similar to that of the variety Amigo in the secalin pattern. The appearance of this translocation in varieties developed in different breeding centers of the forest-steppe of Ukraine indicates its involvement in coadaptive gene associations. PMID:16396327

  18. Return to the wild: Translocation as a tool in conservation of the desert tortoise (Gopherus agassizii)

    USGS Publications Warehouse

    Field, K.J.; Tracy, C.R.; Medica, P.A.; Marlow, R.W.; Corn, P.S.

    2007-01-01

    Translocation could be used as a tool in conservation of the threatened Mojave Desert Tortoise (Gopherus agassizii) by moving individuals from harm's way and into areas where they could contribute to conservation of the species. Numerous factors may affect the success of translocations, including the conditions experienced by tortoises in holding facilities while awaiting translocation. The tortoises available for our translocation study had been provided supplemental water during their years spent in a captive holding facility, potentially inducing carelessness in water conservation. In addition to generally investigating the efficacy of translocation, we compared the effects of continuing with the effects of ceasing the holding facility's water supplementation regimen. After exposure to one of the two water regimens, all tortoises were given the opportunity to hydrate immediately prior to release. We examined behavior, body mass, carapace length, movement, and mortality of tortoises for two activity seasons following release to the wild. Water supplementation was correlated with high rates of carapace growth and distant movements by males after release. Lengthy movements following translocation may be problematic for conservation planning, but this should be evaluated in light of the goals and circumstances of each translocation project. Although the mortality rate was 21.4% in 1997, data suggest that drought conditions at the site rather than the translocation itself negatively affected the tortoises. None of the tortoises died during their second season at the site. Our results indicate that translocation should be considered a useful tool in conservation of the Desert Tortoise.

  19. Role of lipids in the translocation of proteins across membranes.

    PubMed Central

    Van Voorst, F; De Kruijff, B

    2000-01-01

    The architecture of cells, with various membrane-bound compartments and with the protein synthesizing machinery confined to one location, dictates that many proteins have to be transported through one or more membranes during their biogenesis. A lot of progress has been made on the identification of protein translocation machineries and their sorting signals in various organelles and organisms. Biochemical characterization has revealed the functions of several individual protein components. Interestingly, lipid components were also found to be essential for the correct functioning of these translocases. This led to the idea that there is a very intimate relationship between the lipid and protein components that enables them to fulfil their intriguing task of transporting large biopolymers through a lipid bilayer without leaking their contents. In this review we focus on the Sec translocases in the endoplasmic reticulum and the bacterial inner membrane. We also highlight the interactions of lipids and proteins during the process of translocation and integrate this into a model that enables us to understand the role of membrane lipid composition in translocase function. PMID:10769162

  20. H/sup +/-translocating ATPases: advances using membrane vesicles

    SciTech Connect

    Sze, H.

    1985-01-01

    In this paper, two primary active transport systems (H/sup +/ -ATPases) in plant cells are examined using membrane vesicles as a simple experimental tool. One electrogenic, H/sup +/ -translocating ATPase is vanadate-sensitive and associated with the plasma membrane. Another electrogenic, H/sup +/ -translocating ATPases is anion-sensitive, and localized on the tonoplast (and perhaps other membranes). According to the working model, the plasma membrane and tonoplast-type H/sup +/ -ATPases are detectable in inside-out plasma membrane and right-side-out tonoplast vesicles. The direction of H/sup +/ pumping into these vesicles would be consistent with the results from intact cells where H/sup +/ are extruded from the cell across the plasma membrane and pumped into the vacuole from the cytoplasm. Understanding the properties of H/sup +/ -pumping ATPases using membrane vesicles has paved the way for studies to identify secondary active transport systems coupled to the proton electrochemical gradient. Redox-driven transport systems can also be studied directly using the isolated vesicles. As transport proteins are identified, the functional activities can be specifically studied after reconstitution of the purified protein(s) into phospholipid membrane vesicles. 154 references.

  1. Different modes of proton translocation by sensory rhodopsin I.

    PubMed Central

    Haupts, U; Bamberg, E; Oesterhelt, D

    1996-01-01

    The membrane-bound complex between sensory rhodopsin I (SRI) and its transducer HtrI forms the functional photoreceptor unit that allows transmission of light signals to the flagellar motor. Although being a photosensor, SRI, the mutant SRI-D76N and the HtrI-SRI complex can transport protons, as we demonstrate by using the sensitive and ion-specific black lipid membrane technique. SRI sustains an orange light-driven (one-photon-driven) outward proton transport which is enhanced by additional blue light (two-photon-driven). The vectoriality of the two-photon-driven transport could be reversed at neutral pH from the outward to the inward direction by switching the cut-off wavelength of the long wavelength light from 550 to 630 nm. The cut-off wavelength determining the reversal point decreases with decreasing pH. The currents could be enhanced by azide. A two-photon-driven inward proton transport by SRI-D76N (catalyzed by azide) and by the complex HtrI-SRI is demonstrated. The influence of pH and azide concentration on the rise and decay kinetics of the SRI380 intermediate is analyzed. The different modes of proton translocation of the SRI species are discussed on the basis of a general model of proton translocation of retinal proteins and in the context of signal transduction. Images PMID:8617229

  2. pH sensing by intracellular Salmonella induces effector translocation.

    PubMed

    Yu, Xiu-Jun; McGourty, Kieran; Liu, Mei; Unsworth, Kate E; Holden, David W

    2010-05-21

    Salmonella enterica is an important intracellular bacterial pathogen of humans and animals. It replicates within host-cell vacuoles by delivering virulence (effector) proteins through a vacuolar membrane pore made by the Salmonella pathogenicity island 2 (SPI-2) type III secretion system (T3SS). T3SS assembly follows vacuole acidification, but when bacteria are grown at low pH, effector secretion is negligible. We found that effector secretion was activated at low pH from mutant strains lacking a complex of SPI-2-encoded proteins SsaM, SpiC, and SsaL. Exposure of wild-type bacteria to pH 7.2 after growth at pH 5.0 caused dissociation and degradation of SsaM/SpiC/SsaL complexes and effector secretion. In infected cells, loss of the pH 7.2 signal through acidification of host-cell cytosol prevented complex degradation and effector translocation. Thus, intravacuolar Salmonella senses host cytosolic pH, resulting in the degradation of regulatory complex proteins and effector translocation. PMID:20395475

  3. Stat1 Nuclear Translocation by Nucleolin upon Monocyte Differentiation

    PubMed Central

    Jerke, Uwe; Tkachuk, Sergey; Kiyan, Julia; Stepanova, Victoria; Kusch, Angelika; Hinz, Michael; Dietz, Rainer; Haller, Hermann; Fuhrman, Bianca; Dumler, Inna

    2009-01-01

    Background Members of the signal transducer and activator of transcription (Stat) family of transcription factors traverse the nuclear membrane through a specialized structure, called the nuclear pore complex (NPC), which represents a selective filter for the import of proteins. Karyophilic molecules can bind directly to a subset of proteins of the NPC, collectively called nucleoporins. Alternatively, the transport is mediated via a carrier molecule belonging to the importin/karyopherin superfamily, which transmits the import into the nucleus through the NPC. Methodology/Principal Findings In this study, we provide evidence for an alternative Stat1 nuclear import mechanism, which is mediated by the shuttle protein nucleolin. We observed Stat1-nucleolin association, nuclear translocation and specific binding to the regulatory DNA element GAS. Using expression of nucleolin transgenes, we found that the nuclear localization signal (NLS) of nucleolin is responsible for Stat1 nuclear translocation. We show that this mechanism is utilized upon differentiation of myeloid cells and is specific for the differentiation step from monocytes to macrophages. Conclusions/Significance Our data add the nucleolin-Stat1 complex as a novel functional partner for the cell differentiation program, which is uniquely poised to regulate the transcription machinery via Stat1 and nuclear metabolism via nucleolin. PMID:20011528

  4. Microarray analysis of unbalanced translocation in Wolf-Hirschhorn syndrome.

    PubMed

    Dai, Ying; Yang, Jing; Chen, Yuanyuan; Bao, Liming; Cheng, Qian

    2013-06-01

    Wolf-Hirschhorn syndrome (WHS) is caused by deletions involving chromosome region 4p16.3, which is characterized by growth delay, mild-to-severe mental retardation, hypotonia, facial dysmorphisms and shows extensive phenotypic variability include feeding difficulties, epilepsy and congenital anomalies. Variation in the size of the deletion involving chromosome region 4p16.3 may explain the clinical variation. However, previous studies indicate that duplication for another chromosome region due to an unbalanced translocation elucidate approximately 40-45% WHS patients. Therefore, we used whole genomic cytogenetics array to analyze the entire genome at a significantly higher resolution over conventional cytogenetics to characterize the exact subtelomeric aberration region of one patient with developmental delay and several facial characteristics reminiscent Wolf-Hirschhorn syndrome. Here we report that our patient had 3.7 Mb deletion at the 4p16.2 and 6.8 Mb duplication at 8p23.1 resulted from the unbalanced translocations der(4)t(4;8)(p16.2;p23.1). We confirmed that our patient with monosomy 4p16.2 which is consistent with Wolf-Hirschhorn syndrome and trisomy 8p23.1. The combination of the 4p deletion with 8p partial trisomy explains the complex phenotype presented by our patient. PMID:23782367

  5. Programmed -1 frameshifting by kinetic partitioning during impeded translocation.

    PubMed

    Caliskan, Neva; Katunin, Vladimir I; Belardinelli, Riccardo; Peske, Frank; Rodnina, Marina V

    2014-06-19

    Programmed -1 ribosomal frameshifting (-1PRF) is an mRNA recoding event utilized by cells to enhance the information content of the genome and to regulate gene expression. The mechanism of -1PRF and its timing during translation elongation are unclear. Here, we identified the steps that govern -1PRF by following the stepwise movement of the ribosome through the frameshifting site of a model mRNA derived from the IBV 1a/1b gene in a reconstituted in vitro translation system from Escherichia coli. Frameshifting occurs at a late stage of translocation when the two tRNAs are bound to adjacent slippery sequence codons of the mRNA. The downstream pseudoknot in the mRNA impairs the closing movement of the 30S subunit head, the dissociation of EF-G, and the release of tRNA from the ribosome. The slippage of the ribosome into the -1 frame accelerates the completion of translocation, thereby further favoring translation in the new reading frame. PMID:24949973

  6. Electronic transduction of proton translocations in nanoassembled lamellae of bacteriorhodopsin.

    PubMed

    Palazzo, Gerardo; Magliulo, Maria; Mallardi, Antonia; Angione, Maria Daniela; Gobeljic, Danka; Scamarcio, Gaetano; Fratini, Emiliano; Ridi, Francesca; Torsi, Luisa

    2014-08-26

    An organic field-effect transistor (OFET) integrating bacteriorhodopsin (bR) nanoassembled lamellae is proposed for an in-depth study of the proton translocation processes occurring as the bioelectronic device is exposed either to light or to low concentrations of general anesthetic vapors. The study involves the morphological, structural, electrical, and spectroscopic characterizations necessary to assess the functional properties of the device as well as the bR biological activity once integrated into the functional biointerlayer (FBI)-OFET structure. The electronic transduction of the protons phototranslocation is shown as a current increase in the p-type channel only when the device is irradiated with photons known to trigger the bR photocycle, while Raman spectroscopy reveals an associated C═C isomer switch. Notably, higher energy photons bring the cis isomer back to its trans form, switching the proton pumping process off. The investigation is extended also to the study of a PM FBI-OFET exposed to volatile general anesthetics such as halothane. In this case an electronic current increase is seen upon exposure to low, clinically relevant, concentrations of anesthetics, while no evidence of isomer-switching is observed. The study of the direct electronic detection of the two different externally triggered proton translocation effects allows gathering insights into the underpinning of different bR molecular switching processes. PMID:25077939

  7. Deconvoluting chain heterogeneity from driven translocation through a nanopore

    NASA Astrophysics Data System (ADS)

    Adhikari, Ramesh; Bhattacharya, Aniket

    2015-02-01

    We study translocation dynamics of a driven compressible semi-flexible chain consisting of alternate blocks of stiff (S) and flexible (F) segments of size m and n, respectively, for different chain length N in two dimensions (2D). The free parameters in the model are the bending rigidity κb which controls the three-body interaction term, the elastic constant kF in the FENE (bond) potential between successive monomers, as well as the segmental lengths m and n and the repeat unit p (N=m_pn_p) and the solvent viscosity γ. We demonstrate that due to the change in entropic barrier and the inhomogeneous viscous drag on the chain backbone a variety of scenarios are possible, amply manifested in the waiting time distribution of the translocating chain. This information can be deconvoluted to extract the mechanical properties of the chain at various length scales and thus can be used to nanopore based methods to probe bio-molecules, such as DNA, RNA and proteins.

  8. Adenine nucleotide translocator transports haem precursors into mitochondria.

    PubMed

    Azuma, Motoki; Kabe, Yasuaki; Kuramori, Chikanori; Kondo, Masao; Yamaguchi, Yuki; Handa, Hiroshi

    2008-01-01

    Haem is a prosthetic group for haem proteins, which play an essential role in oxygen transport, respiration, signal transduction, and detoxification. In haem biosynthesis, the haem precursor protoporphyrin IX (PP IX) must be accumulated into the mitochondrial matrix across the inner membrane, but its mechanism is largely unclear. Here we show that adenine nucleotide translocator (ANT), the inner membrane transporter, contributes to haem biosynthesis by facilitating mitochondrial accumulation of its precursors. We identified that haem and PP IX specifically bind to ANT. Mitochondrial uptake of PP IX was inhibited by ADP, a known substrate of ANT. Conversely, ADP uptake into mitochondria was competitively inhibited by haem and its precursors, suggesting that haem-related porphyrins are accumulated into mitochondria via ANT. Furthermore, disruption of the ANT genes in yeast resulted in a reduction of haem biosynthesis by blocking the translocation of haem precursors into the matrix. Our results represent a new model that ANT plays a crucial role in haem biosynthesis by facilitating accumulation of its precursors into the mitochondrial matrix. PMID:18728780

  9. Excited states of ribosome translocation revealed through integrative molecular modeling

    PubMed Central

    Whitford, Paul C.; Ahmed, Aqeel; Yu, Yanan; Hennelly, Scott P.; Tama, Florence; Spahn, Christian M. T.; Onuchic, José N.; Sanbonmatsu, Karissa Y.

    2011-01-01

    The dynamic nature of biomolecules leads to significant challenges when characterizing the structural properties associated with function. While X-ray crystallography and imaging techniques (such as cryo-electron microscopy) can reveal the structural details of stable molecular complexes, strategies must be developed to characterize configurations that exhibit only marginal stability (such as intermediates) or configurations that do not correspond to minima on the energy landscape (such as transition-state ensembles). Here, we present a methodology (MDfit) that utilizes molecular dynamics simulations to generate configurations of excited states that are consistent with available biophysical and biochemical measurements. To demonstrate the approach, we present a sequence of configurations that are suggested to be associated with transfer RNA (tRNA) movement through the ribosome (translocation). The models were constructed by combining information from X-ray crystallography, cryo-electron microscopy, and biochemical data. These models provide a structural framework for translocation that may be further investigated experimentally and theoretically to determine the precise energetic character of each configuration and the transition dynamics between them. PMID:22080606

  10. Excited states of ribosome translocation revealed through integrative molecular modeling.

    PubMed

    Whitford, Paul C; Ahmed, Aqeel; Yu, Yanan; Hennelly, Scott P; Tama, Florence; Spahn, Christian M T; Onuchic, José N; Sanbonmatsu, Karissa Y

    2011-11-22

    The dynamic nature of biomolecules leads to significant challenges when characterizing the structural properties associated with function. While X-ray crystallography and imaging techniques (such as cryo-electron microscopy) can reveal the structural details of stable molecular complexes, strategies must be developed to characterize configurations that exhibit only marginal stability (such as intermediates) or configurations that do not correspond to minima on the energy landscape (such as transition-state ensembles). Here, we present a methodology (MDfit) that utilizes molecular dynamics simulations to generate configurations of excited states that are consistent with available biophysical and biochemical measurements. To demonstrate the approach, we present a sequence of configurations that are suggested to be associated with transfer RNA (tRNA) movement through the ribosome (translocation). The models were constructed by combining information from X-ray crystallography, cryo-electron microscopy, and biochemical data. These models provide a structural framework for translocation that may be further investigated experimentally and theoretically to determine the precise energetic character of each configuration and the transition dynamics between them. PMID:22080606

  11. DNA translocation through single-layer boron nitride nanopores.

    PubMed

    Gu, Zonglin; Zhang, Yuanzhao; Luan, Binquan; Zhou, Ruhong

    2016-01-21

    Ultra-thin nanopores have become promising biological sensors because of their outstanding signal-to-noise ratio and spatial resolution. Here, we show that boron nitride (BN), which is a new two-dimensional (2D) material similar to graphene, could be utilized for making a nanopore with an atomic thickness. Using an all-atom molecular dynamics simulation, we investigated the dynamics of DNA translocation through the BN nanopore. The results of our simulations demonstrated that it is possible to detect different double-stranded DNA (dsDNA) sequences from the recording of ionic currents through the pore during the DNA translocation. Surprisingly, opposite to results for a graphene nanopore, we found the calculated blockage current for poly(A-T)40 in a BN nanopore to be less than that for poly(G-C)40. Also in contrast with the case of graphene nanopores, dsDNA models moved smoothly and in an unimpeded manner through the BN nanopores in the simulations, suggesting a potential advantage for using BN nanopores to design stall-free sequencing devices. BN nanopores, which display several properties (such as being hydrophilic and non-metallic) that are superior to those of graphene, are thus expected to find applications in the next generation of high-speed and low-cost biological sensors. PMID:26537824

  12. Reverse Translocation of tRNA in the Ribosome

    PubMed Central

    Shoji, Shinichiro; Walker, Sarah E.; Fredrick, Kurt

    2009-01-01

    Summary A widely held view is that directional movement of tRNA in the ribosome is determined by an intrinsic mechanism and driven thermodynamically by transpeptidation. Here, we show that, in certain ribosomal complexes, the pretranslocation (PRE) state is thermodynamically favored over the posttranslocation (POST) state. Spontaneous and efficient conversion from the POST to PRE state is observed when EF-G is depleted from ribosomes in the POST state or when tRNA is added to the E site of ribosomes containing P-site tRNA. In the latter assay, the rate of tRNA movement is increased by streptomycin and neomycin, decreased by tetracycline, and not affected by the acylation state of the tRNA. In one case, we provide evidence that complex conversion occurs by reverse translocation (i.e., direct movement of the tRNAs from the E and P sites to the P and A sites, respectively). These findings have important implications for the energetics of translocation. PMID:17189194

  13. Mitochondrial translocation of APE1 relies on the MIA pathway.

    PubMed

    Barchiesi, Arianna; Wasilewski, Michal; Chacinska, Agnieszka; Tell, Gianluca; Vascotto, Carlo

    2015-06-23

    APE1 is a multifunctional protein with a fundamental role in repairing nuclear and mitochondrial DNA lesions caused by oxidative and alkylating agents. Unfortunately, comprehensions of the mechanisms regulating APE1 intracellular trafficking are still fragmentary and contrasting. Recent data demonstrate that APE1 interacts with the mitochondrial import and assembly protein Mia40 suggesting the involvement of a redox-assisted mechanism, dependent on the disulfide transfer system, to be responsible of APE1 trafficking into the mitochondria. The MIA pathway is an import machinery that uses a redox system for cysteine enriched proteins to drive them in this compartment. It is composed by two main proteins: Mia40 is the oxidoreductase that catalyzes the formation of the disulfide bonds in the substrate, while ALR reoxidizes Mia40 after the import. In this study, we demonstrated that: (i) APE1 and Mia40 interact through disulfide bond formation; and (ii) Mia40 expression levels directly affect APE1's mitochondrial translocation and, consequently, play a role in the maintenance of mitochondrial DNA integrity. In summary, our data strongly support the hypothesis of a redox-assisted mechanism, dependent on Mia40, in controlling APE1 translocation into the mitochondrial inner membrane space and thus highlight the role of this protein transport pathway in the maintenance of mitochondrial DNA stability and cell survival. PMID:25956655

  14. Molecular determinants of nucleolar translocation of RNA helicase A

    SciTech Connect

    Liu Zhe; Kenworthy, Rachael; Green, Christopher; Tang, Hengli

    2007-10-15

    RNA helicase A (RHA) is a member of the DEAH-box family of DNA/RNA helicases involved in multiple cellular processes and the life cycles of many viruses. The subcellular localization of RHA is dynamic despite its steady-state concentration in the nucleoplasm. We have previously shown that it shuttles rapidly between the nucleus and the cytoplasm by virtue of a bidirectional nuclear transport domain (NTD) located in its carboxyl terminus. Here, we investigate the molecular determinants for its translocation within the nucleus and, more specifically, its redistribution from the nucleoplasm to nucleolus or the perinucleolar region. We found that low temperature treatment, transcription inhibition or replication of hepatitis C virus caused the intranuclear redistribution of the protein, suggesting that RHA shuttles between the nucleolus and nucleoplasm and becomes trapped in the nucleolus or the perinucleolar region upon blockade of transport to the nucleoplasm. Both the NTD and ATPase activity were essential for RHA's transport to the nucleolus or perinucleolar region. One of the double-stranded RNA binding domains (dsRBD II) was also required for this nucleolar translocation (NoT) phenotype. RNA interference studies revealed that RHA is essential for survival of cultured hepatoma cells and the ATPase activity appears to be important for this critical role.

  15. The prognosis of MYC translocation positive diffuse large B‐cell lymphoma depends on the second hit

    PubMed Central

    Clipson, Alexandra; Barrans, Sharon; Zeng, Naiyan; Crouch, Simon; Grigoropoulos, Nicholas F; Liu, Hongxiang; Kocialkowski, Sylvia; Wang, Ming; Huang, Yuanxue; Worrillow, Lisa; Goodlad, John; Buxton, Jenny; Neat, Michael; Fields, Paul; Wilkins, Bridget; Grant, John W; Wright, Penny; EI‐Daly, Hesham; Follows, George A; Roman, Eve; Watkins, A James; Johnson, Peter W M; Jack, Andrew

    2015-01-01

    Abstract A proportion of MYC translocation positive diffuse large B‐cell lymphomas (DLBCL) harbour a BCL2 and/or BCL6 translocation, known as double‐hit DLBCL, and are clinically aggressive. It is unknown whether there are other genetic abnormalities that cooperate with MYC translocation and form double‐hit DLBCL, and whether there is a difference in clinical outcome between the double‐hit DLBCL and those with an isolated MYC translocation. We investigated TP53 gene mutations along with BCL2 and BCL6 translocations in a total of 234 cases of DLBCL, including 81 with MYC translocation. TP53 mutations were investigated by PCR and sequencing, while BCL2 and BCL6 translocation was studied by interphase fluorescence in situ hybridization. The majority of MYC translocation positive DLBCLs (60/81 = 74%) had at least one additional genetic hit. In MYC translocation positive DLBCL treated by R‐CHOP (n = 67), TP53 mutation and BCL2, but not BCL6 translocation had an adverse effect on patient overall survival. In comparison with DLBCL with an isolated MYC translocation, cases with MYC/TP53 double‐hits had the worst overall survival, followed by those with MYC/BCL2 double‐hits. In MYC translocation negative DLBCL treated by R‐CHOP (n = 101), TP53 mutation, BCL2 and BCL6 translocation had no impact on patient survival. The prognosis of MYC translocation positive DLBCL critically depends on the second hit, with TP53 mutations and BCL2 translocation contributing to an adverse prognosis. It is pivotal to investigate both TP53 mutations and BCL2 translocations in MYC translocation positive DLBCL, and to distinguish double‐hit DLBCLs from those with an isolated MYC translocation. PMID:27347428

  16. Inheritance of balanced translocation t(17; 22) from a Down syndrome mother to a phenotypically normal daughter.

    PubMed

    Liu, X Y; Jiang, Y T; Wang, R X; Luo, L L; Liu, Y H; Liu, R Z

    2015-01-01

    We report that a 30-year-old woman with mental retardation was referred for prenatal diagnoses during pregnancy. An ultrasound scan showed that the heart structure and function of the fetus were normal. Cytogenetic analysis showed that the female karyotype was 47,XX, t(17; 22) (q21; q11), +21. The woman's husband had a normal male karyotype and was phenotypically normal. During this first pregnancy, an amniocentesis, which was done at 19 weeks, revealed that the fetal karyotype was 46,XX, t(17; 22) (q21; q11). Fluorescence in situ hybridization testing of amniotic fluid gave a normal result for chromosome 21. The child was a phenotypically normal female baby. PMID:26345964

  17. TFE3-Fusion Variant Analysis Defines Specific Clinicopathologic Associations Among Xp11 Translocation Cancers.

    PubMed

    Argani, Pedram; Zhong, Minghao; Reuter, Victor E; Fallon, John T; Epstein, Jonathan I; Netto, George J; Antonescu, Cristina R

    2016-06-01

    Xp11 translocation cancers include Xp11 translocation renal cell carcinoma (RCC), Xp11 translocation perivascular epithelioid cell tumor (PEComa), and melanotic Xp11 translocation renal cancer. In Xp11 translocation cancers, oncogenic activation of TFE3 is driven by the fusion of TFE3 with a number of different gene partners; however, the impact of individual fusion variant on specific clinicopathologic features of Xp11 translocation cancers has not been well defined. In this study, we analyze 60 Xp11 translocation cancers by fluorescence in situ hybridization using custom bacterial artificial chromosome probes to establish their TFE3 fusion gene partner. In 5 cases RNA sequencing was also used to further characterize the fusion transcripts. The 60 Xp11 translocation cancers included 47 Xp11 translocation RCC, 8 Xp11 translocation PEComas, and 5 melanotic Xp11 translocation renal cancers. A fusion partner was identified in 53/60 (88%) cases, including 18 SFPQ (PSF), 16 PRCC, 12 ASPSCR1 (ASPL), 6 NONO, and 1 DVL2. We provide the first morphologic description of the NONO-TFE3 RCC, which frequently demonstrates subnuclear vacuoles leading to distinctive suprabasal nuclear palisading. Similar subnuclear vacuolization was also characteristic of SFPQ-TFE3 RCC, creating overlapping features with clear cell papillary RCC. We also describe the first RCC with a DVL2-TFE3 gene fusion, in addition to an extrarenal pigmented PEComa with a NONO-TFE3 gene fusion. Furthermore, among neoplasms with the SFPQ-TFE3, NONO-TFE3, DVL2-TFE3, and ASPL-TFE3 gene fusions, the RCCs are almost always PAX8 positive, cathepsin K negative by immunohistochemistry, whereas the mesenchymal counterparts (Xp11 translocation PEComas, melanotic Xp11 translocation renal cancers, and alveolar soft part sarcoma) are PAX8 negative, cathepsin K positive. These findings support the concept that despite an identical gene fusion, the RCCs are distinct from the corresponding mesenchymal neoplasms, perhaps due to

  18. Biophysical Characterization of the Type III Secretion System Translocator Proteins and the Translocator Proteins Attached to Bacterium-Like Particles.

    PubMed

    Chen, Xiaotong; Choudhari, Shyamal P; Kumar, Prashant; Toth, Ronald T; Kim, Jae Hyun; Van Roosmalen, Maarten L; Leenhouts, Kees; Middaugh, C Russell; Picking, Wendy L; Picking, William D

    2015-12-01

    Diarrhea caused by Shigella, Salmonella, and Yersinia is an important public health problem, but development of safe and effective vaccines against such diseases is challenging. A new antigen delivery platform called bacterium-like particles (BLPs) was explored as a means for delivering protective antigens from the type III secretion systems (T3SS) of these pathogens. BLPs are peptidoglycan skeletons derived from Lactococcus lactis that are safe for newborns and can carry multiple antigens. Hydrophobic T3SS translocator proteins were fused to a peptidoglycan anchor (PA) for BLP attachment. The proteins and protein-BLP complexes associated with BLPs were characterized and the resulting data used to create three-index empirical phase diagrams (EPDs). On the basis of these EPDs, IpaB (Shigella) and SipB (Salmonella) behave distinctly from YopB (Yersinia) under different environmental stresses. Adding the PA domain appears to enhance the stability of both the PA and translocator proteins, which was confirmed using differential scanning calorimetry, and although the particles dominated the spectroscopic signals in the protein-loaded BLPs, structural changes in the proteins were still detected. The protein-BLPs were most stable near neutral pH, but these proteins' hydrophobicity made them sensitive to environmental stresses. PMID:26422758

  19. Disulfide bridge formation between SecY and a translocating polypeptide localizes the translocation pore to the center of SecY.

    PubMed

    Cannon, Kurt S; Or, Eran; Clemons, William M; Shibata, Yoko; Rapoport, Tom A

    2005-04-25

    During their biosynthesis, many proteins pass through the membrane via a hydrophilic channel formed by the heterotrimeric Sec61/SecY complex. Whether this channel forms at the interface of multiple copies of Sec61/SecY or is intrinsic to a monomeric complex, as suggested by the recently solved X-ray structure of the Methanococcus jannaschii SecY complex, is a matter of contention. By introducing a single cysteine at various positions in Escherichia coli SecY and testing its ability to form a disulfide bond with a single cysteine in a translocating chain, we provide evidence that translocating polypeptides pass through the center of the SecY complex. The strongest cross-links were observed with residues that would form a constriction in an hourglass-shaped pore. This suggests that the channel makes only limited contact with a translocating polypeptide, thus minimizing the energy required for translocation. PMID:15851514

  20. The molecular structure of the Na(+)-translocating F1F0-ATPase of Acetobacterium woodii, as revealed by electron microscopy, resembles that of H(+)-translocating ATPases.

    PubMed

    Reidlinger, J; Mayer, F; Müller, V

    1994-12-12

    The Na(+)-translocating F1F0-ATPase of Acetobacterium woodii was examined by electron microscopy. After reconstitution into proteoliposomes, knobs typical for the F1 domain were visible on the outside of the membrane. The F1-part of the isolated enzyme showed a hexagonal symmetry suggesting an alpha 3 beta 3 structure, and the F1F0 complex had molecular dimensions very similar to those of H(+)-translocating ATPases of E. coli, chloroplasts, and mitochondria. PMID:7988711

  1. Familial transmission of a deletion of chromosome 21 derived from a translocation between chromosome 21 and an inverted chromosome 22.

    PubMed

    Aviv, H; Lieber, C; Yenamandra, A; Desposito, F

    1997-06-27

    Chromosome analysis of a newborn boy with Down syndrome resulted in the identification of a family with an unusual derivative chromosome 22. The child has 46 chromosomes, including two chromosomes 21, one normal chromosome 22, and a derivative chromosome 22. Giemsa banding and fluorescent in situ hybridization (FISH) studies show that the derivative chromosome is chromosome 22 with evidence of both paracentric and pericentric inversions, joined to the long arm of chromosome 21 from 21q21.2 to qter. The rearrangement results in partial trisomy 21 extending from 21q21.2 to 21q terminus in the patient. The child's mother, brother, maternal aunt, and maternal grandmother are all carriers of the derivative chromosome. All have 45 chromosomes, with one normal chromosome 21, one normal chromosome 22, and the derivative chromosome 22. The rearrangement results in the absence of the short arm, the centromere, and the proximal long arm of chromosome 21 (del 21pter-21q21.2) in carriers. Carriers of the derivative chromosome in this family have normal physical appearance, mild learning disabilities and poor social adjustment. PMID:9182781

  2. Cytotoxic Necrotizing Factor-Y Boosts Yersinia Effector Translocation by Activating Rac Protein*

    PubMed Central

    Wolters, Manuel; Boyle, Erin C.; Lardong, Kerstin; Trülzsch, Konrad; Steffen, Anika; Rottner, Klemens; Ruckdeschel, Klaus; Aepfelbacher, Martin

    2013-01-01

    Pathogenic Yersinia spp. translocate the effectors YopT, YopE, and YopO/YpkA into target cells to inactivate Rho family GTP-binding proteins and block immune responses. Some Yersinia spp. also secrete the Rho protein activator cytotoxic necrotizing factor-Y (CNF-Y), but it has been unclear how the bacteria may benefit from Rho protein activation. We show here that CNF-Y increases Yop translocation in Yersinia enterocolitica-infected cells up to 5-fold. CNF-Y strongly activated RhoA and also delayed in time Rac1 and Cdc42, but when individually expressed, constitutively active mutants of Rac1, but not of RhoA, increased Yop translocation. Consistently, knock-out or knockdown of Rac1 but not of RhoA, -B, or -C inhibited Yersinia effector translocation in CNF-Y-treated and control cells. Activation or knockdown of Cdc42 also affected Yop translocation but much less efficiently than Rac. The increase in Yop translocation induced by CNF-Y was essentially independent of the presence of YopE, YopT, or YopO in the infecting Yersinia strain, indicating that none of the Yops reported to inhibit translocation could reverse the CNF-Y effect. In summary, the CNF-Y activity of Yersinia strongly enhances Yop translocation through activation of Rac. PMID:23803609

  3. Preprotein translocation across the endoplasmic reticulum membrane in milieus crowded by proteins

    NASA Astrophysics Data System (ADS)

    Vélez, José. Antonio; Guzmán, Orlando; Navarro, Fernando

    2012-02-01

    Translocation of preproteins chains between the cytoplasm and the endoplasmic reticulum lumen takes place in a milieu crowded primarily by proteins. We compute translocation and retrotranslocation times for chains of different length in a milieu crowded by spherical agents at volume fractions equivalent to that found in cells. These numerical times obtained from a diffusion-equation model subject to a potential given by the free energy of one chain, indicate that crowding increases the translocation time by up to five times compared to those in dilute conditions for average-size chains and by up to a thousand times for long chains. Retrotranslocation times become smaller than translocation ones, in approximately 75%. Translocation rates obtained in this work are similar to those found in a theoretical model for Brownian-ratchet translocation and coincide with in vitro experimental results (1-8 aminoacid/s) only in the limit of very long chains; for shorter chains, translocation rates are much faster. Our prediction that for long chains translocation rates would be significantly slowed by crowding can be tested experimentally using vesicles. Discrepancy of time-scales with experiments for short chains indicates that other factors beside crowding must be included in our model.

  4. Charge Requirements for Proton Gradient-driven Translocation of Anthrax Toxin*

    PubMed Central

    Brown, Michael J.; Thoren, Katie L.; Krantz, Bryan A.

    2011-01-01

    Anthrax lethal toxin is used as a model system to study protein translocation. The toxin is composed of a translocase channel, called protective antigen (PA), and an enzyme, called lethal factor (LF). A proton gradient (ΔpH) can drive LF unfolding and translocation through PA channels; however, the mechanism of ΔpH-mediated force generation, substrate unfolding, and establishment of directionality are poorly understood. One recent hypothesis suggests that the ΔpH may act through changes in the protonation state of residues in the substrate. Here we report the charge requirements of LF's amino-terminal binding domain (LFN) using planar lipid bilayer electrophysiology. We found that acidic residues are required in LFN to utilize a proton gradient for translocation. Constructs lacking negative charges in the unstructured presequence of LFN translocate independently of the ΔpH driving force. Acidic residues markedly increase the rate of ΔpH-driven translocation, and the presequence is optimized in its natural acidic residue content for efficient ΔpH-driven unfolding and translocation. We discuss a ΔpH-driven charge state Brownian ratchet mechanism for translocation, where glutamic and aspartic acid residues in the substrate are the “molecular teeth” of the ratchet. Our Brownian ratchet model includes a mechanism for unfolding and a novel role for positive charges, which we propose chaperone negative charges through the PA channel during ΔpH translocation. PMID:21507946

  5. Sequence-specific assembly of FtsK hexamers establishes directional translocation on DNA

    PubMed Central

    Graham, James E.; Sherratt, David J.; Szczelkun, Mark D.

    2010-01-01

    FtsK is a homohexameric, RecA-like dsDNA translocase that plays a key role in bacterial chromosome segregation. The FtsK regulatory γ-subdomain determines directionality of translocation through its interaction with specific 8 base pair chromosomal sequences [(KOPS); FtsK Orienting / Polarizing Sequence(s)] that are cooriented with the direction of replication in the chromosome. We use millisecond-resolution ensemble translocation and ATPase assays to analyze the assembly, initiation, and translocation of FtsK. We show that KOPS are used to initiate new translocation events rather than reorient existing ones. By determining kinetic parameters, we show sigmoidal dependences of translocation and ATPase rates on ATP concentration that indicate sequential cooperative coupling of ATP hydrolysis to DNA motion. We also estimate the ATP coupling efficiency of translocation to be 1.63–2.11 bp of dsDNA translocated/ATP hydrolyzed. The data were used to derive a model for the assembly, initiation, and translocation of FtsK hexamers. PMID:21048089

  6. The Effect of Biliary Decompression on Bacterial Translocation in Jaundiced Rats

    PubMed Central

    Ding, Jin Wen; Soltesz, Vasile; Willén, Roger; Loft, Steffen; Poulsen, Henrik E.; Pärsson, Håkan; Olsson, Kjell; Bengmark, Stig

    1993-01-01

    Patients with obstructive jaundice are prone to septic complications after biliary tract operations. Restoring bile flow to the intestine may help to decrease the complication rate. The present study is aimed at evaluating the effect of biliary decompression on bacterial translocation in jaundiced rats. Sixty-six male Sprague-Dawley rats were randomly allocated to six groups subjected to common bile duct ligation (CBDL) and transection (groups 2–6) or sham operation (group 1). In groups and 2 the incidence of enteric bacterial translocation was determined 2 weeks after sham operation or CBDL. In groups 3–6, biliary decompression was achieved by performing a choledochoduodenostomy after 2 weeks of biliary decompression. Bacterial translocation was then studied 1,2,3 and 5 weeks following biliary decompression. The rate of bacterial translocation to mesenteric lymph nodes in obstructive jaundice was significantly higher as compared with controls, and decreased with time to nil three weeks following biliary decompression. The incidence of bacterial translocation was closely correlated (r = 0.844; p = 0.034) with serum alkaline phosphatase activity and seemed to fit with the morphological changes noted in the small intestine. The decrease in bacterial translocation, however, lags behind the recovery of liver function as measured by routine liver function tests and antipyrine clearance. Obstructive jaundice thus promotes bacterial translocation in the rat. Biliary decompression gradually decreases the rate of bacterial translocation. PMID:8268113

  7. A genomic comparison of homoeologous recombinants of the Lr19 (T4) translocation in wheat

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The Lr19 translocation continues to provide broad resistance to Puccinia triticina in many parts of the world and can be particularly useful when employed in resistance gene pyramids. Previously, an associated gene for yellow endosperm pigmentation precluded the use of the translocation in many coun...

  8. Xylem exudate composition and root-to-shoot nickel translocation in Alyssum species

    Technology Transfer Automated Retrieval System (TEKTRAN)

    An improved understanding of Ni root-to-shoot translocation mechanism in hyperaccumulators is necessary to increase Ni uptake efficiency for phytoextraction technologies. It is presumed that an important aspect of Ni translocation and storage involves chelation with organic ligands. It has been re...

  9. Ensemble Methods for Monitoring Enzyme Translocation along Single Stranded Nucleic Acids

    PubMed Central

    Tomko, Eric J.; Fischer, Christopher J.; Lohman, Timothy M.

    2010-01-01

    We review transient kinetic methods developed to study the mechanism of translocation of nucleic acid motor proteins. One useful stopped-flow fluorescence method monitors arrival of the translocase at the end of a fluorescently labeled nucleic acid. When conducted under single-round conditions the time courses can be analyzed quantitatively using n-step sequential models to determine the kinetic parameters for translocation (rate, kinetic step size and processivity). The assay and analysis discussed here can be used to study enzyme translocation along a linear lattice such as ssDNA or ssRNA. We outline the methods for experimental design and two approaches, along with their limitations, that can be used to analyze the time courses. Analysis of the full time courses using n-step sequential models always yields an accurate estimate of the translocation rate. An alternative semi-quantitative “time to peak” analysis yields accurate estimates of translocation rates only if the enzyme initiates translocation from a unique site on the nucleic acid. However, if initiation occurs at random sites along the nucleic acid, then the “time to peak” analysis can yield inaccurate estimates of even the rates of translocation depending on the values of other kinetic parameters, especially the rate of dissociation of the translocase. Thus, in those cases analysis of the full time course is needed to obtain accurate estimates of translocation rates. PMID:20371288

  10. Xp11.2 Translocation Renal Cell Carcinoma Diagnosed by Immunohistochemistry and Cytogenetics

    PubMed Central

    Dey, Biswajit; Badhe, Bhawana; Govindarajan, Krishna Kumar; Ramesh, Ranjith Arumbakkam

    2016-01-01

    Xp11.2 translocation renal cell carcinomas (TRCCs) are a group of neoplasms with distinct clinical, histopathological appearance, immunohistochemical, and cytogenetic profile. We report a case of Xp11.2 translocation TRCC in an 11-year-old male diagnosed based on immunohistochemistry and fluorescence in situ hybridization. PMID:27365924

  11. De Novo nonreciprocal translocation 1;8 confirmed by fluorescent in situ hybridization

    SciTech Connect

    Wiley, J.E.; Stout, C.; Palmer, S.M.

    1995-07-17

    Constitutional nonreciprocal translocations are extremely rare, and even their existence is controversial. We report on a newborn infant with a de novo nonreciprocal translocation between chromosomes 1 and 8 resulting in 1q42.3 deletion syndrome. Fluorescent in situ hybridization with whole chromosome paints confirmed the conventional cytogenetic diagnosis. 3 refs., 2 figs., 1 tab.

  12. Periodic forces trigger knot untying during translocation of knotted proteins.

    PubMed

    Szymczak, Piotr

    2016-01-01

    Proteins need to be unfolded when translocated through the pores in mitochondrial and other cellular membranes. Knotted proteins, however, might get stuck during this process, jamming the pore, since the diameter of the pore is smaller than the size of maximally tightened knot. The jamming probability dramatically increases as the magnitude of the driving force exceeds a critical value, Fc. In this numerical study, we show that for deep knots Fc lies below the force range over which molecular import motors operate, which suggest that in these cases the knots will tighten and block the pores. Next, we show how such topological traps might be prevented by using a pulling protocol of a repetitive, on-off character. Such a repetitive pulling is biologically relevant, since the mitochondrial import motor, like other molecular motors transforms chemical energy into directed motions via nucleotide-hydrolysis-mediated conformational changes, which are cyclic in character. PMID:26996878

  13. Opposite translocation of long and short oligomers through a nanopore

    NASA Astrophysics Data System (ADS)

    Getfert, Sebastian; Töws, Thomas; Reimann, Peter

    2013-06-01

    We consider elongated cylindrical particles, modeling, e.g., DNA fragments or nanorods, while they translocate under the action of an externally applied voltage through a solid state nanopore. Particular emphasis is put on the concomitant potential energy landscape encountered by the particle on its passage through the pore due to the complex interplay of various electrohydrodynamic effects beyond the realm of small Debye lengths. We find that the net potential energy difference across the membrane may be of opposite sign for short and long particles of equal diameters and charge densities (e.g., oligomers). Thermal noise thus leads to biased diffusion through the pore in opposite directions. By means of an additional membrane gate electrode it is even possible to control the specific particle length at which this transport inversion occurs.

  14. Protein Translocation through Tom40: Kinetics of Peptide Release

    PubMed Central

    Mahendran, Kozhinjampara R.; Romero-Ruiz, Mercedes; Schlösinger, Andrea; Winterhalter, Mathias; Nussberger, Stephan

    2012-01-01

    Mitochondrial proteins are almost exclusively imported into mitochondria from the cytosol in an unfolded or partially folded conformation. Regardless of whether they are destined for the outer or inner membrane, the intermembrane space, or the matrix, proteins begin the importation process by crossing the mitochondrial outer membrane via a specialized protein import machinery whose main component is the Tom40 channel. High-resolution ion conductance measurements through the Tom40 channel in the presence of the mitochondrial presequence peptide pF1β revealed the kinetics of peptide binding. Here we show that the rates for association kon and dissociation koff strongly depend on the applied transmembrane voltage. Both kinetic constants increase with an increase in the applied voltage. The increase of koff with voltage provides strong evidence of peptide translocation. This allows us to distinguish quantitatively between substrate blocking and permeation. PMID:22225796

  15. Heterologous protein production using the twin arginine translocation pathway

    DOEpatents

    Pohlschroder, Mechtild; Kissinger, Jessica C; Rose, R. Wesley; Brueser, Thomas; Dilks, Kieran

    2008-11-04

    Provided are means for evaluating and identifying putative substrates of the twin arginine translocation (Tat) secretory pathway in Streptomyces and other bacterial species. Also provided, therefore, are simple ways to express, secrete and purify correctly folded heterologous proteins on a large scale using host microorganisms, such as, Streptomyces and the Tat pathway therein. Many of the thus-produced proteins are of significant therapeutic value in the pharmaceutical and biochemical industries, particularly when they can be secreted from the host in fully-folded active form. Accordingly, there are further provided the heterologous proteins produced by the Tat secretion pathway using the foregoing methods, and the computer algorithm used to identify the Tat signal sequence and putative substrates.

  16. Periodic forces trigger knot untying during translocation of knotted proteins

    NASA Astrophysics Data System (ADS)

    Szymczak, Piotr

    2016-03-01

    Proteins need to be unfolded when translocated through the pores in mitochondrial and other cellular membranes. Knotted proteins, however, might get stuck during this process, jamming the pore, since the diameter of the pore is smaller than the size of maximally tightened knot. The jamming probability dramatically increases as the magnitude of the driving force exceeds a critical value, Fc. In this numerical study, we show that for deep knots Fc lies below the force range over which molecular import motors operate, which suggest that in these cases the knots will tighten and block the pores. Next, we show how such topological traps might be prevented by using a pulling protocol of a repetitive, on-off character. Such a repetitive pulling is biologically relevant, since the mitochondrial import motor, like other molecular motors transforms chemical energy into directed motions via nucleotide-hydrolysis-mediated conformational changes, which are cyclic in character.

  17. Logic Gate Operation by DNA Translocation through Biological Nanopores.

    PubMed

    Yasuga, Hiroki; Kawano, Ryuji; Takinoue, Masahiro; Tsuji, Yutaro; Osaki, Toshihisa; Kamiya, Koki; Miki, Norihisa; Takeuchi, Shoji

    2016-01-01

    Logical operations using biological molecules, such as DNA computing or programmable diagnosis using DNA, have recently received attention. Challenges remain with respect to the development of such systems, including label-free output detection and the rapidity of operation. Here, we propose integration of biological nanopores with DNA molecules for development of a logical operating system. We configured outputs "1" and "0" as single-stranded DNA (ssDNA) that is or is not translocated through a nanopore; unlabeled DNA was detected electrically. A negative-AND (NAND) operation was successfully conducted within approximately 10 min, which is rapid compared with previous studies using unlabeled DNA. In addition, this operation was executed in a four-droplet network. DNA molecules and associated information were transferred among droplets via biological nanopores. This system would facilitate linking of molecules and electronic interfaces. Thus, it could be applied to molecular robotics, genetic engineering, and even medical diagnosis and treatment. PMID:26890568

  18. Logic Gate Operation by DNA Translocation through Biological Nanopores

    PubMed Central

    Takinoue, Masahiro; Tsuji, Yutaro; Osaki, Toshihisa; Kamiya, Koki; Miki, Norihisa; Takeuchi, Shoji

    2016-01-01

    Logical operations using biological molecules, such as DNA computing or programmable diagnosis using DNA, have recently received attention. Challenges remain with respect to the development of such systems, including label-free output detection and the rapidity of operation. Here, we propose integration of biological nanopores with DNA molecules for development of a logical operating system. We configured outputs “1” and “0” as single-stranded DNA (ssDNA) that is or is not translocated through a nanopore; unlabeled DNA was detected electrically. A negative-AND (NAND) operation was successfully conducted within approximately 10 min, which is rapid compared with previous studies using unlabeled DNA. In addition, this operation was executed in a four-droplet network. DNA molecules and associated information were transferred among droplets via biological nanopores. This system would facilitate linking of molecules and electronic interfaces. Thus, it could be applied to molecular robotics, genetic engineering, and even medical diagnosis and treatment. PMID:26890568

  19. Periodic forces trigger knot untying during translocation of knotted proteins

    PubMed Central

    Szymczak, Piotr

    2016-01-01

    Proteins need to be unfolded when translocated through the pores in mitochondrial and other cellular membranes. Knotted proteins, however, might get stuck during this process, jamming the pore, since the diameter of the pore is smaller than the size of maximally tightened knot. The jamming probability dramatically increases as the magnitude of the driving force exceeds a critical value, Fc. In this numerical study, we show that for deep knots Fc lies below the force range over which molecular import motors operate, which suggest that in these cases the knots will tighten and block the pores. Next, we show how such topological traps might be prevented by using a pulling protocol of a repetitive, on-off character. Such a repetitive pulling is biologically relevant, since the mitochondrial import motor, like other molecular motors transforms chemical energy into directed motions via nucleotide-hydrolysis-mediated conformational changes, which are cyclic in character. PMID:26996878

  20. Structure and Activity of Tryptophan-rich TSPO Translocator Proteins

    PubMed Central

    Guo, Youzhong; Kalathur, Ravi C.; Liu, Qun; Kloss, Brian; Bruni, Renato; Ginter, Christopher; Kloppmann, Edda; Rost, Burkhard; Hendrickson, Wayne A.

    2015-01-01

    TSPO translocator proteins bind steroids and porphyrins, and they are implicated in many human diseases, for which they serve as biomarkers and therapeutic targets. TSPOs have tryptophan-rich sequences that are fhighly conserved from bacteria to mammals. We report crystal structures for Bacillus cereus TSPO (BcTSPO) down to 1.7Å resolution, including a complex with the benzodiazepine-like inhibitor PK11195. We also describe BcTSPO-mediated protoporphyrin IX (PpIX) reactions, including catalytic degradation to a previously undescribed heme derivative. We used structure-inspired mutations to investigate reaction mechanisms, and we showed that TSPOs from Xenopus and man have similar PpIX-directed activities. Although TSPOs have been regarded as transporters, the catalytic activity in PpIX degradation suggests physiological importance for TSPOs in protection against oxidative stress. PMID:25635100

  1. Tailoring particle translocation via dielectrophoresis in pore channels.

    PubMed

    Tanaka, Shoji; Tsutsui, Makusu; Theodore, Hu; Yuhui, He; Arima, Akihide; Tsuji, Tetsuro; Doi, Kentaro; Kawano, Satoyuki; Taniguchi, Masateru; Kawai, Tomoji

    2016-01-01

    Understanding and controlling electrophoretic motions of nanoscopic objects in fluidic channels are a central challenge in developing nanopore technology for molecular analyses. Although progress has been made in slowing the translocation velocity to meet the requirement for electrical detections of analytes via picoampere current measurements, there exists no method useful for regulating particle flows in the transverse directions. Here, we report the use of dielectrophoresis to manipulate the single-particle passage through a solid-state pore. We created a trap field by applying AC voltage between electrodes embedded in a low-aspect-ratio micropore. We demonstrated a traffic control of particles to go through center or near side surface via the voltage frequency. We also found enhanced capture efficiency along with faster escaping speed of particles by virtue of the AC-mediated electroosmosis. This method is compatible with nanopore sensing and would be widely applied for reducing off-axis effects to achieve single-molecule identification. PMID:27527126

  2. Structural characterization of mRNA-tRNA translocation intermediates

    PubMed Central

    Agirrezabala, Xabier; Liao, Hstau Y.; Schreiner, Eduard; Fu, Jie; Ortiz-Meoz, Rodrigo F.; Schulten, Klaus; Green, Rachel; Frank, Joachim

    2012-01-01

    Cryo-EM analysis of a wild-type Escherichia coli pretranslocational sample has revealed the presence of previously unseen intermediate substates of the bacterial ribosome during the first phase of translocation, characterized by intermediate intersubunit rotations, L1 stalk positions, and tRNA configurations. Furthermore, we describe the domain rearrangements in quantitative terms, which has allowed us to characterize the processivity and coordination of the conformational reorganization of the ribosome, along with the associated changes in tRNA ribosome-binding configuration. The results are consistent with the view of the ribosome as a molecular machine employing Brownian motion to reach a functionally productive state via a series of substates with incremental changes in conformation. PMID:22467828

  3. Structural characterization of mRNA-tRNA translocation intermediates.

    PubMed

    Agirrezabala, Xabier; Liao, Hstau Y; Schreiner, Eduard; Fu, Jie; Ortiz-Meoz, Rodrigo F; Schulten, Klaus; Green, Rachel; Frank, Joachim

    2012-04-17

    Cryo-EM analysis of a wild-type Escherichia coli pretranslocational sample has revealed the presence of previously unseen intermediate substates of the bacterial ribosome during the first phase of translocation, characterized by intermediate intersubunit rotations, L1 stalk positions, and tRNA configurations. Furthermore, we describe the domain rearrangements in quantitative terms, which has allowed us to characterize the processivity and coordination of the conformational reorganization of the ribosome, along with the associated changes in tRNA ribosome-binding configuration. The results are consistent with the view of the ribosome as a molecular machine employing Brownian motion to reach a functionally productive state via a series of substates with incremental changes in conformation. PMID:22467828

  4. Subversion of Retrograde Trafficking by Translocated Pathogen Effectors.

    PubMed

    Personnic, Nicolas; Bärlocher, Kevin; Finsel, Ivo; Hilbi, Hubert

    2016-06-01

    Intracellular bacterial pathogens subvert the endocytic bactericidal pathway to form specific replication-permissive compartments termed pathogen vacuoles or inclusions. To this end, the pathogens employ type III or type IV secretion systems, which translocate dozens, if not hundreds, of different effector proteins into their host cells, where they manipulate vesicle trafficking and signaling pathways in favor of the intruders. While the distinct cocktail of effectors defines the specific processes by which a pathogen vacuole is formed, the different pathogens commonly target certain vesicle trafficking routes, including the endocytic or secretory pathway. Recently, the retrograde transport pathway from endosomal compartments to the trans-Golgi network emerged as an important route affecting pathogen vacuole formation. Here, we review current insight into the host cell's retrograde trafficking pathway and how vacuolar pathogens of the genera Legionella, Coxiella, Salmonella, Chlamydia, and Simkania employ mechanistically distinct strategies to subvert this pathway, thus promoting intracellular survival and replication. PMID:26924068

  5. Mechanism of long-range proton translocation along biological membranes

    PubMed Central

    Medvedev, Emile S.; Stuchebrukhov, Alexei A.

    2014-01-01

    Recent experiments suggest that protons can travel along biological membranes up to tens of micrometers, but the mechanism of transport is unknown. To explain such a long-range proton translocation we describe a model that takes into account the coupled bulk diffusion that accompanies the migration of protons on the surface. We show that protons diffusing at or near the surface before equilibrating with the bulk desorb and re-adsorb at the surface thousands of times, giving rise to a power-law desorption kinetics. As a result, the decay of the surface protons occurs very slowly, allowing for establishing local gradient and local exchange, as was envisioned in the early local models of biological energy transduction. PMID:23268201

  6. Minireview: Translocator Protein (TSPO) and Steroidogenesis: A Reappraisal

    PubMed Central

    Stocco, Douglas M.; Tu, Lan N.

    2015-01-01

    The 18-kDa translocator protein (TSPO), also known as the peripheral benzodiazepine receptor, is a transmembrane protein in the outer mitochondrial membrane. TSPO has long been described as being indispensable for mitochondrial cholesterol import that is essential for steroid hormone production. In contrast to this initial proposition, recent experiments reexamining TSPO function have demonstrated that it is not involved in steroidogenesis. This fundamental change has forced a reexamination of the functional interpretations made for TSPO that broadly impacts both basic and clinical research across multiple fields. In this minireview, we recapitulate the key studies from 25 years of TSPO research and concurrently examine their limitations that perhaps led towards the incorrect association of TSPO and steroid hormone production. Although this shift in understanding raises new questions regarding the molecular function of TSPO, these recent developments are poised to have a significant positive impact for research progress in steroid endocrinology. PMID:25730708

  7. Tailoring particle translocation via dielectrophoresis in pore channels

    PubMed Central

    Tanaka, Shoji; Tsutsui, Makusu; Theodore, Hu; Yuhui, He; Arima, Akihide; Tsuji, Tetsuro; Doi, Kentaro; Kawano, Satoyuki; Taniguchi, Masateru; Kawai, Tomoji

    2016-01-01

    Understanding and controlling electrophoretic motions of nanoscopic objects in fluidic channels are a central challenge in developing nanopore technology for molecular analyses. Although progress has been made in slowing the translocation velocity to meet the requirement for electrical detections of analytes via picoampere current measurements, there exists no method useful for regulating particle flows in the transverse directions. Here, we report the use of dielectrophoresis to manipulate the single-particle passage through a solid-state pore. We created a trap field by applying AC voltage between electrodes embedded in a low-aspect-ratio micropore. We demonstrated a traffic control of particles to go through center or near side surface via the voltage frequency. We also found enhanced capture efficiency along with faster escaping speed of particles by virtue of the AC-mediated electroosmosis. This method is compatible with nanopore sensing and would be widely applied for reducing off-axis effects to achieve single-molecule identification. PMID:27527126

  8. Retro-translocation of mitochondrial intermembrane space proteins

    PubMed Central

    Bragoszewski, Piotr; Wasilewski, Michal; Sakowska, Paulina; Gornicka, Agnieszka; Böttinger, Lena; Qiu, Jian; Wiedemann, Nils; Chacinska, Agnieszka

    2015-01-01

    The content of mitochondrial proteome is maintained through two highly dynamic processes, the influx of newly synthesized proteins from the cytosol and the protein degradation. Mitochondrial proteins are targeted to the intermembrane space by the mitochondrial intermembrane space assembly pathway that couples their import and oxidative folding. The folding trap was proposed to be a driving mechanism for the mitochondrial accumulation of these proteins. Whether the reverse movement of unfolded proteins to the cytosol occurs across the intact outer membrane is unknown. We found that reduced, conformationally destabilized proteins are released from mitochondria in a size-limited manner. We identified the general import pore protein Tom40 as an escape gate. We propose that the mitochondrial proteome is not only regulated by the import and degradation of proteins but also by their retro-translocation to the external cytosolic location. Thus, protein release is a mechanism that contributes to the mitochondrial proteome surveillance. PMID:26056291

  9. Translocation of Cell Penetrating Peptide Engrafted Nanoparticles Across Skin Layers

    PubMed Central

    Patlolla, Ram R; Desai, Pinaki; Belay, Kalayu; Singh, Mandip

    2010-01-01

    The objective of the current study was to evaluate the ability of cell penetrating peptides (CPP) to translocate the lipid payload into the skin layers. Fluorescent dye (DID-oil) encapsulated nano lipid crystal nanoparticles (FNLCN) were prepared using Compritol, Miglyol and DOGS-NTA-Ni lipids by hot melt homogenization technique. The FNLCN surface was coated with TAT peptide (FNLCNT) or control YKA peptide (FNLCNY) and in vitro rat skin permeation studies were performed using Franz diffusion cells. Observation of lateral skin sections obtained using cryotome with a confocal microscope demonstrated that skin permeation of FNLCNT was time dependent and after 24 h, fluorescence was observed upto a depth of 120 µm which was localized in the hair follicles and epidermis. In case of FNLCN and FNLCNY formulations fluorescence was mainly observed in the hair follicles. This observation was further supported by confocal Raman spectroscopy where higher fluorescence signal intensity was observed at 80 and 120 µm depth with FNLCNT treated skin and intensity of fluorescence peaks was in the ratio of 2:1:1 and 5:3:1 for FNLCNT, FNLCN, and FNLCNY treated skin sections, respectively. Furthermore, replacement of DID-oil with celecoxib (Cxb), a model lipophilic drug showed similar results and after 24 h, the CXBNT formulation increased the Cxb concentration in SC by 3 and 6 fold and in epidermis by 2 and 3 fold as compared to CXBN and CXBNY formulations respectively. Our results strongly suggest that CPP can translocate nanoparticles with their payloads into deeper skin layers. PMID:20413152

  10. DNA translocation through an array of kinked nanopores

    NASA Astrophysics Data System (ADS)

    Chen, Zhu; Jiang, Yingbing; Dunphy, Darren R.; Adams, David P.; Hodges, Carter; Liu, Nanguo; Zhang, Nan; Xomeritakis, George; Jin, Xiaozhong; Aluru, N. R.; Gaik, Steven J.; Hillhouse, Hugh W.; Jeffrey Brinker, C.

    2010-08-01

    Synthetic solid-state nanopores are being intensively investigated as single-molecule sensors for detection and characterization of DNA, RNA and proteins. This field has been inspired by the exquisite selectivity and flux demonstrated by natural biological channels and the dream of emulating these behaviours in more robust synthetic materials that are more readily integrated into practical devices. So far, the guided etching of polymer films, focused ion-beam sculpting, and electron-beam lithography and tuning of silicon nitride membranes have emerged as three promising approaches to define synthetic solid-state pores with sub-nan