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Sample records for 1p36 deletion defines

  1. 1p36 deletion syndrome: an update

    PubMed Central

    Jordan, Valerie K; Zaveri, Hitisha P; Scott, Daryl A

    2015-01-01

    Deletions of chromosome 1p36 affect approximately 1 in 5,000 newborns and are the most common terminal deletions in humans. Medical problems commonly caused by terminal deletions of 1p36 include developmental delay, intellectual disability, seizures, vision problems, hearing loss, short stature, distinctive facial features, brain anomalies, orofacial clefting, congenital heart defects, cardiomyopathy, and renal anomalies. Although 1p36 deletion syndrome is considered clinically recognizable, there is significant phenotypic variation among affected individuals. This variation is due, at least in part, to the genetic heterogeneity seen in 1p36 deletions which include terminal and interstitial deletions of varying lengths located throughout the 30 Mb of DNA that comprise chromosome 1p36. Array-based copy number variant analysis can easily identify genomic regions of 1p36 that are deleted in an affected individual. However, predicting the phenotype of an individual based solely on the location and extent of their 1p36 deletion remains a challenge since most of the genes that contribute to 1p36-related phenotypes have yet to be identified. In addition, haploinsufficiency of more than one gene may contribute to some phenotypes. In this article, we review recent successes in the effort to map and identify the genes and genomic regions that contribute to specific 1p36-related phenotypes. In particular, we highlight evidence implicating MMP23B, GABRD, SKI, PRDM16, KCNAB2, RERE, UBE4B, CASZ1, PDPN, SPEN, ECE1, HSPG2, and LUZP1 in various 1p36 deletion phenotypes. PMID:26345236

  2. 1p36 deletion syndrome: an update.

    PubMed

    Jordan, Valerie K; Zaveri, Hitisha P; Scott, Daryl A

    2015-01-01

    Deletions of chromosome 1p36 affect approximately 1 in 5,000 newborns and are the most common terminal deletions in humans. Medical problems commonly caused by terminal deletions of 1p36 include developmental delay, intellectual disability, seizures, vision problems, hearing loss, short stature, distinctive facial features, brain anomalies, orofacial clefting, congenital heart defects, cardiomyopathy, and renal anomalies. Although 1p36 deletion syndrome is considered clinically recognizable, there is significant phenotypic variation among affected individuals. This variation is due, at least in part, to the genetic heterogeneity seen in 1p36 deletions which include terminal and interstitial deletions of varying lengths located throughout the 30 Mb of DNA that comprise chromosome 1p36. Array-based copy number variant analysis can easily identify genomic regions of 1p36 that are deleted in an affected individual. However, predicting the phenotype of an individual based solely on the location and extent of their 1p36 deletion remains a challenge since most of the genes that contribute to 1p36-related phenotypes have yet to be identified. In addition, haploinsufficiency of more than one gene may contribute to some phenotypes. In this article, we review recent successes in the effort to map and identify the genes and genomic regions that contribute to specific 1p36-related phenotypes. In particular, we highlight evidence implicating MMP23B, GABRD, SKI, PRDM16, KCNAB2, RERE, UBE4B, CASZ1, PDPN, SPEN, ECE1, HSPG2, and LUZP1 in various 1p36 deletion phenotypes.

  3. Monosomy 1p36 deletion syndrome.

    PubMed

    Gajecka, Marzena; Mackay, Katherine L; Shaffer, Lisa G

    2007-11-15

    Monosomy 1p36 results from a heterozygous deletion of the most distal chromosomal band on the short arm of chromosome 1. Occurring in approximately 1 in 5,000 live births, monosomy 1p36 is the most common terminal deletion observed in humans. Monosomy 1p36 is associated with mental retardation, developmental delay, hearing impairment, seizures, growth impairment, hypotonia, and heart defects. The syndrome is also characterized by several distinct dysmorphic features, including large anterior fontanels, microcephaly, brachycephaly, deep-set eyes, flat nose and nasal bridge, and pointed chin. Several genes have been proposed as causative for individual features of the phenotype. In addition, based upon molecular characterization of subjects with monosomy 1p36, several mechanisms for the generation and stabilization of terminal deletions have been proposed.

  4. FISH analysis of a patient with a constitutional 1p36 deletion defines a region for a neuroblastoma tumor suppressor gene

    SciTech Connect

    Biegel, J.; Hilliard, C.; White, P.

    1994-09-01

    Molecular and cytogenetic studies of neuroblastoma have implicated the presence of one or more tumor suppressor genes on chromosome 1p. We previously reported a neuroblastoma patient with a constitutional interstitial deletion of 1p36. As one means of further defining the deleted region, we have analyzed a series of chromosome 1p36 specific probes by FISH to metaphase chromosomes from a lymphoblastoid cell line established from the patient. We have also tested these probes on a neuroblastoma cell line, NGP, which has a t(1;15) translocation involving 1p36. The probes analyzed to date in order from centromere to telomere include ID-3 (heir-1), D1S56, D1S160, and CDC2L1 (p58). Cosmids for ID-3 and D1S56 were present in 2 copies and proximal to the breakpoint in the constitutional case, and retained on the derivative 1 in NGP. CDC2L1 was also present in 2 copies in the constitutional case, but is distal to the deletion. In NGP, CDC2L1 was translocated to the derivative 15. The D1S160 locus was deleted from one of the chromosomes 1 in the constitutional case, and was present in three copies in NGP: on the normal chromosome 1, the derivative chromosome 1, and the derivative chromosome 15. Molecular studies have suggested that there is a duplication involving this region in NGP, and so it is not clear where the translocation breakpoint is in this cell line. These studies have localized a critical region for a neuroblastoma tumor suppressor gene to 1p36.2, distal to D1S56, proximal to CDC2L1, and including D1S160. This region overlaps with the smallest area of deletion defined by loss of heterozygosity studies of primary neuroblastomas and neuroblastoma cell lines. Additional studies with probes that flank the D1S160 locus will facilitate a molecular cloning approach for a neuroblastoma tumor suppressor gene.

  5. Growth patterns of patients with 1p36 deletion syndrome.

    PubMed

    Sangu, Noriko; Shimojima, Keiko; Shimada, Shino; Ando, Tomohiro; Yamamoto, Toshiyuki

    2014-05-01

    1p36 deletion syndrome is one of the most common subtelomeric deletion syndromes. Obesity is frequently observed in patients with this syndrome. Thus, it is important to evaluate the growth status of an individual patient. For this purpose, we accumulated recorded growth data from 44 patients with this syndrome and investigated the growth patterns of patients. Most of the patients showed weight parameters within normal limits, whereas a few of these patients showed intrauterine growth delay and microcephaly. The length of the patients after birth was under the 50th centile in most patients. Many patients showed poor weight gain after birth, and only two female patients were overweight. These findings indicate two different phenotypes of the 1p36 deletion syndrome. The overweight patients with 1p36 deletion started excessive weight gain after two years of life. This characteristic of the patients with 1p36 deletion syndrome is similar to Prader-Willi syndrome.

  6. Genetics Home Reference: 1p36 deletion syndrome

    MedlinePlus

    ... shaped. People with 1p36 deletion syndrome may have vision or hearing problems. Some have abnormalities ... to affect between 1 in 5,000 and 1 in 10,000 newborns. However, this may be an underestimate because some ...

  7. Spectrum of epilepsy in terminal 1p36 deletion syndrome.

    PubMed

    Bahi-Buisson, Nadia; Guttierrez-Delicado, Eva; Soufflet, Christine; Rio, Marlène; Daire, Valérie Cormier; Lacombe, Didier; Héron, Delphine; Verloes, Alain; Zuberi, Sameer; Burglen, Lydie; Afenjar, Alexandra; Moutard, Marie Laure; Edery, Patrick; Novelli, Antonio; Bernardini, Laura; Dulac, Olivier; Nabbout, Rima; Plouin, Perrine; Battaglia, Agatino

    2008-03-01

    Previous reports have summarized the seizures types occurring in 1p36 deletion syndrome. To better define the spectrum of epilepsy, we studied 91 patients (median age 7.8 years) with confirmed 1p36 deletion. Based on clinical charts, we retrospectively analyzed the evolution of both the EEG findings and seizures. Epilepsy occurred in 53 patients (58.2%), with onset at a median 2.75 months. First seizures were generalized tonic (8 cases), tonic and clonic (6) or myoclonic (12), simple partial (6), or complex partial (14). Thereafter, 20 patients (21.9%) developed infantile spasms with hypsarrhythmia, at a median age of 5 months. High doses of oral steroids were tried in nine cases, with a prompt remission of seizures in six. Among them, five were seizure-free at the time of evaluation. Conversely, two of three nonresponders to steroids developed severe and refractory epilepsy. At the time of evaluation, 32 patients were seizure-free, from a median age of 1.8 years. Nineteen patients (20.9%) had developed refractory epilepsy with polymorphic seizures, including generalized tonic and tonic-clonic seizures (13) combined with myoclonic seizures (11) and atypical absences (3), atonic seizures (2), or complex partial seizures (3). The EEG showed focal, multifocal or generalized spikes, polyspike, and waves, with poverty of the usual background rhythmic activities. Early epilepsy is a frequent finding in 1p36 deletion syndrome with infantile spasms as of the most common features that can contribute to a poor clinical outcome. Early diagnosis and management of infantile spasm in this condition is mandatory.

  8. [An updated review of 1p36 deletion (monosomy) syndrome].

    PubMed

    Bello, Sabina; Rodríguez-Moreno, Antonio

    The Monosomy 1p36 deletion syndrome is part of the group of diseases known as Rare Diseases. The objective of the present work is to review the characteristics of Monosomy 1p36 deletion syndrome. The monosomy 1p36 deletion syndrome phenotype includes: dysmorphic craniofacial features; large anterior fontanelle, unibrow, deep-set eyes, epicanthus, wide nasal root/bridge, mandible hypoplasia, abnormal location of the pinna, philtrum and pointed chin; neurological alterations: seizures and hydrocephalus (in some cases). Cerebral malformations: ventricular hypertrophy, increased subarachnoid space, morphological alterations of corpus callosum, cortical atrophy, delays in myelinisation, periventricular leukomalacia and periventricular heterotopia. These alterations produce intellectual disability and delays in motor growth, communication skills, language, social and adaptive behaviour. It is Hearing and vision impairments are also observed in subjects with this syndrome, as well as alterations of cardiac, endocrine and urinary systems and alterations at skin and skeletal level. Approximately 100 cases have been documented since 1981. This rare disease is the most common subtelomeric-micro-deletion syndrome. In situ hybridization with fluorescence (FISH) and array-comparative genomic hybridization (CGH-array) are at present the two best diagnostic techniques. There is currently no effective medical treatment for this disease. Copyright © 2016 Sociedad Chilena de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

  9. Epilepsy and neurological findings in 11 individuals with 1p36 deletion syndrome.

    PubMed

    Kurosawa, Kenji; Kawame, Hiroshi; Okamoto, Nobuhiko; Ochiai, Yukikatsu; Akatsuka, Akira; Kobayashi, Masahisa; Shimohira, Masayuki; Mizuno, Seiji; Wada, Kazuko; Fukushima, Yoshimitsu; Kawawaki, Hisashi; Yamamoto, Toshiyuki; Masuno, Mitsuo; Imaizumi, Kiyoshi; Kuroki, Yoshikazu

    2005-08-01

    The 1p36 deletion syndrome is a newly delineated multiple congenital anomalies/mental retardation syndrome characterized by mental retardation, growth delay, epilepsy, congenital heart defects, characteristic facial appearance, and precocious puberty. We analyzed 11 patients by fluorescence in situ hybridization (FISH) using commercially available bacterial artificial chromosome and P1-derived artificial chromosome genomic clones to define the chromosomal deletion responsible for the 1p36 deletion syndrome. Cytogenetic investigation revealed two cases with a terminal deletion of 1p36. Nine patients had an apparently normal karyotype with standard G-bands by trypsin using Giemsa (GTG), but FISH screening with the highly polymorphic genetic marker D1Z2, which is mapped to 1p36.3 and contains an unusual reiterated 40-bp variable number tandem repeat, revealed a submicroscopic deletion. All patients had severe to profound mental retardation. Based on the University of California Santa Cruz Genome Browser, we constructed a deletion map and analyzed the relationship between neurological findings and chromosomal deletions for the 11 cases. Six cases had intractable epilepsy and three had no seizures. The common deletion interval was about 1 million base pairs (Mbp) located between RP11-82D16 and RP4-785P20 (Rho guanine exchange factor (GEF) 16). The severity of clinical symptoms correlates with the size of the deletion. This is demonstrated by the 3 patients with at least 8Mbp deletions that display profound mental retardation and congenital heart defects. Although haploinsufficiency of the potassium channel beta-subunit (KCNAB2) is thought to be responsible for intractable seizures in the 1p36 deletion syndrome, this was not the case for 3 of the 11 patients in this study. Further investigation of the 1p36 region is necessary to allow identification of genes responsible for the 1p36 deletion syndrome.

  10. A girl with 1p36 deletion syndrome and congenital fiber type disproportion myopathy.

    PubMed

    Okamoto, Nobuhiko; Toribe, Yasuhisa; Nakajima, Tohru; Okinaga, Takeshi; Kurosawa, Kenji; Nonaka, Ikuya; Shimokawa, Osamu; Matsumoto, Noamichi

    2002-01-01

    Chromosome 1p36 deletion syndrome is characterized by hypotonia, moderate to severe developmental and growth retardation, and characteristic craniofacial dysmorphism. Muscle hypotonia and delayed motor development are almost constant features of the syndrome. We report a 4-year-old Japanese girl with 1p36 deletion syndrome whose muscle pathology showed congenital fiber type disproportion (CFTD) myopathy. This is the first case report of 1p36 deletion associated with CFTD. This association may indicate that one of the CFTD loci is located at 1p36. Ski proto-oncogene -/- mice have phenotypes that resemble some of the features observed in patients with 1p36 deletion syndrome. Because fluorescent in situ hybridization analysis revealed that the human SKI gene is deleted in our patient, some genes in 1p36, including SKI proto-oncogene, may be involved in muscle hypotonia and delayed motor development in this syndrome.

  11. Definition and characterization of a region of 1p36.3 consistently deleted in neuroblastoma.

    PubMed

    White, Peter S; Thompson, Patricia M; Gotoh, Takahiro; Okawa, Erin R; Igarashi, Jun; Kok, Marleen; Winter, Cynthia; Gregory, Simon G; Hogarty, Michael D; Maris, John M; Brodeur, Garrett M

    2005-04-14

    Substantial genomic and functional evidence from primary tumors and cell lines indicates that a consistent region of distal chromosome 1p is deleted in a sizable proportion of human neuroblastomas, suggesting that this region contains one or more tumor suppressor genes. To determine systematically and precisely the location and extent of 1p deletion in neuroblastomas, we performed allelic loss studies of 737 primary neuroblastomas and genotype analysis of 46 neuroblastoma cell lines. Together, the results defined a single region within 1p36.3 that was consistently deleted in 25% of tumors and 87% of cell lines. Two neuroblastoma patients had constitutional deletions of distal 1p36 that overlapped the tumor-defined region. The tumor- and constitutionally-derived deletions together defined a smallest region of consistent deletion (SRD) between D1S2795 and D1S253. The 1p36.3 SRD was deleted in all but one of the 184 tumors with 1p deletion. Physical mapping and DNA sequencing determined that the SRD minimally spans an estimated 729 kb. Genomic content and sequence analysis of the SRD identified 15 characterized, nine uncharacterized, and six predicted genes in the region. The RNA expression profiles of 21 of the genes were investigated in a variety of normal tissues. The SHREW1 and KCNAB2 genes both had tissue-restricted expression patterns, including expression in the nervous system. In addition, a novel gene (CHD5) with strong homology to proteins involved in chromatin remodeling was expressed mainly in neural tissues. Together, these results suggest that one or more genes involved in neuroblastoma tumorigenesis or tumor progression are likely contained within this region.

  12. A region of consistent deletion in neuroblastoma maps within human chromosome 1p36.2-36.3

    SciTech Connect

    White, P.S.; Maris, J.M.; Beltinger, C.

    1995-06-06

    Deletion of the short arm of human chromosome 1 is the most common cytogenetic abnormality observed in neuroblastoma. To characterize the region of consistent deletion, we performed loss of heterozygosity (LOH) studies on 122 neuroblastoma tumor samples with 30 distal chromosome 1p polymorphisms. LOH was detected in 32 of the 122 tumors (26%). A single region of LOH, marked distally by D1Z2 and proximally by D1S228, was detected in all tumors demonstrating loss. Also, cells from a patient with a constitutional deletion of 1p36, and from a neuroblastoma cell line with a small 1p36 deletion, were analyzed by fluorescence in situ hybridization. Cells from both sources had interstitial deletions of 1p36.2-36.3 which overlapped the consensus region of LOH defined by the tumors. Interstitial deletion in the constitutional case was confirmed by allelic loss studies using the panel of polymorphic markers. Four proposed candidate genes-DAN, ID3 (heir-1), CDC2L1 (p58), and TNFR2-were shown to lie outside of the consensus region of allelic loss, as defined by the above deletions. These results more precisely define the location of a neuroblastoma suppressor gene within 1p36.2-36.3, eliminating 33 centimorgans of proximal 1p36 from consideration. Furthermore, a consensus region of loss, which excludes the four leading candidate genes, was found in all tumors with 1p36 LOH. 31 refs., 4 figs.

  13. Abdominal paraganglioma in a young woman with 1p36 deletion syndrome.

    PubMed

    Murakoshi, Miki; Takasawa, Kei; Nishioka, Masato; Asakawa, Masahiro; Kashimada, Kenichi; Yoshimoto, Takanobu; Yamamoto, Toshiyuki; Takekoshi, Kazuhiro; Ogawa, Yoshihiro; Shimohira, Masayuki

    2017-02-01

    1p36 deletion syndrome is the most common terminal deletion syndrome, and the genomic regions that contribute to specific 1p36 deletion syndrome-related phenotypes were recently identified. Deletions in the 1p36 region have been documented in various tumor tissues, which indicates correlation between loss of heterozygosity of 1p36 and tumor development, and the existence of tumor suppressors in this region. Therefore, it was suspected that patients with 1p36 deletion syndrome have a higher risk of tumor development; however, only a few child cases of neuroblastoma with 1p36 deletion syndrome have been reported. We report the first case of 1p36 deletion syndrome with paraganglioma (PGL) and include genetic investigation. The 24-year-old woman with 1p36 deletion syndrome had severe intellectual disability, dilated cardiomyopathy, and distinct dysmorphic features, and presented with persistent vomiting accompanied by hypertension (178/115 mmHg). Abdominal CT revealed a 40 × 50 mm retroperitoneal mass and substantial elevations of plasma and urine norepinephrine (15.4 nmol/L and 1022 µmol/mol creatinine, respectively); abnormal uptake of (123) I-MIBG in the tumor led to PGL diagnosis. The patient was not able to have surgery because of substantial surgical risks; however, a combination of α- and β-blockade was effective for blood pressure control. Array CGH revealed a deletion over 4.5 Mb, from the 1p telomere but excluding the SDHB region. Comprehensive mutational analysis of PGL-associated genes (RET, VHL, TMEM127, MAX, and SDHA/B/C/D) was negative. These results indicate that the germline 1p36 deletion might be "1st hit" of tumor development, and PGL might be a novel complication of 1p36 deletion syndrome. © 2016 Wiley Periodicals, Inc.

  14. FISH analysis of hematological neoplasias with 1p36 rearrangements allows the definition of a cluster of 2.5 Mb included in the minimal region deleted in 1p36 deletion syndrome.

    PubMed

    Lahortiga, Idoya; Vázquez, Iria; Belloni, Elena; Román, José P; Gasparini, Patrizia; Novo, Francisco J; Zudaire, Isabel; Pelicci, Pier G; Hernández, Jesús M; Calasanz, María J; Odero, María D

    2005-05-01

    Rearrangements in the distal region of the short arm of chromosome 1 are recurrent aberrations in a broad spectrum of human neoplasias. However, neither the location of the breakpoints (BP) on 1p36 nor the candidate genes have been fully determined. We have characterized, by fluorescence in situ hybridization (FISH), the BP in 26 patients with hematological neoplasias and 1p36 rearrangements in the G-banding karyotype. FISH allowed a better characterization of all samples analyzed. Nine cases (35%) showed reciprocal translocations, 15 (58%) unbalanced rearrangements, and two (7%) deletions. We describe two new recurrent aberrations. In 18 of the 26 cases analyzed the BP were located in band 1p36, which is 25.5 Mb long. In 14 of these 18 cases (78%) and without distinction between myeloid and lymphoid neoplasias, the BP clustered in a 2.5 Mb region located between 1p36.32 and the telomere. Interestingly, this region is contained in the 10.5 Mb cluster on 1p36.22-1pter defined in cases with 1p36 deletion syndrome. The 2.5 Mb region, located on 1p36.32-1pter, has a higher frequency of occurrence of tandem repeats and segmental duplications larger than 1 kb, when compared with the 25.5 Mb of the complete 1p36 band. This could explain its proneness for involvement in chromosomal rearrangements in hematological neoplasias.

  15. Mini-Review: Monosomy 1p36 syndrome: reviewing the correlation between deletion sizes and phenotypes.

    PubMed

    Rocha, C F; Vasques, R B; Santos, S R; Paiva, C L A

    2016-02-22

    The major clinical features of monosomy 1p36 deletion are developmental delay and hypotonia associated with short stature and craniofacial dysmorphisms. The objective of this study was to review the cases of 1p36 deletion that was reported between 1999 and 2014, in order to identify a possible correlation between the size of the 1p36-deleted segment and the clinical phenotype of the disease. Scientific articles published in the (National Center for Biotechnology Information; NCBI http://www.ncbi.nlm.nih.gov/pubmed) and Scientific Electronic Library Online (www.scielo.com.br) databases were searched using key word combinations, such as "1p36 deletion", "monosomy 1p36 deletion", and "1p36 deletion syndrome". Articles in English or Spanish reporting the correlation between deletion sizes and the respective clinical phenotypes were retrieved, while letters, reviews, guidelines, and studies with mouse models were excluded. Among the 746 retrieved articles, only 17 (12 case reports and 5 series of cases), comprising 29 patients (9 males and 20 females, aged 0 months (neonate) to 22 years) bearing the 1p36 deletions and whose clinical phenotypes were described, met the inclusion criteria. The genotype-phenotype correlation in monosomy 1p36 is a challenge because of the variability in the size of the deleted segment, as well as in the clinical manifestations of similar size deletions. Therefore, the severity of the clinical features was not always associated with the deletion size, possibly because of the other influences, such as stochastic factors, epigenetic events, or reduced penetration of the deleted genes.

  16. Novel airway findings in a patient with 1p36 deletion syndrome.

    PubMed

    Ferril, Geoffrey R; Barham, Henry P; Prager, Jeremy D

    2014-01-01

    1p36 deletion syndrome comprises a phenotypic presentation that includes central nervous system, cardiac, and craniofacial anomalies. There has been no report of associated airway anomalies with this syndrome. We present here a case report and literature review. Prenatally, amniocentesis for chromosomal analysis was performed on our patient, with results consistent with 1p36 deletion syndrome. Respiratory distress and unsuccessful attempts at intubation prompted transfer to Children's Hospital of Colorado. Microlaryngoscopy was subsequently performed, revealing a persistent buccopharyngeal membrane and unidentifiable larynx. Emergent tracheostomy was then performed to secure the airway. Airway anomalies may be associated with 1p36 deletion syndrome.

  17. Identification of proximal 1p36 deletions using array-CGH: a possible new syndrome.

    PubMed

    Kang, S-H L; Scheffer, A; Ou, Z; Li, J; Scaglia, F; Belmont, J; Lalani, S R; Roeder, E; Enciso, V; Braddock, S; Buchholz, J; Vacha, S; Chinault, A C; Cheung, S W; Bacino, C A

    2007-10-01

    Monosomy 1p36 is the most common terminal deletion syndrome with an estimated occurrence of 1:5000 live births. Typically, the deletions span <10 Mb of 1pter-1p36.23 and result in mental retardation, developmental delay, sensorineural hearing loss, seizures, cardiomyopathy and cardiovascular malformations, and distinct facies including large anterior fontanel, deep-set eyes, straight eyebrows, flat nasal bridge, asymmetric ears, and pointed chin. We report five patients with 'atypical' proximal interstitial deletions from 1p36.23-1p36.11 using array-comparative genomic hybridization. Four patients carry large overlapping deletions of approximately 9.38-14.69 Mb in size, and one patient carries a small 2.97 Mb deletion. Interestingly, these patients manifest many clinical characteristics that are different from those seen in 'classical' monosomy 1p36 syndrome. The clinical presentation in our patients included: pre- and post-natal growth deficiency (mostly post-natal), feeding difficulties, seizures, developmental delay, cardiovascular malformations, microcephaly, limb anomalies, and dysmorphic features including frontal and parietal bossing, abnormally shaped and posteriorly rotated ears, hypertelorism, arched eyebrows, and prominent and broad nose. Most children also displayed hirsutism. Based on the analysis of the clinical and molecular data from our patients and those reported in the literature, we suggest that this chromosomal abnormality may constitute yet another deletion syndrome distinct from the classical distal 1p36 deletion syndrome.

  18. [Turner syndrome and monosomy 1p36 deletion syndrome misdiagnosed as thyropenia: report of one case].

    PubMed

    Meng, Xubiao; Li, Zhiming; Liu, Tingting; Wen, Zhiming

    2013-12-01

    A 21-year-old woman with a short stature presented with primary amenorrhoea and a 45X karyotype, and comparative genomic hybridization revealed 1p36 deletion and abnormal genes in multiple chromosomes to support the diagnosis of Turner syndrome and monosomy 1p36 deletion syndrome. The main clinical features of this condition include microsomia, poor sexual development, menoschesis, gigantorectum, absence of internal genitalia, sometimes with thyropenia and low intelligence. This disease can be easily diagnosed for its heterogeneous clinical manifestations.

  19. Mild developmental delay and obesity in two patients with mosaic 1p36 deletion syndrome.

    PubMed

    Shimada, Shino; Maegaki, Yoshihiro; Osawa, Makiko; Yamamoto, Toshiyuki

    2014-02-01

    We identified mosaic 1p36 deletions in two patients with developmental delay, distinctive features, and obesity, who can walk alone and communicate with others. Thus, their neurological defects are milder than those in typical patients with 1p36 deletion syndrome because most patients with 1p36 deletion cannot acquire expressive language. Chromosomal microarray testing revealed 3.0 and 4.5 Mb aberrations in the subtelomeric region of the short arm of chromosome 1. Mean signal ratios of the identified aberrations were -0.4 and -0.5, indicating mosaicism, which was confirmed by fluorescence in situ hybridization analysis with a mosaic ratio of 70% and 77%, respectively. Previous studies demonstrated that deletion of the distal 2-3 Mb region would be responsible for hyperphagia and obesity seen in patients. On the other hand, the severity of the neurological defect often correlates with the size of the terminal deletion of 1p36, and patients with larger deletions of 1p36 would usually show severely impaired developmental milestones and be immobile and aphasic. In such cases, hyperphagia and obesity could be clinically masked. In this study, two patients with mosaic deletions of 1p36 showed obesity as a consequence of hyperphagia. This study suggests that patients with 1p36 deletion would be at risk for hyperphagia and obesity when they have both risk factors, that is, (1) deletions including the 2-3 Mb critical region and (2) milder phenotypes that allow them to reach food on their own and to overeat.

  20. Polymicrogyria and infantile spasms in a patient with 1p36 deletion syndrome.

    PubMed

    Saito, Yoshiaki; Kubota, Masaya; Kurosawa, Kenji; Ichihashi, Izumi; Kaneko, Yuu; Hattori, Ayako; Komaki, Hirofumi; Nakagawa, Eiji; Sugai, Kenji; Sasaki, Masayuki

    2011-05-01

    A 3-months-old boy presented with partial seizures that soon evolved into infantile spasms. Magnetic resonance imaging revealed bilateral perisylvian polymicrogyria with right-sided predominance. ACTH therapy successfully controlled epilepsy and electroencephalograms were normalized. Conventional G-banded chromosomal analysis was performed due to his distinctive features and a derivative chromosome 1 derived from parental balanced translocation with a karyoptype of 46,XY,der(1)t(1;4)(p36.23;q35) was detected. Fluorescent in situ hybridization analysis confirmed the deleted region of 1p36 as large as 8.6Mb. This is the first delineation of concurrent complications of infantile spasms and polymicrogyria in patient with 1p36 deletion. 1p36 deletion syndrome should be broadly recognized as a differential diagnosis of regional polymicrogyria and/or infantile spasms.

  1. Delineating the phenotype of 1p36 deletion in adolescents and adults.

    PubMed

    Brazil, Ashley; Stanford, Kevin; Smolarek, Teresa; Hopkin, Robert

    2014-10-01

    1p36 deletion is the most common telomeric deletion syndrome, with an incidence of 1/5,000-1/10,000. A variety of clinical complications have been reported including seizures, hypotonia, heart malformations, cardiomyopathy, vision problems, and hearing loss. Approximately 90% are reported to have severe to profound intellectual disability and 75% to have absent expressive language. Little is known about long-term outcomes. The current literature suggests a poor prognosis for most patients. This study attempted to assess medical conditions and function of adolescent and adult patients with 1p36 deletion. A survey was distributed through three support groups to identify patients >12 years of age to assess functional status and medical problems in older patients with 1p36 deletion syndrome. 40 patients were identified between 12 and 46 years old. Among our survey sample, medical complications including seizures, hypotonia, structural heart defects, hearing loss, and vision problems, were similar to previous reports. However, functional skills were better than anticipated, with an overwhelming majority reported to independently sit, walk, and receive the majority of nutrition orally. Forty-four percent were reported to use complex speech abilities. While medical problems in patients with 1p36 deletion were similar to those that have been previously reported, we also demonstrated these same concerns persist into adolescence and adulthood. Additionally, patients were reported to have better functional skills than anticipated. Thus, quality of life and level of function appear to be better than anticipated from previous studies. © 2014 Wiley Periodicals, Inc.

  2. Identification of 1p36 deletion syndrome in patients with facial dysmorphism and developmental delay

    PubMed Central

    Seo, Go Hun; Kim, Ja Hye; Cho, Ja Hyang; Kim, Gu-Hwan; Seo, Eul-Ju; Lee, Beom Hee; Choi, Jin-Ho

    2016-01-01

    Purpose The 1p36 deletion syndrome is a microdeletion syndrome characterized by developmental delays/intellectual disability, craniofacial dysmorphism, and other congenital anomalies. To date, many cases of this syndrome have been reported worldwide. However, cases with this syndrome have not been reported in Korean populations anywhere. This study was performed to report the clinical and molecular characteristics of five Korean patients with the 1p36 deletion syndrome. Methods The clinical characteristics of the 5 patients were reviewed. Karyotyping and multiplex ligation-dependent probe amplification (MLPA) analyses were performed for genetic diagnoses. Results All 5 patients had typical dysmorphic features including frontal bossing, flat right parietal bone, low-set ears, straight eyebrows, down-slanting palpebral fissure, hypotelorism, flat nasal roots, midface hypoplasia, pointed chins, small lips, and variable degrees of developmental delay. Each patient had multiple and variable anomalies such as a congenital heart defect including ventricular septal defect, atrial septal defect, and patent duct arteriosus, ventriculomegaly, cryptorchism, or hearing loss. Karyotyping revealed the 1p36 deletion in only 1 patient, although it was confirmed in all 5 patients by MLPA analyses. Conclusion All the patients had the typical features of 1p36 deletion. These hallmarks can be used to identify other patients with this condition in their early years in order to provide more appropriate care. PMID:26893599

  3. Recurrent interstitial 1p36 deletions: Evidence for germline mosaicism and complex rearrangement breakpoints.

    PubMed

    Gajecka, Marzena; Saitta, Sulagna C; Gentles, Andrew J; Campbell, Lindsey; Ciprero, Karen; Geiger, Elizabeth; Catherwood, Anne; Rosenfeld, Jill A; Shaikh, Tamim; Shaffer, Lisa G

    2010-12-01

    Deletions of chromosome 1p36 are one of the most frequently encountered subtelomeric alterations. Clinical features of monosomy 1p36 include neurocognitive impairment, hearing loss, seizures, cardiac defects, and characteristic facial features. The majority of cases have occurred sporadically, implying that genomic instability plays a role in the prevalence of the syndrome. Here, we report two siblings with mild phenotypic features of the deletion syndrome, including developmental delay, hearing loss, and left ventricular non-compaction (LVNC). Microarray analysis using bacterial artificial chromosome and oligonucleotide microarrays indicated the deletions were identical, suggesting germline mosaicism. Parental phenotypes were normal, and analysis by fluorescence in situ hybridization (FISH) did not show mosaicism. These small interstitial deletions were not detectable by conventional subtelomeric FISH analysis. To investigate the mechanism of deletion further, the breakpoints were cloned and sequenced, demonstrating the presence of a complex rearrangement. Sequence analysis of genes in the deletion interval did not reveal any mutations on the intact homologue that may have contributed to the LVNC seen in both children. This is the first report of apparent germline mosaicism for this disorder. Thus, our findings have important implications for diagnostic approaches and for recurrence risk counseling in families with a child with monosomy 1p36. In addition, our results further refine the minimal critical region for LVNC and hearing loss.

  4. OEIS complex associated with chromosome 1p36 deletion: a case report and review.

    PubMed

    El-Hattab, Ayman W; Skorupski, Josh C; Hsieh, Michael H; Breman, Amy M; Patel, Ankita; Cheung, Sau Wai; Craigen, William J

    2010-02-01

    OEIS complex (Omphalocele, Exstrophy of the cloaca, Imperforate anus, and Spine abnormalities) is a rare defect with estimated incidence of 1 in 200,000 live births. Most cases are sporadic, with no obvious cause. However, it has been rarely reported in patients with family members having similar malformations or with chromosomal anomalies. In addition, OEIS complex has been observed in association with environmental exposures, twinning, and in vitro fertilization. Monosomy 1p36 is the most common terminal deletion syndrome, with a prevalence of 1 in 5,000 newborns. It is characterized by specific facial features, developmental delay, and heart, skeletal, genitourinary, and neurological defects. We describe an infant with OEIS complex and 1p36 deletion who had features of both disorders, including omphalocele, cloacal exstrophy, imperforate anus, sacral multiple segmentation, renal malposition and malrotation, genital anomalies, diastasis of the symphysis pubis, microbrachycephaly, large anterior fontanel, cardiac septal defects, rib fusion, a limb deformity, developmental delay, and typical facial features. Chromosomal microarray analysis detected a 2.4 Mb terminal deletion of chromosome 1p. This is the first reported case with OEIS complex in association with a chromosome 1p36 deletion.

  5. Is 1p36 deletion associated with anterior body wall defects?

    PubMed

    Çöllü, Medis; Yüksel, Şirin; Şirin, Başak Kumbasar; Abbasoğlu, Latif; Alanay, Yasemin

    2016-07-01

    Epispadias and exstrophy of the cloaca, also known as OEIS complex (omphalocele, exstrophy, imperforate anus, spinal defects), respectively constitute the most benign and severe ends of the bladder exstrophy-epispadias complex (BEEC) spectrum. In 2009, El-Hattab et al. reported the first patient with OEIS complex associated with a chromosome 1p36 deletion. Here we report a second patient with 1p36 deletion who also has classic bladder exstrophy, supporting the possible role of genes in this region in the development of BEEC. The absence of omphalocele and imperforate anus in our patient places him toward classic bladder exstrophy while presence of spina bifida and the absence of coccyx suggest an overlap with OEIS complex. An additional differential diagnosis is the pentalogy of Cantrell in our patient as he also has a diaphragmatic hernia and an incomplete sternum. This is the second observation of a ventral midline birth defect in association with 1p36 deletion syndrome, following El-Hattab et al.'s report [2009]. The three genes (NOCL2, DVL1, and MMP23B) discussed as possible candidates are also among the deleted ones in our patient, supporting the possible role of these genes in BEEC spectrum. © 2016 Wiley Periodicals, Inc.

  6. Mild craniosynostosis with 1p36.3 trisomy and 1p36.3 deletion syndrome caused by familial translocation t(Y;1).

    PubMed

    Hiraki, Yoko; Fujita, Hiroko; Yamamori, Shunji; Ohashi, Hirofumi; Eguchi, Maki; Harada, Naoki; Mizuguchi, Takeshi; Matsumoto, Naomichi

    2006-08-15

    We report on a 20-year-old man and a 16-year-old woman with a chromosomal imbalance derived from a balanced translocation, t(Y;1)(q12;p36.3) of the father. The man had a partial trisomy for 1p36.3-pter [46,X,der(Y)t(Y:1)(q12;p36.3)] and mild craniosynostosis of metopic and sagittal sutures as well as a borderline mental impairment, while the woman with a deletion for 1p36.3-pter [46,XX,der(1)t(Y;1)(q12;p36.3)] showed dysmorphic face with large anterior fontanel and severe developmental delay. Fluorescence in situ hybridization (FISH) showed that his trisomy spanned the 5.3-Mb region from 1p telomere harboring the critical region for craniosynostosis. To our knowledge, the man is the first case of a pure type of simple 1p36.3 trisomy as the effect of heterochromatic Yq12-qter deletion likely does not affect phenotype.

  7. Complex structural rearrangement features suggesting chromoanagenesis mechanism in a case of 1p36 deletion syndrome.

    PubMed

    Zanardo, Évelin Aline; Piazzon, Flavia Balbo; Dutra, Roberta Lelis; Dias, Alexandre Torchio; Montenegro, Marília Moreira; Novo-Filho, Gil Monteiro; Costa, Thaís Virgínia Moura Machado; Nascimento, Amom Mendes; Kim, Chong Ae; Kulikowski, Leslie Domenici

    2014-12-01

    Genome rearrangements are caused by the erroneous repair of DNA double-strand breaks, leading to several alterations that result in loss or gain of the structural genomic of a dosage-sensitive genes. However, the mechanisms that promote the complexity of rearrangements of congenital or developmental defects in human disease are unclear. The investigation of complex genomic abnormalities could help to elucidate the mechanisms and causes for the formation and facilitate the understanding of congenital or developmental defects in human disease. We here report one case of a patient with atypical clinical features of the 1p36 syndrome and the use of cytogenomic techniques to characterize the genomic alterations. Analysis by multiplex ligation-dependent probe amplification and array revealed a complex rearrangement in the 1p36.3 region with deletions and duplication interspaced by normal sequences. We also suggest that chromoanagenesis could be a possible mechanism involved in the repair and stabilization of this rearrangement.

  8. Dying at 23 with 1p36 deletion syndrome: Laura's family story.

    PubMed

    Tandy, P A

    2012-09-01

    Laura was unusual. She had always been different and at times difficult. She was born with a genetic disorder, diagnosed as 1p36 deletion syndrome when she was 21 years old. At 23 she suffered her first cardiac arrest at home and entered the hospital system for the first time apart from infancy. After initially appearing to do well, she suffered a second cardiac arrest 10 weeks after admission. This was followed by an irreversible deterioration and she died 14 weeks after admission. We her family had been with her throughout her traumatic experience. This is our story.

  9. Neurodevelopmental profile of a new dysmorphic syndrome associated with submicroscopic partial deletion of 1p36.3.

    PubMed

    Knight-Jones, E; Knight, S; Heussler, H; Regan, R; Flint, J; Martin, K

    2000-03-01

    We describe four children with dysmorphic syndrome with severe learning disability (SLD). Their chromosomes had been normal on conventional cytogenetic examination. However, screening using a multiprobe fluorescence in situ hybridisation (FISH) technique for subtelomeric abnormalities revealed a deletion of the p arm of chromosome 1. The physical features include body asymmetry, microcephaly, distinctive facies with deep-set eyes, sharply defined eye sockets, and mid-face hypoplasia; the neurodevelopmental profile was characterised by SLD, motor delay with hypotonia, markedly delayed visual maturation, and postural asymmetry together with epilepsy. This phenotype is consistent with that described for partial monosomy for 1p36.3.

  10. [Effect of carbamazepine on epilepsy with 1p36 deletion syndrome].

    PubMed

    Nabatame, Shin; Okinaga, Takeshi; Imai, Katsumi; Kamio, Noriko; Kagitani-Shimono, Kuriko; Nagai, Toshisaburo; Kurosawa, Kenji; Ozono, Keiichi

    2007-07-01

    The 1p36 deletion syndrome is caused by submicroscopic deletion in the subtelomeric region of chromosome 1. Epilepsy is one of the most important features of the syndrome, in addition to the characteristic facial appearance, cardiac anomaly, dysphagia, deafness, mental retardation and growth delay. We identified three patients with this syndrome and assessed the features of complicated epilepsy. In all cases, epilepsy developed during infancy. The seizure types were mainly focal seizure and multiple seizure types including tonic seizure and tonic-clonic seizure. Interictal electroencephalogram showed focal abnormalities. Noticeably, two developed epileptic spasms and hypsarrhythmia in electroencephalogram, just after the administration of carbamazepine (CBZ). Including cases showing epileptic spasms, their epilepsy was easily tractable with anti-epileptic drugs, which could be withdrawn as they aged. All had deleted potassium channel beta subunit (KCNAB2) and gamma-aminobutyric acid A receptor delta (GABRD). CBZ may aggravate various epileptic syndromes, especially, those caused by GABA-A receptor gene mutation. Our cases may suggest the novel correspondence of GABA-A receptor-related epilepsy syndrome and exacerbation of epilepsy triggered by CBZ.

  11. Molecular refinement of the 1p36 deletion syndrome reveals size diversity and a preponderance of maternally derived deletions.

    PubMed

    Wu, Y Q; Heilstedt, H A; Bedell, J A; May, K M; Starkey, D E; McPherson, J D; Shapira, S K; Shaffer, L G

    1999-02-01

    The deletion of chromosome 1p36 is a newly recognized, relatively common contiguous gene deletion syndrome with a variable phenotype. The clinical features have recently been delineated and molecular analysis indicates that the prevalence of certain phenotypic features appears to correlate with deletion size. Phenotype/genotype comparisons have allowed the assignment of certain clinical features to specific deletion intervals, significantly narrowing the regions within which to search for candidate genes. We have extensively characterized the deletion regions in 30 cases using microsatellite markers and fluorescence in situ hybridization analyses. The map order of 28 microsatellite markers spanning the deletion region was obtained by a combination of genotypic analysis and physical mapping. The deletion region was divided into six intervals and breakpoints were found to cluster in mainly two regions. Molecular analysis of the deletions showed that two patients had complex re-arrangements; these cases shared their distal and proximal breakpoints in the two common breakpoint regions. Of the de novo deletions ( n = 28) in whichparental samples were available and the analysis was informative ( n = 27), there were significantly morematernally derived deletions ( n = 21) than paternally derived deletions ( n = 6) (chi1(2) = 8.35, P < 0.0001). Phenotype/genotype correlations and refinements of critical regions in our naturally occurring deletion panel have delineated specific areas in which to focus the search for the causative genes for the features of this syndrome.

  12. Refinement of causative genes in monosomy 1p36 through clinical and molecular cytogenetic characterization of small interstitial deletions.

    PubMed

    Rosenfeld, Jill A; Crolla, John A; Tomkins, Susan; Bader, Patricia; Morrow, Bernice; Gorski, Jerome; Troxell, Robin; Forster-Gibson, Cynthia; Cilliers, Deirdre; Hislop, R Gordon; Lamb, Allen; Torchia, Beth; Ballif, Blake C; Shaffer, Lisa G

    2010-08-01

    Monosomy 1p36 is the most common terminal deletion syndrome seen in humans, occurring in approximately 1 in 5,000 live births. Common features include mental retardation, characteristic dysmorphic features, hypotonia, seizures, hearing loss, heart defects, cardiomyopathy, and behavior abnormalities. Similar phenotypes are seen among patients with a variety of deletion sizes, including terminal and interstitial deletions, complex rearrangements, and unbalanced translocations. Consequently, critical regions harboring causative genes for each of these features have been difficult to identify. Here we report on five individuals with 200-823 kb overlapping deletions of proximal 1p36.33, four of which are apparently de novo. They present with features of monosomy 1p36, including developmental delay and mental retardation, dysmorphic features, hypotonia, behavioral abnormalities including hyperphagia, and seizures. The smallest region of deletion overlap is 174 kb and contains five genes; these genes are likely candidates for some of the phenotypic features in monosomy 1p36. Other genes deleted in a subset of the patients likely play a contributory role in the phenotypes, including GABRD and seizures, PRKCZ and neurologic features, and SKI and dysmorphic and neurologic features. Characterization of small deletions is important for narrowing critical intervals and for the identification of causative or candidate genes for features of monosomy 1p36 syndrome.

  13. Relation between deletion of chromosome 1p36 and DNA ploidy in breast carcinoma: an interphase cytogenetic study

    PubMed Central

    Farabegoli, F; Baldini, N; Santini, D; Ceccarelli, C; Taffurelli, M; Treré, D; Derenzini, M

    1996-01-01

    Aims—To investigate whether deletion of the 1p36 region of chromosome 1 is independent of DNA ploidy in breast cancer cells. Methods—Preparations of nuclei from 64 fresh primary breast tumours were studied using dual target fluorescence in situ hybridisation (FISH) combining probes specific for the 1q12 (pUC 1.77) and 1p36 (1p-79) regions of chromosome 1. Signals were counted in 100-300 nuclei and the percentage of cells showing fewer p1-79 than pUC 1.77 signals was measured in each sample. DNA ploidy was investigated by cytofluorimetry in 55 tumour samples. Results—Chromosome 1 aberrations were detected in 56 samples. There were fewer p1-79 than pUC 1.77 signals in 53 samples. The 1p36 region was deleted in 11 samples in which a single p1-79 signal was detected; seven of these samples were diploid. Abnormalities were found in 17/24 diploid and 30/31 aneuploid tumours. Conclusions—Chromosome 1 aberrations, including deletion of the 1p36 region, were observed in diploid breast tumours. Deletion of the 1p36 region may be an early event in tumorigenesis. Given the frequency and importance of chromosome 1 aberrations in the biological behaviour of breast tumours, FISH, used in conjunction with cytofluorimetry, may be helpful for determining prognosis in patients with diploid tumours. Images PMID:16696058

  14. 1p36 deletion syndrome confirmed by fluorescence in situ hybridization and array-comparative genomic hybridization analysis

    PubMed Central

    Kang, Dong Soo; Shin, Eunsim

    2016-01-01

    Pediatric epilepsy can be caused by various conditions, including specific syndromes. 1p36 deletion syndrome is reported in 1 in 5,000–10,000 newborns, and its characteristic clinical features include developmental delay, mental retardation, hypotonia, congenital heart defects, seizure, and facial dysmorphism. However, detection of the terminal deletion in chromosome 1p by conventional G-banded karyotyping is difficult. Here we present a case of epilepsy with profound developmental delay and characteristic phenotypes. A 7-year- and 6-month-old boy experienced afebrile generalized seizure at the age of 5 years and 3 months. He had recurrent febrile seizures since 12 months of age and showed severe global developmental delay, remarkable hypotonia, short stature, and dysmorphic features such as microcephaly; small, low-set ears; dark, straight eyebrows; deep-set eyes; flat nasal bridge; midface hypoplasia; and a small, pointed chin. Previous diagnostic work-up, including conventional chromosomal analysis, revealed no definite causes. However, array-comparative genomic hybridization analysis revealed 1p36 deletion syndrome with a 9.15-Mb copy loss of the 1p36.33-1p36.22 region, and fluorescence in situ hybridization analysis (FISH) confirmed this diagnosis. This case highlights the need to consider detailed chromosomal study for patients with delayed development and epilepsy. Furthermore, 1p36 deletion syndrome should be considered for patients presenting seizure and moderate-to-severe developmental delay, particularly if the patient exhibits dysmorphic features, short stature, and hypotonia. PMID:28018437

  15. 1p36 deletion syndrome confirmed by fluorescence in situ hybridization and array-comparative genomic hybridization analysis.

    PubMed

    Kang, Dong Soo; Shin, Eunsim; Yu, Jeesuk

    2016-11-01

    Pediatric epilepsy can be caused by various conditions, including specific syndromes. 1p36 deletion syndrome is reported in 1 in 5,000-10,000 newborns, and its characteristic clinical features include developmental delay, mental retardation, hypotonia, congenital heart defects, seizure, and facial dysmorphism. However, detection of the terminal deletion in chromosome 1p by conventional G-banded karyotyping is difficult. Here we present a case of epilepsy with profound developmental delay and characteristic phenotypes. A 7-year- and 6-month-old boy experienced afebrile generalized seizure at the age of 5 years and 3 months. He had recurrent febrile seizures since 12 months of age and showed severe global developmental delay, remarkable hypotonia, short stature, and dysmorphic features such as microcephaly; small, low-set ears; dark, straight eyebrows; deep-set eyes; flat nasal bridge; midface hypoplasia; and a small, pointed chin. Previous diagnostic work-up, including conventional chromosomal analysis, revealed no definite causes. However, array-comparative genomic hybridization analysis revealed 1p36 deletion syndrome with a 9.15-Mb copy loss of the 1p36.33-1p36.22 region, and fluorescence in situ hybridization analysis (FISH) confirmed this diagnosis. This case highlights the need to consider detailed chromosomal study for patients with delayed development and epilepsy. Furthermore, 1p36 deletion syndrome should be considered for patients presenting seizure and moderate-to-severe developmental delay, particularly if the patient exhibits dysmorphic features, short stature, and hypotonia.

  16. Pathologic features of dilated cardiomyopathy with localized noncompaction in a child with deletion 1p36 syndrome.

    PubMed

    Pearce, F Bennett; Litovsky, Silvio H; Dabal, Robert J; Robin, Nathaniel; Dure, Leon J; George, James F; Kirklin, James K

    2012-01-01

    Dilated cardiomyopathy and ventricular noncompaction have been reported in association with deletion 1p36 syndrome. Previous descriptions include echocardiographic and/or gross pathologic descriptions. There are no previous reports of microscopic findings. We report a case with descriptions of echocardiographic, gross pathologic, and microscopic findings.

  17. Fine mapping of the 1p36 deletion syndrome identifies mutation of PRDM16 as a cause of cardiomyopathy.

    PubMed

    Arndt, Anne-Karin; Schafer, Sebastian; Drenckhahn, Jorg-Detlef; Sabeh, M Khaled; Plovie, Eva R; Caliebe, Almuth; Klopocki, Eva; Musso, Gabriel; Werdich, Andreas A; Kalwa, Hermann; Heinig, Matthias; Padera, Robert F; Wassilew, Katharina; Bluhm, Julia; Harnack, Christine; Martitz, Janine; Barton, Paul J; Greutmann, Matthias; Berger, Felix; Hubner, Norbert; Siebert, Reiner; Kramer, Hans-Heiner; Cook, Stuart A; MacRae, Calum A; Klaassen, Sabine

    2013-07-11

    Deletion 1p36 syndrome is recognized as the most common terminal deletion syndrome. Here, we describe the loss of a gene within the deletion that is responsible for the cardiomyopathy associated with monosomy 1p36, and we confirm its role in nonsyndromic left ventricular noncompaction cardiomyopathy (LVNC) and dilated cardiomyopathy (DCM). With our own data and publically available data from array comparative genomic hybridization (aCGH), we identified a minimal deletion for the cardiomyopathy associated with 1p36del syndrome that included only the terminal 14 exons of the transcription factor PRDM16 (PR domain containing 16), a gene that had previously been shown to direct brown fat determination and differentiation. Resequencing of PRDM16 in a cohort of 75 nonsyndromic individuals with LVNC detected three mutations, including one truncation mutant, one frameshift null mutation, and a single missense mutant. In addition, in a series of cardiac biopsies from 131 individuals with DCM, we found 5 individuals with 4 previously unreported nonsynonymous variants in the coding region of PRDM16. None of the PRDM16 mutations identified were observed in more than 6,400 controls. PRDM16 has not previously been associated with cardiac disease but is localized in the nuclei of cardiomyocytes throughout murine and human development and in the adult heart. Modeling of PRDM16 haploinsufficiency and a human truncation mutant in zebrafish resulted in both contractile dysfunction and partial uncoupling of cardiomyocytes and also revealed evidence of impaired cardiomyocyte proliferative capacity. In conclusion, mutation of PRDM16 causes the cardiomyopathy in 1p36 deletion syndrome as well as a proportion of nonsyndromic LVNC and DCM.

  18. Microarray analysis of 50 patients reveals the critical chromosomal regions responsible for 1p36 deletion syndrome-related complications.

    PubMed

    Shimada, Shino; Shimojima, Keiko; Okamoto, Nobuhiko; Sangu, Noriko; Hirasawa, Kyoko; Matsuo, Mari; Ikeuchi, Mayo; Shimakawa, Shuichi; Shimizu, Kenji; Mizuno, Seiji; Kubota, Masaya; Adachi, Masao; Saito, Yoshiaki; Tomiwa, Kiyotaka; Haginoya, Kazuhiro; Numabe, Hironao; Kako, Yuko; Hayashi, Ai; Sakamoto, Haruko; Hiraki, Yoko; Minami, Koichi; Takemoto, Kiyoshi; Watanabe, Kyoko; Miura, Kiyokuni; Chiyonobu, Tomohiro; Kumada, Tomohiro; Imai, Katsumi; Maegaki, Yoshihiro; Nagata, Satoru; Kosaki, Kenjiro; Izumi, Tatsuro; Nagai, Toshiro; Yamamoto, Toshiyuki

    2015-05-01

    Monosomy 1p36 syndrome is the most commonly observed subtelomeric deletion syndrome. Patients with this syndrome typically have common clinical features, such as intellectual disability, epilepsy, and characteristic craniofacial features. In cooperation with academic societies, we analyzed the genomic copy number aberrations using chromosomal microarray testing. Finally, the genotype-phenotype correlation among them was examined. We obtained clinical information of 86 patients who had been diagnosed with chromosomal deletions in the 1p36 region. Among them, blood samples were obtained from 50 patients (15 males and 35 females). The precise deletion regions were successfully genotyped. There were variable deletion patterns: pure terminal deletions in 38 patients (76%), including three cases of mosaicism; unbalanced translocations in seven (14%); and interstitial deletions in five (10%). Craniofacial/skeletal features, neurodevelopmental impairments, and cardiac anomalies were commonly observed in patients, with correlation to deletion sizes. The genotype-phenotype correlation analysis narrowed the region responsible for distinctive craniofacial features and intellectual disability into 1.8-2.1 and 1.8-2.2 Mb region, respectively. Patients with deletions larger than 6.2 Mb showed no ambulation, indicating that severe neurodevelopmental prognosis may be modified by haploinsufficiencies of KCNAB2 and CHD5, located at 6.2 Mb away from the telomere. Although the genotype-phenotype correlation for the cardiac abnormalities is unclear, PRDM16, PRKCZ, and RERE may be related to this complication. Our study also revealed that female patients who acquired ambulatory ability were likely to be at risk for obesity. Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  19. 576 kb deletion in 1p36.33-p36.32 containing SKI is associated with limb malformation, congenital heart disease and epilepsy.

    PubMed

    Zhu, Xin; Zhang, Yi; Wang, Jian; Yang, Jin-Fu; Yang, Yi-Feng; Tan, Zhi-Ping

    2013-10-10

    1p36 deletion (monosomy 1p36) is one of the most common terminal deletions observed in humans, characterized by special facial features, mental retardation, heart defects, development delay and epilepsy. Previously, we reported molecular findings in patients with limb, congenital heart disease (CHD) and other malformations with SNP-array. In a syndromic patient of the same cohort, we detected a small deletion of 1p36.33-p36.32 containing SKI (Sloan-Kettering Institute protooncoprotein). Recently, dominant mutations in SKI were identified to be correlated with Shprintzen-Goldberg syndrome. Retrospective examination revealed this patient with limb malformations, CHD, epilepsy and mild development delay. Together with previous reports, our study suggests that the 1p36.33-1p36.32 deletion encompassing SKI may represents a previous undescribed microdeletion disorder.

  20. [A case of partial 1p36.1 deletion and partial trisomy 6p diagnosed by karyotype].

    PubMed

    Fernández Pineda, Monica; Ramírez-Cheyne, Julián; Isaza, Carolina; Saldarriaga, Wilmar

    The deletion of chromosomal region 1p36 is one of the most common sub-telomeric microdeletion syndromes and has distinctive dysmorphic features. On the other hand, partial trisomy of the short arm of chromosome 6 is a rare chromosomal abnormality with a variable phenotype. To report a case with both chromosome abnormalities, and to highlight the importance of the karyotype as a diagnostic tool in dysmorphology. The case of is presented of a two month-old infant with several craniofacial anomalies, neck haemangioma, sacral pit, rhizomelic shortening, small hands and feet, left unilateral cryptorchidism, and hypotonia. The infant also suffered intrauterine growth restriction and is the product of the eighth pregnancy of a 28 years old woman. Due to the unspecific findings in phenotype, a karyotype was requested, which showed a partial deletion of 1p36.1 and a partial trisomy of chromosome 6. The development of new techniques in molecular biology has improved diagnostic possibilities in medical genetics. However, the traditional karyotype remains as an important diagnostic tool in patients with multiple congenital anomalies. Copyright © 2016 Sociedad Chilena de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

  1. Left-ventricular non-compaction (LVNC): a clinical feature more often observed in terminal deletion 1p36 than previously expected.

    PubMed

    Cremer, Kirsten; Lüdecke, Hermann-Josef; Ruhr, Frauke; Wieczorek, Dagmar

    2008-01-01

    Deletion of 1p36 (OMIM 607872) is estimated to be the most common distal terminal deletion syndrome. We describe a previously unreported, typically affected two-month-old girl with this microdeletion syndrome, who additionally suffers from left-ventricular non-compaction (LVNC). Recently, this congenital heart defect, characterized by prominent left-ventricular trabeculae and deep intertrabecular recesses, was reported in 12 further patients (excluding those reported only in abstract form) with terminal deletion of 1p36, leading to the conclusion that this cardiomyopathy is common in patients with this chromosomal aberration. We hypothesize that a gene in 1p36 might be responsible for LVNC.

  2. Telomeric 1p36.3 deletion and Ki-67 expression in B-Non-Hodgkin's Lymphoma patients associated with chronic hepatitis C virus infection.

    PubMed

    Mosad, E; Said Abd El-Rahman Allam, M; Moustafa, H M; Mohammed, A Eliaw; El kebeer, A M; Abdel-Moneim, S S

    2014-12-01

    The hepatitis C virus (HCV) core protein is able to accumulate genetic p53 mutations and may be considered co-oncogenic. This study investigates 1p36.3 telomere deletion in B-non-Hodgkin's lymphoma (NHL) patients with chronic HCV infection using fluorescence in situ hybridization (FISH) in relation to survival to assess Ki-67 antigen expression. A study group and a control group of 100 patients with B-NHL (50 HCV positive and 50 HCV negative) and 60 control bone marrow biopsies were subjected to FISH for the detection of 1P36.3 deletion and to immunohistochemical staining with Ki-67 antigens. 1p36.3 deletion by FISH was detected in 40% of the study group, and Ki-67 was expressed in approximately 74% of patients. A significant difference was found between positive and negative HCV patients in their overall survival, the qualitative expression of Ki-67 and the quantitative detection of 1p36.3 deletion by FISH. The overall survival was shorter with the presence of an 1p36 deletion by FISH and HCV positive. We concluded that the coexistence of Ki-67 positivity, HCV positivity and 1p36.3 deletion may contribute to infection-related cancers at the 1p36.3 locus.

  3. Type II diabetes and impaired glucose tolerance due to severe hyperinsulinism in patients with 1p36 deletion syndrome and a Prader-Willi-like phenotype

    PubMed Central

    2014-01-01

    Background Deletion of the subtelomeric region of 1p36 is one of the most common subtelomeric deletion syndromes. In monosomy 1p36, the presence of obesity is poorly defined, and glucose metabolism deficiency is rarely reported. However, the presence of a typical Prader-Willi-like phenotype in patients with monosomy 1p36 is controversial. Case presentation In this report, we describe two female patients, one who is 6 years 2 months of age and another who is 10 years 1 month of age, both referred to our hospital for obesity and a Prader-Willi-like phenotype. These patients presented with severe obesity (body mass index [BMI] was 26.4 and 27.7, respectively), hyperphagia and developmental delay. Analysis of basal hormone levels showed normal thyroid function and adrenal function but considerable basal hyperinsulinism (the insulin levels were 54.5 and 49.2 μU/ml, respectively). In patient 1, glycaemia was 75 mg/dl (HOMA-R 10.09), and the HbA1c level was 6.1%; in patient 2, glycaemia was 122 mg/dl, and the HbA1c level was 6.6% (HOMA-R 14.82). An oral glucose tolerance test demonstrated impaired glucose tolerance and diabetes mellitus with marked insulin resistance (the peak insulin level for each patient was 197 and 279 μU/mL, respectively, while the 120’ insulin level of each patient was 167 and 234 μU/mL, respectively). Conclusion some patients with monosomy 1p36 may show Prader-Willi-like physical and physiologic characteristics such as obesity and hyperinsulinism with impaired glucose metabolism, which can cause type II diabetes mellitus. Further studies are necessary to evaluate these findings. PMID:24479866

  4. Bilateral perisylvian polymicrogyria, periventricular nodular heterotopia, and left ventricular noncompaction in a girl with 10.5-11.1 Mb terminal deletion of 1p36.

    PubMed

    Saito, Shoji; Kawamura, Rie; Kosho, Tomoki; Shimizu, Takashi; Aoyama, Koki; Koike, Kenichi; Wada, Takahito; Matsumoto, Naomichi; Kato, Mitsuhiro; Wakui, Keiko; Fukushima, Yoshimitsu

    2008-11-15

    Monosomy 1p36 is a common subtelomeric microdeletion syndrome, characterized by craniofacial dysmorphisms, developmental delay, mental retardation, hypotonia, epilepsy, cardiovascular complications, and hearing impairment; deleted regions have been mapped within 10.0 Mb from the telomere in most documented cases. We report on a girl with a 10.5-11.1 Mb terminal deletion of 1p36 shown by fluorescence in situ hybridization (FISH). She had three distinct structural abnormalities: bilateral perisylvian polymicrogyria, periventricular nodular heterotopia, and left ventricular noncompaction. She died in early infancy with intractable epilepsy, progressive congestive heart failure and pulmonary hypertension. To date, this is the first case with monosomy 1p36, complicated by this combination of manifestations; she is also the first who had possibly a simple terminal deletion of 1p36 and died in early infancy. An atypically large deletion in this patient might be the basis for the development of these features and the severe clinical course.

  5. Deletion of the mouse homolog of KCNAB2, a gene linked to monosomy 1p36, results in associative memory impairments and amygdala hyperexcitability.

    PubMed

    Perkowski, John J; Murphy, Geoffrey G

    2011-01-05

    Ablation of the distal end of the short arm of chromosome 1 [1p36 deletion syndrome (1p36DS)] is one of the most commonly occurring terminal deletion syndromes in humans, occurring in ∼1 in 5000 newborns. Subjects with 1p36DS manifest a wide range of clinical features including growth delay, congenital heart defects, and craniofacial dysmorphism. In addition, individuals with 1p36DS often exhibit some form of neurological abnormality and are typically cognitively impaired. Although there is significant variability with regard to the extent of the deletion, several genes have been mapped to region 1p36 that are known to regulate neuronal function. One such gene--KCNAB2--encodes the potassium channel auxiliary subunit Kvβ2, which has been previously shown to modulate voltage-gated potassium currents in heterologous expression systems. Here, we present experiments characterizing mice in which the ortholog of KCNAB2 was deleted. We find that deletion of Kcnab2 in mice leads to deficits in associative learning and memory. In addition, using whole-cell current-clamp, we find that deletion of Kcnab2 leads to a reduction in the slow afterhyperpolarization following a burst of action potentials and a concomitant increase in neuronal excitability in projection neurons in the lateral nucleus of the amygdala. Our results suggest that loss of Kvβ2 likely contributes to the cognitive and neurological impairments observed in 1p36DS patients.

  6. Monosomy 1p36 breakpoint junctions suggest pre-meiotic breakage-fusion-bridge cycles are involved in generating terminal deletions.

    PubMed

    Ballif, Blake C; Yu, Wei; Shaw, Chad A; Kashork, Catherine D; Shaffer, Lisa G

    2003-09-01

    Terminal deletions of 1p36 result in a mental retardation syndrome that is presumably caused by haploinsufficiency of a number of genes. Although monosomy 1p36 is the most commonly observed terminal deletion syndrome in humans, the molecular mechanism(s) that generates and stabilizes terminal deletions of 1p36 is not completely understood. Our previous molecular analysis of a large cohort of monosomy 1p36 subjects demonstrated that deletion sizes vary widely from approximately 1 Mb to >10.5 Mb in the most distal portion of 1p36 with no single common breakpoint. In this report, we have identified the precise breakpoint junctions in three subjects with apparently pure terminal deletions of 1p36 ranging from 2.5 to 4.25 Mb. These junctions revealed one deletion to be stabilized by telomeric repeat sequences and two to have terminal deletions associated with cryptic interrupted inverted duplications at the ends of the chromosomes. These interrupted inverted duplication/deletion breakpoints are reminiscent of those seen in tumor cell lines that have undergone breakage-fusion-bridge (BFB) cycles leading to gene amplification. We propose a pre-meiotic model for the formation of these deletions in which a terminally deleted chromosome is generated in the germ line and passes through at least one BFB cycle to produce gametes with terminal deletions associated with interrupted inverted duplications. These data suggest that, on a molecular level, seemingly pure terminal deletions visualized cytogenetically may be more complex, and BFB cycles may play an important role in generating terminal deletions associated with genetic disease in humans.

  7. 1p36 is a preferential target of chromosome 1 deletions in astrocytic tumours and homozygously deleted in a subset of glioblastomas

    PubMed Central

    Ichimura, K; Vogazianou, AP.; Liu, L; Pearson, DM.; Bäcklund, LM; Plant, K; Baird, K; Langford, CF.; Gregory, SG.; Collins, VP

    2009-01-01

    Astrocytic, oligodendroglial and mixed gliomas are the commonest gliomas in adults. They have distinct phenotypes and clinical courses, but as they exist as a continuous histological spectrum differentiating them can be difficult. Co-deletions of total 1p and 19q are found in the majority of oligodendrogliomas and considered as a diagnostic marker and a prognostic indicator. The 1p status of astrocytomas has not yet been thoroughly examined. Using a chromosome 1 tile path array, we investigated 108 adult astrocytic tumours for copy number alterations. Total 1p deletions were rare (2%), however partial deletions involving 1p36 were frequently identified in anaplastic astrocytomas (22%) and glioblastomas (34%). Multivariate analysis showed that patients with total 1p deletions had significantly longer survival (p=0.005). In 9 glioblastomas homozygous deletions at 1p36 were identified. No somatic mutations were found among the 5 genes located in the homozygously deleted region. However, the CpG island of TNFRSF9 was hypermethylated in 19% of astrocytic tumours and 87% of glioma cell lines. TNFRSF9 expression was upregulated after demethylation of glioma cell lines. Akt3 amplifications were found in four glioblastomas. Our results indicate that 1p deletions are common anaplastic astrocytomas and glioblastomas but are distinct from the 1p abnormalities in oligodendrogliomas. PMID:17934521

  8. Monosomy 1p36 breakpoints indicate repetitive DNA sequence elements may be involved in generating and/or stabilizing some terminal deletions.

    PubMed

    Ballif, Blake C; Gajecka, Marzena; Shaffer, Lisa G

    2004-01-01

    Monosomy 1p36 is the most commonly observed terminal deletion syndrome in humans. Our previous molecular studies on a large cohort of subjects suggest that monosomy 1p36 can result from a variety of chromosomal rearrangements including terminal truncations, interstitial deletions, derivative chromosomes, inverted duplications, and complex rearrangements. However, the mechanism(s) by which rearrangements of 1p36 are generated and/or stabilized is not understood. Sequence analysis of breakpoint junctions may provide valuable clues to the underlying mechanisms of many chromosomal aberrations. In this report, we analyze the breakpoints at the DNA-sequence level in four subjects with variable-sized deletions of 1p36. All four breakpoints fall within repetitive DNA-sequence elements (LINEs, SINEs, etc). This suggests that repetitive DNA-sequence elements may play an important role in generating and/or stabilizing terminal deletions of 1p36. Mechanisms by which repetitive elements may be involved in the process of terminal deletion formation and stabilization are discussed.

  9. De Novo Mutations of RERE Cause a Genetic Syndrome with Features that Overlap Those Associated with Proximal 1p36 Deletions

    PubMed Central

    Fregeau, Brieana; Kim, Bum Jun; Hernández-García, Andrés; Jordan, Valerie K.; Cho, Megan T.; Schnur, Rhonda E.; Monaghan, Kristin G.; Juusola, Jane; Rosenfeld, Jill A.; Bhoj, Elizabeth; Zackai, Elaine H.; Sacharow, Stephanie; Barañano, Kristin; Bosch, Daniëlle G.M.; de Vries, Bert B.A.; Lindstrom, Kristin; Schroeder, Audrey; James, Philip; Kulch, Peggy; Lalani, Seema R.; van Haelst, Mieke M.; van Gassen, Koen L.I.; van Binsbergen, Ellen; Barkovich, A. James; Scott, Daryl A.; Sherr, Elliott H.

    2016-01-01

    Deletions of chromosome 1p36 affect approximately 1 in 5,000 newborns and are associated with developmental delay, intellectual disability, and defects involving the brain, eye, ear, heart, and kidney. Arginine-glutamic acid dipeptide repeats (RERE) is located in the proximal 1p36 critical region. RERE is a widely-expressed nuclear receptor coregulator that positively regulates retinoic acid signaling. Animal models suggest that RERE deficiency might contribute to many of the structural and developmental birth defects and medical problems seen in individuals with 1p36 deletion syndrome, although human evidence supporting this role has been lacking. In this report, we describe ten individuals with intellectual disability, developmental delay, and/or autism spectrum disorder who carry rare and putatively damaging changes in RERE. In all cases in which both parental DNA samples were available, these changes were found to be de novo. Associated features that were recurrently seen in these individuals included hypotonia, seizures, behavioral problems, structural CNS anomalies, ophthalmologic anomalies, congenital heart defects, and genitourinary abnormalities. The spectrum of defects documented in these individuals is similar to that of a cohort of 31 individuals with isolated 1p36 deletions that include RERE and are recapitulated in RERE-deficient zebrafish and mice. Taken together, our findings suggest that mutations in RERE cause a genetic syndrome and that haploinsufficiency of RERE might be sufficient to cause many of the phenotypes associated with proximal 1p36 deletions. PMID:27087320

  10. De Novo Mutations of RERE Cause a Genetic Syndrome with Features that Overlap Those Associated with Proximal 1p36 Deletions.

    PubMed

    Fregeau, Brieana; Kim, Bum Jun; Hernández-García, Andrés; Jordan, Valerie K; Cho, Megan T; Schnur, Rhonda E; Monaghan, Kristin G; Juusola, Jane; Rosenfeld, Jill A; Bhoj, Elizabeth; Zackai, Elaine H; Sacharow, Stephanie; Barañano, Kristin; Bosch, Daniëlle G M; de Vries, Bert B A; Lindstrom, Kristin; Schroeder, Audrey; James, Philip; Kulch, Peggy; Lalani, Seema R; van Haelst, Mieke M; van Gassen, Koen L I; van Binsbergen, Ellen; Barkovich, A James; Scott, Daryl A; Sherr, Elliott H

    2016-05-05

    Deletions of chromosome 1p36 affect approximately 1 in 5,000 newborns and are associated with developmental delay, intellectual disability, and defects involving the brain, eye, ear, heart, and kidney. Arginine-glutamic acid dipeptide repeats (RERE) is located in the proximal 1p36 critical region. RERE is a widely-expressed nuclear receptor coregulator that positively regulates retinoic acid signaling. Animal models suggest that RERE deficiency might contribute to many of the structural and developmental birth defects and medical problems seen in individuals with 1p36 deletion syndrome, although human evidence supporting this role has been lacking. In this report, we describe ten individuals with intellectual disability, developmental delay, and/or autism spectrum disorder who carry rare and putatively damaging changes in RERE. In all cases in which both parental DNA samples were available, these changes were found to be de novo. Associated features that were recurrently seen in these individuals included hypotonia, seizures, behavioral problems, structural CNS anomalies, ophthalmologic anomalies, congenital heart defects, and genitourinary abnormalities. The spectrum of defects documented in these individuals is similar to that of a cohort of 31 individuals with isolated 1p36 deletions that include RERE and are recapitulated in RERE-deficient zebrafish and mice. Taken together, our findings suggest that mutations in RERE cause a genetic syndrome and that haploinsufficiency of RERE might be sufficient to cause many of the phenotypes associated with proximal 1p36 deletions.

  11. Cytogenetic and array CGH characterization of de novo 1p36 duplications and deletion in a patient with congenital cataracts, hearing loss, choanal atresia, and mental retardation.

    PubMed

    Chen, Emily; Obolensky, Elise; Rauen, Katherine A; Shaffer, Lisa G; Li, Xu

    2008-11-01

    We describe a 14-year-old boy with congenital bilateral cataracts, blepharophimosis, ptosis, choanal atresia, sensorineural hearing loss, short, webbed neck, poor esophageal motility, severe growth and mental retardation, skeletal anomalies, seizures, and no speech. As an infant, he had transient hypogammaglobulinemia requiring IVIG therapy. Cytogenetic studies show an apparently de novo visible duplication at 1p36.3. Fluorescence in situ hybridization (FISH) studies confirm that the common region for the 1p36 deletion syndrome (p58) is duplicated. Probes for D1Z2 at 1p36.3 and the subtelomeric region of 1p (TEL1p) are also duplicated. Array comparative genomic hybridization (aCGH) studies were done at three separate laboratories, each with somewhat different results. BAC whole genome array CGH suggests a single clone gain at the 1p terminus and a single clone deletion at 1p36.3. A targeted BAC array panel with higher resolution at the distal 1p36 region detects a telomeric duplication and an interstitial deletion. Oligonucleotide whole genomic aCGH shows the highest resolution and a more complex rearrangement: two duplications, an interstitial deletion, and a normal region. The MMP23A/B "matrix metalloproteinase 23A/B" genes are within the distal duplication region in our patient, and this patient does not have craniosynostosis. This is the first association of congenital cataracts, choanal atresia, and transient immune abnormalities with 1p36 duplication/deletion. This case illustrates the limitations of different cytogenetic technologies, and shows how three separate aCGH platforms allow for refined delineation and interpretation of the complex cytogenetic rearrangement which would not have been discovered by standard high-resolution chromosome analysis.

  12. Loss of the SKI proto-oncogene in individuals affected with 1p36 deletion syndrome is predicted by strain-dependent defects in Ski-/- mice.

    PubMed

    Colmenares, Clemencia; Heilstedt, Heidi A; Shaffer, Lisa G; Schwartz, Stuart; Berk, Michael; Murray, Jeffrey C; Stavnezer, Ed

    2002-01-01

    Experiments involving overexpression of Ski have suggested that this gene is involved in neural tube development and muscle differentiation. In agreement with these findings, Ski-/- mice display a cranial neural tube defect that results in exencephaly and a marked reduction in skeletal muscle mass. Here we show that the penetrance and expressivity of the phenotype changes when the null mutation is backcrossed into the C57BL6/J background, with the principal change involving a switch from a neural tube defect to midline facial clefting. Other defects, including depressed nasal bridge, eye abnormalities, skeletal muscle defects and digit abnormalities, show increased penetrance in the C57BL6/J background. These phenotypes are interesting because they resemble some of the features observed in individuals diagnosed with 1p36 deletion syndrome, a disorder caused by monosomy of the short arm of human chromosome 1p (refs. 6-9). These similarities prompted us to re-examine the chromosomal location of human SKI and to determine whether SKI is included in the deletions of 1p36. We found that human SKI is located at distal 1p36.3 and is deleted in all of the individuals tested so far who have this syndrome. Thus, SKI may contribute to some of the phenotypes common in 1p36 deletion syndrome, and particularly to facial clefting.

  13. Clinical presentation of two β-thalassemic Indian patients with 1p36 deletion syndrome: Case report.

    PubMed

    De, Puspal; Chatterjee, Tridip; Chakravarty, Sudipa; Chakravarty, Amit

    2014-09-01

    Here, we present two thalassemic patients (one male and one female), having unusual clinical phenotypes. Both had mental retardation in which one was associated with microcephaly and other had congenital cataract. They were referred to our institute for clinical evaluation and cytogenetic testing. Both patients were tested for presence of abnormal hemoglobin by high performance liquid chromatography and found to be thalassemic. Their β-globin mutation was also determined by amplification refractory mutation system-polymerase chain reaction. The male patient was found to have intervening sequence 1-5 (G-C)/+, indicating β-thalassemia trait and the female was found to have Cod 26 (G-A)/IVS 1-5 (G-C), indicating hemoglobin E-β thalassemia. Their cytogenetic analysis of blood lymphocytes were studied with high-resolution GTG-banding analysis by using chromosome profiling (Cyto-vision software 3.6) on their chromosomes. Results revealed 46,XY,del(1)(p36.21) in the male and 46,XX,del(1)(p36.3) in the female. Their genotype variation showed (based on genome browser) significant gene loss which probably leads to marked phenotype variation. We believe, thalassemia with mental retardation associated with microcephaly and congenital cataract, both having loss in chromosome 1, p36 position, is reported probably first time from India. This report will definitely enlighten all concerns and add to the information in growing literature.

  14. Interstitial deletion 1p36.32 in two brothers with a distinct phenotype--overgrowth, macrocephaly and nearly normal intellectual function.

    PubMed

    Di Donato, N; Klink, B; Hahn, G; Schrock, E; Hackmann, K

    2014-09-01

    We report on two adult patients, who both presented with overgrowth and one of them additionally with macrocephaly while carrying an 1p36 microdeletion of about 2.1 Mb. They are full brothers born to unaffected parents. Although both brothers attended special schools, they lived independently without a legal guardian and were able to succeed in regular jobs. One of the brothers received a professional education. Genetic analysis of the parents revealed neither the microdeletion nor a cryptical translocation or inversion. We suggest that the recurrent deletion is a result of germline mosaicism, a phenomenon reported only once in the context of the 1p36 microdeletion syndrome. Our report confirms the recurrence of the apparently de novo 1p36 microdeletion due to a likely germline mosaicism of one of the parents. Furthermore, it illustrates the possibility of the distinct phenotype with a nearly normal intellectual outcome of the 1p36 microdeletion syndrome that might be due to the region involved in our patients.

  15. Frequent hemizygous deletion at 1p36 and hypermethylation downregulate RUNX3 expression in human lung cancer cell lines.

    PubMed

    Yanada, Masashi; Yaoi, Takeshi; Shimada, Junichi; Sakakura, Chouhei; Nishimura, Motohiro; Ito, Kazuhiro; Terauchi, Kunihiko; Nishiyama, Katsuhiko; Itoh, Kyoko; Fushiki, Shinji

    2005-10-01

    Runt-related transcription factor 3 (RUNX3) has been recognized as a tumor suppressor gene in gastric cancer because its expression level was reduced or disappeared due to epigenetic changes. To evaluate the usefulness of the RUNX3 gene as a biomarker of lung cancer, we have analyzed the expression of the RUNX3 gene in 15 lung cancer cell lines by real-time reverse transcription-polymerase chain reaction (RT-PCR), and demonstrated that RUNX3 gene expression was reduced or disappeared in all cell lines examined (100%). In addition, we have attempted to classify all the cell lines into three groups according to the expression level; less than 10% (group I), 10-30% (group II) and approximately 50% (group III). We further investigated methylation status of the CpG sites in the exon 1 region of RUNX3 by methylation specific PCR (MSP), and studied the correlation between the expression level and hemizygous deletion as revealed by bicolor fluorescence in situ hybridization (FISH). The CpG sites were hypermethylated in 8 cell lines (53%) and the RUNX3 loci were hemizygously deleted in another 8 cell lines (53%). Furthermore group I, II, and III corresponded well to methylation-positive cell lines, cell lines showing hemizygous deletion, and the rest of cell lines without methylation or hemizygous deletion, respectively. These results suggest that a comprehensive study on RUNX3 using real-time RT-PCR, MSP, and FISH could be beneficial in understanding the pathogenetic mechanisms of human lung cancer at the molecular level.

  16. An allelic series of mice reveals a role for RERE in the development of multiple organs affected in chromosome 1p36 deletions.

    PubMed

    Kim, Bum Jun; Zaveri, Hitisha P; Shchelochkov, Oleg A; Yu, Zhiyin; Hernández-García, Andrés; Seymour, Michelle L; Oghalai, John S; Pereira, Fred A; Stockton, David W; Justice, Monica J; Lee, Brendan; Scott, Daryl A

    2013-01-01

    Individuals with terminal and interstitial deletions of chromosome 1p36 have a spectrum of defects that includes eye anomalies, postnatal growth deficiency, structural brain anomalies, seizures, cognitive impairment, delayed motor development, behavior problems, hearing loss, cardiovascular malformations, cardiomyopathy, and renal anomalies. The proximal 1p36 genes that contribute to these defects have not been clearly delineated. The arginine-glutamic acid dipeptide (RE) repeats gene (RERE) is located in this region and encodes a nuclear receptor coregulator that plays a critical role in embryonic development as a positive regulator of retinoic acid signaling. Rere-null mice die of cardiac failure between E9.5 and E11.5. This limits their usefulness in studying the role of RERE in the latter stages of development and into adulthood. To overcome this limitation, we created an allelic series of RERE-deficient mice using an Rere-null allele, om, and a novel hypomorphic Rere allele, eyes3 (c.578T>C, p.Val193Ala), which we identified in an N-ethyl-N-nitrosourea (ENU)-based screen for autosomal recessive phenotypes. Analyses of these mice revealed microphthalmia, postnatal growth deficiency, brain hypoplasia, decreased numbers of neuronal nuclear antigen (NeuN)-positive hippocampal neurons, hearing loss, cardiovascular malformations-aortic arch anomalies, double outlet right ventricle, and transposition of the great arteries, and perimembranous ventricular septal defects-spontaneous development of cardiac fibrosis and renal agenesis. These findings suggest that RERE plays a critical role in the development and function of multiple organs including the eye, brain, inner ear, heart and kidney. It follows that haploinsufficiency of RERE may contribute-alone or in conjunction with other genetic, environmental, or stochastic factors-to the development of many of the phenotypes seen in individuals with terminal and interstitial deletions that include the proximal region of

  17. Prader-Willi-like phenotype: investigation of 1p36 deletion in 41 patients with delayed psychomotor development, hypotonia, obesity and/or hyperphagia, learning disabilities and behavioral problems.

    PubMed

    D'Angelo, Carla S; Da Paz, José A; Kim, Chong A; Bertola, Débora R; Castro, Claudia I E; Varela, Monica C; Koiffmann, Célia P

    2006-01-01

    Monosomy 1p36 is one of the most commonly observed mental retardation (MR) syndromes that results in a clinically recognizable phenotype including delayed psychomotor development and/or MR, hypotonia, epilepsy, hearing loss, growth delay, microcephaly, deep-set eyes, flat nasal bridge and pointed chin. Besides, a Prader-Willi syndrome (PWS)-like phenotype has been described in patients with 1p36 monosomy. Forty-one patients presenting hypotonia, developmental delay, obesity and/or hyperphagia and behavioral problems who tested negative for PWS were investigated by FISH and/or microsatellite markers. Twenty-six were analyzed with a 1p-specific subtelomeric probe, and one terminal deletion was identified. Thirty patients (15 of which also studied by FISH) were investigated by microsatellite markers, and no interstitial 1p36 deletion was found. Our patient presenting the 1p36 deletion did not have the striking features of this monosomy, but her clinical and behavioral features were quite similar to those observed in patients with PWS, except for the presence of normal sucking at birth. The extent of the deletion could be limited to the most terminal 2.5 Mb of 1p36, within the chromosomal region 1p36.33-1p36.32, that is smaller than usually seen in monosomy 1p36 patients. Therefore, chromosome 1p36.33 deletion should be investigated in patients with hypotonia, developmental delay, obesity and/or hyperphagia and behavioral problems who test negative for PWS.

  18. Refined FISH characterization of a de novo 1p22-p36.2 paracentric inversion and associated 1p21-22 deletion in a patient with signs of 1p36 microdeletion syndrome.

    PubMed

    Finelli, P; Giardino, D; Russo, S; Gottardi, G; Cogliati, F; Grugni, G; Natacci, F; Larizza, L

    2001-04-01

    We report on a 10-year-old boy presenting with obesity, moderate mental retardation, large anterior fontanelle at birth, mild physical anomalies including mid-face hypoplasia, deep-set eyes, long philtrum, and small mouth. He was found to carry a paracentric inversion inv(1)(p22p36.2) associated with a 10 cM deletion at the proximal breakpoint. By YAC FISH, the boundaries of the deletion were established at IB1028 (1p21) and WI-5166 (1p22) STSs contained in YACs 781E8 and 954F6, respectively. This large region, covering about 10 cM, contains the COL11A1 and AMY2B genes, whose haploinsufficiency does not seem to contribute significantly to the clinical phenotype. On the other hand, the patient's clinical manifestations, also including visual problems and moderate mental retardation, are those typically observed in the 1p36 deletion syndrome. Refined mapping of the telomeric 1p36.2 inversion breakpoint was obtained by FISH of a PAC contig constructed to encompass this subinterval of the 1p36 microdeletion syndrome region. PACs 1024B10 and 884E7 were found to span the breakpoint, suggesting that the clinical signs of the 1p36 microdeletion syndrome might be due to disruption of a sequence lying at 1p36.2.

  19. Proximal interstitial 1p36 deletion syndrome: the most proximal 3.5-Mb microdeletion identified on a dysmorphic and mentally retarded patient with inv(3)(p14.1q26.2).

    PubMed

    Shimojima, Keiko; Páez, Marco T; Kurosawa, Kenji; Yamamoto, Toshiyuki

    2009-09-01

    From the investigation by microarray-based comparative genomic hybridization (aCGH), a new syndrome with "atypical" proximal interstitial deletion of 1p36.23-36.11 has been suggested. Here, we report on an 8.5-year-old girl with psychomotor developmental delay and a dysmorphic appearance. Although her G-banded chromosomal analysis showed inv(3)(p14.1q26.2), detailed FISH analyses denied pathogenic deletions around the breakpoints of chromosome 3. Accordingly, aCGH analysis was performed to identify a genomic aberration related to her phenotype, and a 3.5-Mb interstitial deletion of 1p36.13-36.12 was revealed. This deletion was the most proximal interstitial deletion of 1p36. Compared to the previously reported patients, abnormally shaped teeth, delayed tooth eruption, and leg malformation are unique phenotypes only to this patient, which might be due to the centromeric unique deletion region with 0.8-Mb.

  20. Cryptic trisomy 5q35.2qter and deletion 1p36.3 characterised using FISH and array-based CGH.

    PubMed

    Utine, Eda G; Alanay, Yasemin; Aktas, Dilek; Alikasifoglu, Mehmet; Boduroglu, Koray; Vermeesch, Joris; Tuncbilek, Ergul; Fryns, Jean-Pierre

    2008-01-01

    A 10(6/12)-year-old boy was referred to the genetics department because of mental retardation and dysmorphic findings including microcephaly, flat face, down-slanting palpebral fissures, strabismus, prominent ears, bulbous nasal tip, down-turned corners of the mouth, narrow palate, clinodactyly of the fifth fingers and generalised eczema. Cytogenetic analysis revealed a karyotype of 47,XY,+mar of paternal origin. Multicolour FISH showed the marker chromosome to be derived from chromosome 15. For further elucidation of the phenotype, array-based comparative genomic hybridisation (aCGH) was performed, which revealed dup(5)(q35.2qter) and del(1)(p36.3). Parental FISH analysis revealed that the translocation occurred de novo. Despite the presence of a clinical phenotype along with a microscopically visible chromosomal aberration, a complex cryptic cytogenetic abnormality was causative for the phenotype of the patient. Elucidation of this complex aberration required combination of the whole cytogenetic toolbox.

  1. Physical map of 1p36, placement of breakpoints in monosomy 1p36, and clinical characterization of the syndrome.

    PubMed

    Heilstedt, Heidi A; Ballif, Blake C; Howard, Leslie A; Lewis, Richard A; Stal, Samuel; Kashork, Catherine D; Bacino, Carlos A; Shapira, Stuart K; Shaffer, Lisa G

    2003-05-01

    Monosomy 1p36 is the most common terminal deletion syndrome. This contiguous gene deletion syndrome is presumably caused by haploinsufficiency of a number of genes. We have constructed a contig of overlapping large-insert clones for the most distal 10.5 Mb of 1p36, evaluated the deletion sizes in 61 subjects with monosomy 1p36 from 60 families, and created a natural deletion panel. We found pure terminal deletions, interstitial deletions, derivative chromosomes, and more complex rearrangements. Breakpoints were "binned" into 0.5-Mb regions. Analyses revealed some clustering of breakpoints but no single common breakpoint. Determination of the parental origin showed that 60% of de novo 1p36 terminal deletions arose from the maternally inherited chromosome. Of the 61 subjects, 30 were examined systematically through a protocol at the Texas Children's Hospital General Clinical Research Center. Specifically, we report hearing evaluations, palatal and ophthalmological examinations, echocardiograms, neurological assessments, and thyroid function tests. To our knowledge, this systematic molecular and clinical characterization of monosomy 1p36 is the largest and most comprehensive study of this deletion syndrome to date. Many cytogenetically visible, apparent terminal deletions are more complex than anticipated by cytogenetics, as revealed at the molecular level by our study. Our clinical findings allow for the more accurate recognition of the syndrome and for proper medical evaluation.

  2. Del 1p36 syndrome: a newly emerging clinical entity.

    PubMed

    Battaglia, Agatino

    2005-08-01

    Monosomy 1p36 is a recently delineated contiguous gene syndrome, which is now considered to be the most common subtelomeric microdeletion syndrome. From the recent literature it appears as if 1p36 deletions account for 0.5-1.2% of idiopathic mental retardation. The deletions can be detected by high resolution cytogenetic studies in a minority of patients, and fluorescence in situ hybridisation (FISH) is required in most. The deletions' parent of origin seems still unclear, although in one large series it was shown to be maternal. 1p36 deletion syndrome is characterized by distinct craniofacial features, associated with developmental delay/mental retardation, hypotonia, muscle hypotrophy, seizures, brain abnormalities, and heart defects. To help child neurologists and other professionals in the recognition of this emerging and common chromosomal syndrome, we have reviewed published articles on patients with this deletion.

  3. 1p36 tumor suppression--a matter of dosage?

    PubMed

    Henrich, Kai-Oliver; Schwab, Manfred; Westermann, Frank

    2012-12-01

    A broad range of human malignancies is associated with nonrandom 1p36 deletions, suggesting the existence of tumor suppressors encoded in this region. Evidence for tumor-specific inactivation of 1p36 genes in the classic "two-hit" manner is scarce; however, many tumor suppressors do not require complete inactivation but contribute to tumorigenesis by partial impairment. We discuss recent data derived from both human tumors and functional cancer models indicating that the 1p36 genes CHD5, CAMTA1, KIF1B, CASZ1, and miR-34a contribute to cancer development when reduced in dosage by genomic copy number loss or other mechanisms. We explore potential interactions among these candidates and propose a model where heterozygous 1p36 deletion impairs oncosuppressive pathways via simultaneous downregulation of several dosage-dependent tumor suppressor genes.

  4. CNV analysis in a large schizophrenia sample implicates deletions at 16p12.1 and SLC1A1 and duplications at 1p36.33 and CGNL1

    PubMed Central

    Rees, Elliott; Walters, James T.R.; Chambert, Kimberly D.; O'Dushlaine, Colm; Szatkiewicz, Jin; Richards, Alexander L.; Georgieva, Lyudmila; Mahoney-Davies, Gerwyn; Legge, Sophie E.; Moran, Jennifer L.; Genovese, Giulio; Levinson, Douglas; Morris, Derek W.; Cormican, Paul; Kendler, Kenneth S.; O'Neill, Francis A.; Riley, Brien; Gill, Michael; Corvin, Aiden; Sklar, Pamela; Hultman, Christina; Pato, Carlos; Pato, Michele; Sullivan, Patrick F.; Gejman, Pablo V.; McCarroll, Steven A.; O'Donovan, Michael C.; Owen, Michael J.; Kirov, George

    2014-01-01

    Large and rare copy number variants (CNVs) at several loci have been shown to increase risk for schizophrenia. Aiming to discover novel susceptibility CNV loci, we analyzed 6882 cases and 11 255 controls genotyped on Illumina arrays, most of which have not been used for this purpose before. We identified genes enriched for rare exonic CNVs among cases, and then attempted to replicate the findings in additional 14 568 cases and 15 274 controls. In a combined analysis of all samples, 12 distinct loci were enriched among cases with nominal levels of significance (P < 0.05); however, none would survive correction for multiple testing. These loci include recurrent deletions at 16p12.1, a locus previously associated with neurodevelopmental disorders (P = 0.0084 in the discovery sample and P = 0.023 in the replication sample). Other plausible candidates include non-recurrent deletions at the glutamate transporter gene SLC1A1, a CNV locus recently suggested to be involved in schizophrenia through linkage analysis, and duplications at 1p36.33 and CGNL1. A burden analysis of large (>500 kb), rare CNVs showed a 1.2% excess in cases after excluding known schizophrenia-associated loci, suggesting that additional susceptibility loci exist. However, even larger samples are required for their discovery. PMID:24163246

  5. Are Angelman and Prader-Willi syndromes more similar than we thought? Food-related behavior problems in Angelman, Cornelia de Lange, fragile X, Prader-Willi and 1p36 deletion syndromes.

    PubMed

    Welham, Alice; Lau, Johnny; Moss, Joanna; Cullen, Jenny; Higgs, Suzanne; Warren, Gemma; Wilde, Lucy; Marr, Abby; Cook, Faye; Oliver, Chris

    2015-03-01

    Food-related behavior problems are well documented in Prader-Willi syndrome (PWS), with impaired satiety, preoccupation with food and negative food-related behaviors (such as taking and storing food) frequently reported as part of the behavioral phenotype of older children and adults. Food-related behavior problems in other genetic neurodevelopmental syndromes remain less well studied, including those seen in Angelman Syndrome (AS), the 'sister imprinted disorder' of PWS. Food-related behavior problems were assessed in 152 participants each with one of five genetic neurodevelopmental syndromes – PWS, AS, 1p36 deletion, Cornelia de Lange, and fragile X. Predictably, levels of food-related behavior problems reported in participants with PWS significantly exceeded those of at least one other groups in most areas (impaired satiety; preoccupation with food; taking and storing food; composite negative behavior). However, in some areas people with AS were reported to display food-related problems at least as severe as those with PWS, with the AS group reported to display significantly more food-related behavior problems than at least one comparison group on measures of taking and storing food, composite negative behaviors, impaired satiety and preoccupation with food. Over 50% of participants in the AS group scored above the median point of the distribution of PWS scores on a measure of taking and storing food. These findings indicate further investigation of eating problems in AS are warranted and have implications for current theoretical interpretations of the behavioral differences between AS and PWS.

  6. Young-Simpson syndrome (YSS), a variant of del(1)(p36) syndrome?

    PubMed

    Robinson, Deanne Mraz; Meagher, Cecilia C; Orlowski, Craig C; Lagoe, Erin Caine; Fong, Chin-To

    2008-06-15

    The Young-Simpson syndrome (YSS) and 1p36 deletion syndrome are both characterized by facial and heart abnormalities, congenital hypothyroidism, and severe growth and developmental retardation. However, the YSS is characterized by the presence of blepharophimosis and epicanthus inversus, findings not described in monosomy 1p36 patients. We describe a girl with YSS, who presented with the typical facial findings, global retardation, congenital hypothyroidism, and congenital dilated cardiomyopathy. Comparative genomic hybridization chromosomal microarray analysis showed a 1p36.3 deletion, a finding not previously reported in other YSS cases. We propose that YSS is a variant of the 1p36 deletion syndrome.

  7. Severe lysosomal storage disease of liver in del(1)(p36): a new presentation.

    PubMed

    Haimi, Motti; Iancu, Theodore C; Shaffer, Lisa G; Lerner, Aaron

    2011-01-01

    1p36 deletion is the most common terminal deletion syndrome with an estimated occurrence of 1:5000 live births. The deletion is of variable size. It usually involves less than 10 Mb in the 1pter-1p36.23 interval. Variability of the phenotype is partially related to the extent of the deletion. Some children with a 1p36 deletion were reported with obesity and hyperphagia, raising the question of possible phenotypic overlap with Prader-Willi syndrome. Correlation between presence of obesity and the size of the deletion has only been documented in one case. We report a 11-year-old girl with 1p36 deletion and the classical dysmorphological features. In late infancy, she developed an uncontrolled voracious appetite, overweight, truncal obesity and elevated serum transaminases. Liver biopsy disclosed severe steatosis. The hepatocytes contained accumulation of lipofuscins. Lipolysosomes were abnormally numerous and extremely enlarged. These features have not been previously reported in 1p36 deletion. Oligonucleotide-based microarray analysis showed a subtelomeric 2.2 Mb deletion at 1p36.33p36.32. This suggests that this chromosome segment is a critical region for obesity and hyperphagia. The accumulation in the liver with abnormal ultrastructure may be an additional feature of this form of syndromal obesity. 1p36 deletion syndrome should be considered in patients with obesity, hyperphagia and liver fat accumulation.

  8. A patient with monosomy 1p36, atypical features and phenotypic similarities with Cantu syndrome.

    PubMed

    Tan, Tiong Yang; Bankier, Agnes; Slater, Howard R; Northrop, Emma L; Zacharin, Margaret; Savarirayan, Ravi

    2005-12-15

    We report on a 16-year-old boy with a distal 1p36 deletion with some clinical features consistent with Cantu syndrome (OMIM#239850). He also has hypercholesterolemia, type II diabetes, recurrent bony fractures, and non-alcoholic steatohepatitis, not previously described in either condition. The 1p36 deletion was detected in a screen of all chromosome subtelomeres using multiplex ligation-dependent probe amplification and was verified using FISH with a region-specific BAC clone. We suggest that patients suspected of having Cantu syndrome, especially those with unusual or more severe manifestations be analyzed for distal 1p36 deletions.

  9. Molecular characterization of a monosomy 1p36 presenting as an Aicardi syndrome phenocopy.

    PubMed

    Bursztejn, Anne-Claire; Bronner, Myriam; Peudenier, Sylviane; Grégoire, Marie-José; Jonveaux, Philippe; Nemos, Christophe

    2009-11-01

    Monosomy 1p36 is the most frequent terminal deletion known in Humans. Typical craniofacial features, developmental delay/mental retardation, seizures and sensorineural defects characterize 1p36 deletion syndrome. Aicardi syndrome (AIS) is a rare genetic disorder characterized by chorioretinal lacunae, corpus callosum agenesis and infantile spasms responsible for mental retardation. By screening DNA from diagnosed AIS patients with oligonucleotide array-based comparative genomic hybridization (aCGH), we report a 1p36 monosomy in this study. There were no other deletions or duplications. Regarding clinical criteria, the patient did not have the typical facial appearance commonly described for 1p36 monosomy patients. We showed that this 1p36 monosomy corresponded to combined interstitial and terminal de novo deletions of the chromosome 1 leading to an 11.73 Mb deletion confirmed with qPCR. By microsatellite markers and FISH analyses, we have concluded that this deletion occurred on maternal chromosome 1 during oogenesis. We did find some clinical features shared by the 1p36 monosomy and AIS: infantile spasms, corpus callosum dysgenesis, ophthalmological abnormalities, and skeletal malformations. To date, no relationship between these two phenotypes has been established. We conclude that the monosomy 1p36 should be considered in the differential diagnosis of AIS.

  10. Lack of evidence for monosomy 1p36 in patients with Prader-Willi-like phenotype.

    PubMed

    Rodríguez, V R; Mazzucato, L F; Pina-Neto, J M

    2008-08-01

    Monosomy 1p36 is the most common subtelomeric microdeletion syndrome with an incidence rate estimated to be 1 in 5000 births. A hypothesis of a similarity between patients with 1p36 deletion and those with Prader-Willi syndrome and the existence of two different phenotypes for 1p36 microdeletion has been suggested. The main objective of the present study was to determine the existence of 1p36 microdeletion in a sample of patients with mental retardation, obesity and hyperphagia who tested negative by the methylation test for Prader-Willi syndrome. Sixteen patients (7 females, 9 males), 16-26 years old, were evaluated with high-resolution cytogenetic analysis at 550-850 band levels and with 11 polymorphic microsatellite markers located in the 1p36 region. All patients had normal cytogenetic and molecular results. The results obtained by high-resolution cytogenetic methodology were confirmed by the molecular analyses. We did not detect a 1p36 microdeletion in 16 subjects with the Prader-Willi-like phenotype, which reinforces that no correlation seems to exist between Prader-Willi-like phenotype and the 1p36 microdeletion syndrome.

  11. Left-ventricular non-compaction in a patient with monosomy 1p36.

    PubMed

    Thienpont, Bernard; Mertens, Luc; Buyse, Gunnar; Vermeesch, Joris R; Devriendt, Koen

    2007-01-01

    We report on a new-born girl with left ventricular non-compaction (LVNC), dysmorphism and epilepsy. Array-CGH at 1 Mb resolution revealed a deletion of the terminal 4.6 to 5.9 Mb of the short arm of chromosome 1. Cardiac abnormalities such as dilated cardiomyopathy and structural cardiac defects are common findings in patients with monosomy 1p36. This is however the first report describing LVNC in association with the 1p36 deletion syndrome, broadening the spectrum of cardiac anomalies found in association with this syndrome.

  12. Monosomy 1p36 uncovers a role for OX40 in survival of activated CD4+ T cells.

    PubMed

    Suhoski, M M; Perez, E E; Heltzer, M L; Laney, A; Shaffer, L G; Saitta, S; Nachman, S; Spinner, N B; June, C H; Orange, J S

    2008-08-01

    Monosomy 1p36 is a subtelomeric deletion syndrome associated with congenital anomalies presumably due to haploinsufficiency of multiple genes. Although immunodeficiency has not been reported, genes encoding costimulatory molecules of the TNF receptor superfamily (TNFRSF) are within 1p36 and may be affected. In one patient with monosomy 1p36, comparative genome hybridization and fluorescence in- situ hybridization confirmed that TNFRSF member OX40 was included within the subtelomeric deletion. T cells from this patient had decreased OX40 expression after stimulation. Specific, ex vivo T cell activation through OX40 revealed enhanced proliferation, and reduced viability of patient CD4+ T cells, providing evidence for the association of monosomy 1p36 with reduced OX40 expression, and decreased OX40-induced T cell survival. These results support a role for OX40 in human immunity, and calls attention to the potential for haploinsufficiency deletions of TNFRSF costimulatory molecules in monosomy 1p36.

  13. Prenatal diagnosis and prenatal imaging features of fetal monosomy 1p36.

    PubMed

    Lissauer, D; Larkins, S A; Sharif, S; MacPherson, L; Rhodes, C; Kilby, M D

    2007-09-01

    Deletion of the distal end of the short arm of chromosome 1 (1p36) is thought to be a common terminal chromosomal deletion. However, few cases prospectively diagnosed prenatally have been reported. In this case, prenatal ultrasound at 21 weeks of gestation noted the fetus to have mild ventriculomegaly (Vhanterior = 11 mm and Vhposterior = 12 mm) and increased nuchal edema (6 mm). Maternal serum alpha-fetoprotein was normal unlike in a majority of previously described cases. The prenatal ultrasound features were further clarified with fetal MRI. Chromosome analysis following amniocentesis demonstrated a 1p36 deletion, which was confirmed by fluorescence in situ hybridization (FISH). The syndrome associated with 1p36 deletion is well described in infants and is characterized by typical facial features (prominent forehead, straight eyebrows. deep-set eyes, flat nasal bridge and a pointed chin). Other associated features are neurodevelopmental delay, seizures, cardiomyopathy and neurosensory hearing impairment. This case supplements our knowledge of the prenatal features of 1p36. Identification of this deletion by direct chromosomal analysis can be technically difficult and vigilance is required to improve diagnosis. FISH analysis is an important diagnostic adjunct where the diagnosis is suspected following classical G-banding techniques. However, in this chromosomal anomaly there remain few characteristic prenatal signs that are readily diagnosed with prenatal imaging.

  14. Morbid obesity in a child with monosomy 1p36 syndrome

    PubMed Central

    Zagalo, Ana; Dias, Patricia; Pereira, Carla; Sampaio, Maria de Lurdes

    2012-01-01

    The monosomy 1p36 syndrome is a cause of syndromic obesity. It is characterised by psychomotor delay, hypotonia and typical craniofacial dysmorphism. Other features commonly associated are behavioural anomalies including hyperphagia and self-injuring, seizures, congenital heart disease and hypothyroidism. The authors report the case of a 9-year and 5-month-boy referred to the paediatric endocrinology clinics for morbid obesity. Clinical findings were generalised obesity with a body mass index >95th centile, acanthosis nigricans of the neck, arms with self inflicted lesions, deep-set eyes, straight eyebrows, broad nasal bridge and pointed chin. He was unable to walk and had no expressive language. Cytogenetic analysis identified 1p36.33-pter deletion (~139 Mb terminal deletion in chromosome 1 short arm) and Y chromosome duplication. The blood analysis showed insulin resistance and dyslipidaemia. The authors emphasise the need to consider monosomy 1p36 as a cause of severe psychomotor delay and obesity. PMID:22605691

  15. Morbid obesity in a child with monosomy 1p36 syndrome.

    PubMed

    Zagalo, Ana; Dias, Patricia; Pereira, Carla; Sampaio, Maria de Lurdes

    2012-03-20

    The monosomy 1p36 syndrome is a cause of syndromic obesity. It is characterised by psychomotor delay, hypotonia and typical craniofacial dysmorphism. Other features commonly associated are behavioural anomalies including hyperphagia and self-injuring, seizures, congenital heart disease and hypothyroidism. The authors report the case of a 9-year and 5-month-boy referred to the paediatric endocrinology clinics for morbid obesity. Clinical findings were generalised obesity with a body mass index >95th centile, acanthosis nigricans of the neck, arms with self inflicted lesions, deep-set eyes, straight eyebrows, broad nasal bridge and pointed chin. He was unable to walk and had no expressive language. Cytogenetic analysis identified 1p36.33-pter deletion (~139 Mb terminal deletion in chromosome 1 short arm) and Y chromosome duplication. The blood analysis showed insulin resistance and dyslipidaemia. The authors emphasise the need to consider monosomy 1p36 as a cause of severe psychomotor delay and obesity.

  16. Choroid plexus hyperplasia and monosomy 1p36: report of new findings.

    PubMed

    Puvabanditsin, Surasak; Garrow, Eugene; Patel, Neisha; D'Elia, Alexis; Zaafran, Ahmed; Phattraprayoon, Nanthida; Davis, Suzanne Elizabeth

    2008-08-01

    Monosomy 1p36 is a newly delineated multiple congenital anomalies/mental retardation syndrome characterized by mental retardation, growth delay, epilepsy, congenital heart defects, characteristic facial appearance, and precocious puberty. It is now considered to be one of the most common subtelomeric micro-deletion syndromes. This article reports new findings of choroid plexus hyperplasia and dextrocardia with situs solitus in a patient who had deletion of chromosome 1p26.33 with a brief review of the literature.

  17. Accurate, Fast and Cost-Effective Diagnostic Test for Monosomy 1p36 Using Real-Time Quantitative PCR

    PubMed Central

    Cunha, Pricila da Silva; Pena, Heloisa B.; D'Angelo, Carla Sustek; Koiffmann, Celia P.; Rosenfeld, Jill A.; Shaffer, Lisa G.; Stofanko, Martin; Gonçalves-Dornelas, Higgor; Pena, Sérgio Danilo Junho

    2014-01-01

    Monosomy 1p36 is considered the most common subtelomeric deletion syndrome in humans and it accounts for 0.5–0.7% of all the cases of idiopathic intellectual disability. The molecular diagnosis is often made by microarray-based comparative genomic hybridization (aCGH), which has the drawback of being a high-cost technique. However, patients with classic monosomy 1p36 share some typical clinical characteristics that, together with its common prevalence, justify the development of a less expensive, targeted diagnostic method. In this study, we developed a simple, rapid, and inexpensive real-time quantitative PCR (qPCR) assay for targeted diagnosis of monosomy 1p36, easily accessible for low-budget laboratories in developing countries. For this, we have chosen two target genes which are deleted in the majority of patients with monosomy 1p36: PRKCZ and SKI. In total, 39 patients previously diagnosed with monosomy 1p36 by aCGH, fluorescent in situ hybridization (FISH), and/or multiplex ligation-dependent probe amplification (MLPA) all tested positive on our qPCR assay. By simultaneously using these two genes we have been able to detect 1p36 deletions with 100% sensitivity and 100% specificity. We conclude that qPCR of PRKCZ and SKI is a fast and accurate diagnostic test for monosomy 1p36, costing less than 10 US dollars in reagent costs. PMID:24839341

  18. Partial monosomy of chromosome 1p36.3: Characterization of the critical region and delineation of a syndrome

    SciTech Connect

    Reish, O.; Berry, S.A.; Hirsch, B.

    1995-12-04

    We describe 5 patients ranging in age from 3 to 47 years, with karyotypic abnormalities resulting in monosomy for portion of 1p36.3, microcephaly, mental retardation, prominent forehead, deep-set eyes, depressed nasal bridge, flat midface, relative prognathism, and abnormal ears. Four patients have small hands and feet. All exhibited selfabusive behavior. Additional findings in some of the patients include brain anomalies, optic atrophy, hearing loss and skeletal deformities. The breakpoints within chromosome 1 were designated at 1p36.31 (3 cases), 1p36.32 (1 case) and 1p36.33 (1 case). Thus, the smallest region of deletion overlap is 1p36.33{r_arrow}pter. Detection of the abnormal 1 relied on high resolution G-band analysis. Fluorescence in situ hybridization (FISH) utilizing a DNA probe (Oncor D1Z2) containing the repetitive sequences in distal 1p36, confirmed a deletion of one 1 homologue in all 5 cases. The abnormal 1 resulted from a de novo deletion in only one patient. The remaining patients were either confirmed (3 cases) or suspected (1 case) to have unbalanced translocations. Despite the additional genetic imbalance present in these four cases, monosomy of 1p36.33 appears to be responsible for a specific clinical phenotype. Characterization of this phenotype should assist in the clinical diagnosis of this chromosome abnormality. 26 refs., 4 figs., 2 tabs.

  19. Accurate, fast and cost-effective diagnostic test for monosomy 1p36 using real-time quantitative PCR.

    PubMed

    Cunha, Pricila da Silva; Pena, Heloisa B; D'Angelo, Carla Sustek; Koiffmann, Celia P; Rosenfeld, Jill A; Shaffer, Lisa G; Stofanko, Martin; Gonçalves-Dornelas, Higgor; Pena, Sérgio Danilo Junho

    2014-01-01

    Monosomy 1p36 is considered the most common subtelomeric deletion syndrome in humans and it accounts for 0.5-0.7% of all the cases of idiopathic intellectual disability. The molecular diagnosis is often made by microarray-based comparative genomic hybridization (aCGH), which has the drawback of being a high-cost technique. However, patients with classic monosomy 1p36 share some typical clinical characteristics that, together with its common prevalence, justify the development of a less expensive, targeted diagnostic method. In this study, we developed a simple, rapid, and inexpensive real-time quantitative PCR (qPCR) assay for targeted diagnosis of monosomy 1p36, easily accessible for low-budget laboratories in developing countries. For this, we have chosen two target genes which are deleted in the majority of patients with monosomy 1p36: PRKCZ and SKI. In total, 39 patients previously diagnosed with monosomy 1p36 by aCGH, fluorescent in situ hybridization (FISH), and/or multiplex ligation-dependent probe amplification (MLPA) all tested positive on our qPCR assay. By simultaneously using these two genes we have been able to detect 1p36 deletions with 100% sensitivity and 100% specificity. We conclude that qPCR of PRKCZ and SKI is a fast and accurate diagnostic test for monosomy 1p36, costing less than 10 US dollars in reagent costs.

  20. Extending the phenotype of monosomy 1p36 syndrome and mapping of a critical region for obesity and hyperphagia.

    PubMed

    D'Angelo, Carla S; Kohl, Ilana; Varela, Monica Castro; de Castro, Cláudia I E; Kim, Chong A; Bertola, Débora R; Lourenço, Charles M; Koiffmann, Célia P

    2010-01-01

    Rearrangements of 1p36 are the most frequently detected abnormalities in diagnostic testing for chromosomal cryptic imbalances and include variably sized simple terminal deletions, derivative chromosomes, interstitial deletions, and complex rearrangements. These rearrangements result in the specific pattern of malformation and neurodevelopmental disabilities that characterizes monosomy 1p36 syndrome. Thus far, no individual gene within this region has been conclusively determined to be causative of any component of the phenotype. Nor is it known if the rearrangements convey phenotypes via a haploinsufficiency mechanism or through a position effect. We have used multiplex ligation-dependent probe amplification to screen for deletions of 1p36 in a group of 154 hyperphagic and overweight/obese, PWS negative individuals, and in a separate group of 83 patients initially sent to investigate a variety of other conditions. The strategy allowed the identification and delineation of rearrangements in nine subjects with a wide spectrum of clinical presentations. Our work reinforces the association of monosomy 1p36 and obesity and hyperphagia, and further suggests that these features may be associated with non-classical manifestations of this disorder in addition to a submicroscopic deletion of approximately 2-3 Mb in size. Multiplex ligation probe amplification using the monosomy 1p36 syndrome-specific kit coupled to the subtelomeric kit is an effective approach to identify and delineate rearrangements at 1p36.

  1. 1p36.32 rearrangements and the role of PI-PLC η2 in nervous tumours.

    PubMed

    Lo Vasco, Vincenza Rita

    2011-07-01

    Deletions in the distal region of the short arm of chromosome 1 (1p36) are widely diffuse, both in congenital 1p36 Deletion Syndrome and as somatic abnormalities in tumours. Rearrangements in 1p36 have been described in a broad spectrum of human neoplasias in addition to other chromosomal abnormalities. In neuroblastomas, wide hemizygous deletions in 1p36.23-1p36.32 have been described suggesting that the 1p36 region contains a tumour-suppressor gene involved in malignancy. A role for phosphoinositide (PI)-specific phospholipase C (PLC) η2, whose gene maps on 1p36.32, was suggested. PI-PLC η2 belongs to a family of enzymes related to the phosphoinositide signalling pathway, which provide an important intracellular signalling system involved in a variety of cell functions such as hormone secretion, neurotransmitter signal transduction, cell growth, membrane trafficking, ion channel activity, regulation of the cytoskeleton, cell cycle control and apoptosis. Expression of PI-PLC η2 occurs after birth and continues throughout the life. Synapse formation occurs during a short period of postnatal development. Thus, it is likely that PI-PLC η2 acts in formation and maintenance of the neuronal network in the brain. The fact that PI-PLC η2, a highly neuron-specific isozyme, is abundantly expressed in the postnatal brain suggests the importance of PI-PLC η2 in formation and maintenance of the neuronal network in the postnatal brain. Further studies are required to verify the possible involvement of PI-PLC η2 mutation/deletion in central nervous tumour tissues presenting abnormalities of the 1p36 chromosomal band.

  2. Monosomy 1p36 - a multifaceted and still enigmatic syndrome: four clinically diverse cases with shared white matter abnormalities.

    PubMed

    Õiglane-Shlik, Eve; Puusepp, Sanna; Talvik, Inga; Vaher, Ulvi; Rein, Reet; Tammur, Pille; Reimand, Tiia; Teek, Rita; Žilina, Olga; Tomberg, Tiiu; Õunap, Katrin

    2014-05-01

    Monosomy 1p36 is the most common subtelomeric deletion syndrome seen in humans. Uniform features of the syndrome include early developmental delay and consequent intellectual disability, muscular hypotonia, and characteristic dysmorphic facial features. The gene-rich nature of the chromosomal band, inconsistent deletion sizes and overlapping clinical features have complicated relevant genotype-phenotype correlations. We describe four patients with isolated chromosome 1p36 deletions. All patients shared white matter abnormalities, allowing us to narrow the critical region for white matter involvement to the deletion size of up to 2.5 Mb from the telomere. We hypothesise that there might be a gene(s) responsible for myelin development in the 1p36 subtelomeric region. Other significant clinical findings were progressive spastic paraparesis, epileptic encephalopathy, various skeletal anomalies, Prader-Willi-like phenotype, neoplastic changes - a haemangioma and a benign skin tumour, and in one case, sleep myoclonus, a clinical entity not previously described in association with 1p36 monosomy. Combined with prior studies, our results suggest that the clinical features seen in monosomy 1p36 have more complex causes than a classical contiguous gene deletion syndrome.

  3. RAP1GA1: A candidate tumor suppressor locus in 1p36.1

    SciTech Connect

    Ranade, K.; Hussussian, C.J.; Higgins, P.

    1994-09-01

    The rap1/Krev-1 gene (RAP1A) encodes a p21-related protein that suppresses transformation by activated p21{sup ras}. The GTPase activating protein (GAP) gene for p21{sup rap1A} (RAP1GA1) has recently been assigned to chromosome 1p36.1-p35, a region of the genome that is frequently involved in deletions and rearrangements in several different tumors including breast, colon and hepatocellular carcinomas, melanoma, and neuroblastoma. GAP genes negatively regulate the activity of p21 proteins by catalyzing the conversion of the active GTP-bound forms to the inactive GDP-bound forms. The physiological function of p21{sup rap1A}-GAP makes it a strong candidate as a tumor suppressor gene that may have a role in the development of one or more of these malignancies. We have refined the localization of RAP1GA1 by linkage analysis with a highly informative (CA){sub n} repeat contained within the gene, and demonstrated that it is within the minimal deleted region for breast and colon carcinomas, and that it is excluded from the minimally deleted region in melanoma and neuroblastoma. Genetic mapping in the mouse demonstrated that Rap1ga1 is located {approximately}10 cM proximal to Pnd and therefore maps within the interval containing the modifier of Min gene (Mom-1) and the plasmocytoma susceptibility locus (Pcts). The human RAP1GA1 gene contains at least 27 exons. The coding region contains 22 exons, and there are at least five 5{prime}-UT exons that are assembled in a complex pattern of alternative splicing in different tissues. The localization of RAP1GA1 makes it a very strong candidate for a role as a modifier gene involved in the common secondary abnormalities involving 1p36 in several different carcinomas. The potential role of RAP1GA1 in these malignancies is currently being investigated by sequence analysis of breast and colon carcinomas with loss of heterozygosity in 1p36.

  4. ECK, a human EPH-related gene, maps to 1p36.1, a common region of alteration in human cancers

    SciTech Connect

    Sulman, E.P.; Brodeur, G.M.; Ikegaki, N.

    1997-03-01

    Mouse eck, a member of the EPH gene family, has been mapped to mouse chromosome 4. The syntenic relationship between this chromosome and human chromosome 1 suggests that the human ECK gene maps to the distal short arm of human chromosome 1 (1p). Since this region is frequently deleted or altered in certain tumors of neuroectodermal origin, it is important to define the specific chromosomal localization of the human ECK gene. PCR screening of a rodent-human somatic cell hybrid panel by ECK-specific primers showed that ECK is indeed localized to human chromosome 1. Additional PCR screening of a regional screening panel for chromosome 1p indicated that ECK is localized to 1p36, distal to FUCA1. Furthermore, fluorescence in situ hybridization analysis with an ECK-specific P1 clone showed that ECK maps proximal to genetic marker D1S228. Taken together, the data suggest that ECK maps to 1p36.1, a region that is frequently deleted in neuroblastoma, melanoma, and other neuroectodermal tumors. 23 refs., 3 figs.

  5. Left ventricular noncompaction: a rare disorder in adults and its association with 1p36 chromosomal anomaly.

    PubMed

    Dod, Harvinder S; Bhardwaj, Ravindra; Hummel, Marybeth; Morise, Anthony P; Batish, Satdev; Warden, Bradford E; Beto, Robert J; Jain, Abnash C

    2010-01-01

    We report on a case of a 25-year-old male with 1p36 deletion syndrome, who was diagnosed with left ventricular noncompaction (LVNC). The association of this rare chromosomal abnormality with LVNC is reported in the pediatric literature, but it has not previously been specifically reported in adults. It is important to diagnose this unclassified cardiomyopathy in the adult population with this chromosomal abnormality for appropriate management and treatment as highlighted in our case.

  6. Ebstein anomaly: Genetic heterogeneity and association with microdeletions 1p36 and 8p23.1.

    PubMed

    Digilio, Maria Cristina; Bernardini, Laura; Lepri, Francesca; Giuffrida, Maria Grazia; Guida, Valentina; Baban, Anwar; Versacci, Paolo; Capolino, Rossella; Torres, Barbara; De Luca, Alessandro; Novelli, Antonio; Marino, Bruno; Dallapiccola, Bruno

    2011-09-01

    Ebstein anomaly is an uncommon congenital heart defect (CHD), characterized by downward displacement of the tricuspid valve into the right ventricle. To uncover the genetic associations with Ebstein anomaly, we have searched chromosomal imbalances using standard cytogenetic and array-CGH analysis, and single gene conditions associated with syndromic Ebstein anomaly (with extracardiac anomalies), and screened GATA4 and NKX2.5 mutations in nonsyndromic patients (without extracardiac anomalies). Between January 1997 and September 2009, 44 consecutive patients with Ebstein anomaly were evaluated in two centers of Pediatric Cardiology. Ebstein anomaly was syndromic in 12 (27%) patients, and nonsyndromic in 32 (73%). A recognizable syndrome or complex was diagnosed by clinical criteria in seven patients. In one syndromic patient an 18q deletion was diagnosed by standard cytogenetic analysis. Array-CGH analysis performed in 10 of the 12 syndromic patients detected an interstitial deletion of about 4 Mb at 8p23.1 in one patient, and a deletion 1pter > 1p36.32/dup Xpter- > Xp22.32 in another patient. In the 28 of 32 nonsyndromic patients who underwent molecular testing, no mutation in GATA4 and NKX2.5 genes were detected. We conclude that Ebstein anomaly is a genetically heterogeneous defect, and that deletion 1p36 and deletion 8p23.1 are the most frequent chromosomal imbalances associated with Ebstein anomaly. Candidate genes include the GATA4 gene (in patients with del 8p23.1), NKX2.5 (based on published patients with isolated Ebstein anomaly) and a hypothetical gene in patients with del 1p36). Copyright © 2011 Wiley-Liss, Inc.

  7. Recurrent loss of heterozygosity in 1p36 associated with TNFRSF14 mutations in IRF4 translocation negative pediatric follicular lymphomas.

    PubMed

    Martin-Guerrero, Idoia; Salaverria, Itziar; Burkhardt, Birgit; Szczepanowski, Monika; Baudis, Michael; Bens, Susanne; de Leval, Laurence; Garcia-Orad, Africa; Horn, Heike; Lisfeld, Jasmin; Pellissery, Shoji; Klapper, Wolfram; Oschlies, Ilske; Siebert, Reiner

    2013-08-01

    Pediatric follicular lymphoma is a rare disease that differs genetically and clinically from its adult counterpart. With the exception of pediatric follicular lymphoma with IRF4-translocation, the genetic events associated with these lymphomas have not yet been defined. We applied array-comparative genomic hybridization and molecular inversion probe assay analyses to formalin-fixed paraffin-embedded tissues from 18 patients aged 18 years and under with IRF4 translocation negative follicular lymphoma. All evaluable cases lacked t(14;18). Only 6 of 16 evaluable cases displayed chromosomal imbalances with gains or amplifications of 6pter-p24.3 (including IRF4) and deletion and copy number neutral-loss of heterozygosity in 1p36 (including TNFRSF14) being most frequent. Sequencing of TNFRSF14 located in the minimal region of loss in 1p36.32 showed nine mutations in 7 cases from our series. Two subsets of pediatric follicular lymphoma were delineated according to the presence of molecular alterations, one with genomic aberrations associated with higher grade and/or diffuse large B-cell lymphoma component and more widespread disease, and another one lacking genetic alterations associated with more limited disease.

  8. Mapping of the chromosome 1p36 region surrounding the Charcot-Marie-Tooth disease type 2A locus

    SciTech Connect

    Denton, P.; Gere, S.; Wolpert, C.

    1994-09-01

    Charcot-Marie-Tooth (CMT) disease is the most common inherited peripheral neuropathy. Although CMT2 is clinically indistinguishable from CMT1, the two forms can be differentiated by pathological and neurophysiological methods. We have established one locus, CMT2A on chromosome 1p36, and have established genetic heterogeneity. This locus maps to the region of the deletions associated with neuroblastoma. We have now identified an additional 11 CMT2 families. Three families are linked to chromosome 1p36 while six families are excluded from this region. Another six families are currently under analysis and collection. To date the CMT2A families represent one third of those CMT2 families examined. We have established a microdissection library of the 1p36 region which is currently being characterized for microsatellite repeats and STSs using standard hybridization techniques and a modified degenerate primer method. In addition, new markers (D1S253, D1S450, D1S489, D1S503, GATA27E04, and GATA4H04) placed in this region are being mapped using critical recombinants in the CEPH reference pedigrees. Fluorescent in situ hybridization (FISH) has been used to confirm mapping. A YAC contig is being assembled from the CEPH megabase library using STSs to isolate key YACs which are extended by vectorette end clone and Alu-PCR. These findings suggest that the CMT2 phenotype is secondary to at least two different genes and demonstrates further heterogeneity in the CMT phenotype.

  9. Further delineation of nonhomologous-based recombination and evidence for subtelomeric segmental duplications in 1p36 rearrangements.

    PubMed

    D'Angelo, Carla S; Gajecka, Marzena; Kim, Chong A; Gentles, Andrew J; Glotzbach, Caron D; Shaffer, Lisa G; Koiffmann, Célia P

    2009-06-01

    The mechanisms involved in the formation of subtelomeric rearrangements are now beginning to be elucidated. Breakpoint sequencing analysis of 1p36 rearrangements has made important contributions to this line of inquiry. Despite the unique architecture of segmental duplications inherent to human subtelomeres, no common mechanism has been identified thus far and different nonexclusive recombination-repair mechanisms seem to predominate. In order to gain further insights into the mechanisms of chromosome breakage, repair, and stabilization mediating subtelomeric rearrangements in humans, we investigated the constitutional rearrangements of 1p36. Cloning of the breakpoint junctions in a complex rearrangement and three non-reciprocal translocations revealed similarities at the junctions, such as microhomology of up to three nucleotides, along with no significant sequence identity in close proximity to the breakpoint regions. All the breakpoints appeared to be unique and their occurrence was limited to non-repetitive, unique DNA sequences. Several recombination- or cleavage-associated motifs that may promote non-homologous recombination were observed in close proximity to the junctions. We conclude that NHEJ is likely the mechanism of DNA repair that generates these rearrangements. Additionally, two apparently pure terminal deletions were also investigated, and the refinement of the breakpoint regions identified two distinct genomic intervals ~25-kb apart, each containing a series of 1p36 specific segmental duplications with 90-98% identity. Segmental duplications can serve as substrates for ectopic homologous recombination or stimulate genomic rearrangements.

  10. Further delineation of novel 1p36 rearrangements by array-CGH analysis: narrowing the breakpoints and clarifying the "extended" phenotype.

    PubMed

    Giannikou, Krinio; Fryssira, Helen; Oikonomakis, Vasilis; Syrmou, Areti; Kosma, Konstantina; Tzetis, Maria; Kitsiou-Tzeli, Sofia; Kanavakis, Emmanouel

    2012-09-15

    High resolution oligonucleotide array Comparative Genome Hybridization technology (array-CGH) has greatly assisted the recognition of the 1p36 contiguous gene deletion syndrome. The 1p36 deletion syndrome is considered to be one of the most common subtelomeric microdeletion syndromes and has an incidence of ~1 in 5000 live births, while respectively the "pure" 1p36 microduplication has not been reported so far. We present seven new patients who were referred for genetic evaluation due to Developmental Delay (DD), Mental Retardation (MR), and distinct dysmorphic features. They all had a wide phenotypic spectrum. In all cases previous standard karyotypes were negative. Array-CGH analysis revealed five patients with interstitial 1p36 microdeletion (four de novo and one maternal) and two patients with de novo reciprocal duplication of different sizes. These were the first reported "pure" 1p36 microduplication cases so far. Three of our patients carrying the 1p36 microdeletion syndrome were also found to have additional pathogenetic aberrations. These findings (del 3q27.1; del 4q21.22-q22.1; del 16p13.3; dup 21q21.2-q21.3; del Xp22.12) might contribute to the patients' severe phenotype, acting as additional modifiers of their clinical manifestations. We review and compare the clinical and array-CGH findings of our patients to previously reported cases with the aim of clearly delineating more accurate genotype-phenotype correlations for the 1p36 syndrome that could allow for a more precise prognosis.

  11. Case report of individual with cutaneous immunodeficiency and novel 1p36 duplication

    PubMed Central

    Hatter, Alyn D; Soler, David C; Curtis, Christine; Cooper, Kevin D; McCormick, Thomas S

    2016-01-01

    Introduction Crusted or Norwegian scabies is an infectious skin dermatopathology usually associated with an underlying immunodeficiency condition. It is caused when the mite Sarcoptes scabiei infects the skin, and the immune system is unable to control its spread, leading to a massive hyperinfestation with a simultaneous inflammatory and hyperkeratotic reaction. This is the first report of a novel 1p36 duplication associated with a recurrent infection of crusted scabies. Case report We describe a 34-year-old patient with a cutaneous immunodeficiency characterized by recurrent crusted scabies infestation, diffuse tinea, and recurrent staphylococcal cellulitis, who we suspected had an undiagnosed syndrome. The patient also suffered from mental retardation, renal failure, and premature senescence. A cytogenetic fluorescence in situ hybridization analysis revealed a 9.34 Mb duplication within the short (p) arm of chromosome 1, precisely from 1p36.11 to 1p36.21, with an adjacent 193 kb copy gain entirely within 1p36.11. In addition, chromosome 4 had a 906 kb gain in 4p16.1 and chromosome 9 had a 81 kb copy gain in 9p24.3. Over 100 genes localized within these duplicated regions. Gene expression array revealed 82 genes whose expression changed >1.5-fold compared to a healthy age-matched skin control, but among them only the lipolytic enzyme arylacetamide deacetylase-like 3 was found within the duplicated 1p36 region of chromosome 1. Discussion Although genetic duplications in the 1p36 region have been previously described, our report describes a novel duplicative variant within the 1p36 region. The patient did not have a past history of immunosuppression but was afflicted by a recurrent case of crusted scabies, raising the possibility that the recurrent infection was associated with the 1p36 genetic duplication. Conclusion To our knowledge, the specific duplicated sequence between 1p36.11 and p36.21 found in our patient has never been previously reported. We reviewed and

  12. The 1p36 Tumor Suppressor KIF 1Bβ Is Required for Calcineurin Activation, Controlling Mitochondrial Fission and Apoptosis.

    PubMed

    Li, Shuijie; Fell, Stuart M; Surova, Olga; Smedler, Erik; Wallis, Karin; Chen, Zhi Xiong; Hellman, Ulf; Johnsen, John Inge; Martinsson, Tommy; Kenchappa, Rajappa S; Uhlén, Per; Kogner, Per; Schlisio, Susanne

    2016-01-25

    KIF1Bβ is a candidate 1p36 tumor suppressor that regulates apoptosis in the developing sympathetic nervous system. We found that KIF1Bβ activates the Ca(2+)-dependent phosphatase calcineurin (CN) by stabilizing the CN-calmodulin complex, relieving enzymatic autoinhibition and enabling CN substrate recognition. CN is the key mediator of cellular responses to Ca(2+) signals and its deregulation is implicated in cancer, cardiac, neurodegenerative, and immune disease. We show that KIF1Bβ affects mitochondrial dynamics through CN-dependent dephosphorylation of Dynamin-related protein 1 (DRP1), causing mitochondrial fission and apoptosis. Furthermore, KIF1Bβ actuates recognition of all known CN substrates, implying a general mechanism for KIF1Bβ in Ca(2+) signaling and how Ca(2+)-dependent signaling is executed by CN. Pathogenic KIF1Bβ mutations previously identified in neuroblastomas and pheochromocytomas all fail to activate CN or stimulate DRP1 dephosphorylation. Importantly, KIF1Bβ and DRP1 are silenced in 1p36 hemizygous-deleted neuroblastomas, indicating that deregulation of calcineurin and mitochondrial dynamics contributes to high-risk and poor-prognosis neuroblastoma.

  13. Chromothripsis with at least 12 breaks at 1p36.33-p35.3 in a boy with multiple congenital anomalies.

    PubMed

    Gamba, Bruno Faulin; Richieri-Costa, Antônio; Costa, Silvia; Rosenberg, Carla; Ribeiro-Bicudo, Lucilene Arilho

    2015-12-01

    Terminal deletion in the short arm of chromosome 1 results in a disorder described as 1p36 deletion syndrome. The resulting phenotype varies among patients including mental retardation, developmental delay, sensorineural hearing loss, seizures, heart defects, and distinct facies. In the present case, we performed array-comparative genomic hybridization in a boy with multiple congenital malformations presenting some features overlapping the 1p36 deletion phenotype for whom chromosomal analysis did not reveal a terminal deletion in 1p. Results showed complex chromosome rearrangements involving the 1p36.33-p35.3 region. While the mechanism of origin of these rearrangements is still unclear, chromothripsis-a single catastrophic event leading to shattering chromosomes or chromosome regions and rejoining of the segments-has been described to occur in a fraction of cancers. The presence of at least 12 clustered breaks at 1p and apparent lack of mosaicism in the present case suggests that a single event like chromothripsis occurred. This finding suggests that chromothripsis is responsible for some constitutive complex chromosome rearrangements.

  14. Genomewide Linkage Analysis of Obsessive Compulsive Disorder Implicates Chromosome 1p36

    PubMed Central

    Mathews, Carol A.; Badner, Judith A.; Andresen, J. Michael; Sheppard, Brooke; Himle, Joseph A.; Grant, Jon E.; Williams, Kyle A; Chavira, Denise A.; Azzam, Amin; Schwartz, Maxine; Reus, Victor I.; Kim, Suck Won; Cook, Edwin H.; Hanna, Gregory L.

    2012-01-01

    Background Obsessive compulsive disorder (OCD) has a complex etiology involving both genetic and environmental factors. However, the genetic causes of OCD are largely unknown, despite the identification of several promising candidate genes and linkage regions. Methods Our objective was to conduct genetic linkage studies of the type of OCD thought to have the strongest genetic etiology (i.e., childhood-onset OCD), in 33 Caucasian families with ≥2 childhood-onset OCD-affected individuals from the United States (US) (N=245 individuals with genotype data). Parametric and non-parametric genome-wide linkage analyses were conducted with Morgan and Merlin in these families using a selected panel of single nucleotide repeat polymorphisms (SNPs) from the Illumina 610-Quad Bead Chip. The initial analyses were followed by fine-mapping analyses in genomic regions with initial heterogeneity LOD (HLOD) scores of ≥2.0. Results We identified five areas of interest (HLOD score ≥2) on chromosomes 1p36, 2p14, 5q13, 6p25, and 10p13. The strongest result was on chromosome 1p36.33-p36.32 (HLOD=3.77, suggestive evidence for linkage after fine-mapping). At this location, several of the families showed haplotypes co-segregating with OCD. Conclusions The results of this study represent the strongest linkage finding for OCD in a primary analysis to date, and suggest that chromosome 1p36, and possibly several other genomic regions, may harbor susceptibility loci for OCD. Multiple brain-expressed genes lie under the primary linkage peak (approximately 4 mb in size). Follow-up studies, including replication in additional samples and targeted sequencing of the areas of interest, are needed to confirm these findings and to identify specific OCD risk variants. PMID:22633946

  15. Identification of a locus (LCA9) for Leber's congenital amaurosis on chromosome 1p36.

    PubMed

    Keen, T Jeffrey; Mohamed, Moin D; McKibbin, Martin; Rashid, Yasmin; Jafri, Hussain; Maumenee, Irene H; Inglehearn, Chris F

    2003-05-01

    Leber's congenital amaurosis (LCA) is the most common cause of inherited childhood blindness and is characterised by severe retinal degeneration at or shortly after birth. We have identified a new locus, LCA9, on chromosome 1p36, at which the disease segregates in a single consanguineous Pakistani family. Following a whole genome linkage search, an autozygous region of 10 cM was identified between the markers D1S1612 and D1S228. Multipoint linkage analysis generated a lod score of 4.4, strongly supporting linkage to this region. The critical disease interval contains at least 5.7 Mb of DNA and around 50 distinct genes. One of these, retinoid binding protein 7 (RBP7), was screened for mutations in the family, but none was found.

  16. Motility defects in Campylobacter jejuni defined gene deletion mutants caused by second-site mutations

    PubMed Central

    de Vries, Stefan P. W.; Gupta, Srishti; Baig, Abiyad; L'Heureux, Joanna; Pont, Elsa; Wolanska, Dominika P.; Maskell, Duncan J.

    2015-01-01

    Genetic variation due to mutation and phase variation has a considerable impact on the commensal and pathogenic behaviours of Campylobacter jejuni. In this study, we provide an example of how second-site mutations can interfere with gene function analysis in C. jejuni. Deletion of the flagellin B gene (flaB) in C. jejuni M1 resulted in mutant clones with inconsistent motility phenotypes. From the flaB mutant clones picked for further analysis, two were motile, one showed intermediate motility and two displayed severely attenuated motility. To determine the molecular basis of this differential motility, a genome resequencing approach was used. Second-site mutations were identified in the severely attenuated and intermediate motility flaB mutant clones: a TA-dinucleotide deletion in fliW and an A deletion in flgD, respectively. Restoration of WT fliW, using a newly developed genetic complementation system, confirmed that the second-site fliW mutation caused the motility defect as opposed to the primary deletion of flaB. This study highlights the importance of (i) screening multiple defined gene deletion mutant clones, (ii) genetic complementation of the gene deletion and ideally (iii) screening for second-site mutations that might interfere with the pathways/mechanisms under study. PMID:26385289

  17. Linkage to Chromosome 1p36 for Attention Deficit Hyperactivity Disorder Traits in School and Home Settings

    PubMed Central

    Zhou, Kaixin; Asherson, Philip; Sham, Pak; Franke, Barbara; Anney, Richard JL; Buitelaar, Jan; Ebstein, Richard; Gill, Michael; Brookes, Keeley; Buschgens, Cathelijne; Campbell, Desmond; Chen, Wai; Christiansen, Hanna; Fliers, Ellen; Gabriëls, Isabel; Johansson, Lena; Marco, Rafaela; Mulas, Fernando; Müller, Ueli; Mulligan, Aisling; Neale, Benjamin M.; Rijsdijk, Fruhling; Rommelse, Nanda; Uebel, Henrik; Psychogiou, Lamprini; Xu, Xiaohui; Banaschewski, Tobias; Sonuga-Barke, Edmund; Eisenberg, Jacques; Manor, Iris; Miranda, Ana; Oades, Robert D.; Roeyers, Herbert; Rothenberger, Aribert; Sergeant, Joseph; Steinhausen, Hans-Christoph; Taylor, Eric; Thompson, Margaret; Faraone, Stephen V

    2013-01-01

    Background Limited success has been achieved through previous ADHD linkage scans which were all designed to map genes underlying the dichotomous phenotype. The International Multi-centre ADHD Genetics (IMAGE) project performed a whole genome linkage scan specifically designed to map ADHD quantitative trait loci. Methods A set of 1,094 single selected Caucasian ADHD nuclear families was genotyped on a highly accurate and informative SNP panel. Two quantitative traits measuring the children’s symptoms in home and school settings were collected and standardized according to a population sample of 8000 children to reflect the developmental nature and gender prevalence difference of ADHD. Univariate linkage test was performed on both traits and their mean score. Results A significant common linkage locus was found at chromosome 1p36 with a locus-specific heritability of 5.1% and a genomewide empirical p<0.04. Setting-specific suggestive linkage signals were also found: LOD=2.2 at 9p23 for home trait and LOD=2.6 at 11q21 for school trait. Conclusions These results indicate that given large samples with proper phenotypic measures, searching for ADHD genes with a QTL strategy is an important alternative to using the clinical diagnosis. The fact that our linkage region 1p36 overlaps with the dyslexia QTL DYX8 further suggests it is potentially a pleiotropic locus for ADHD and dyslexia. PMID:18439570

  18. Deletions of the Aequorea victoria green fluorescent protein define the minimal domain required for fluorescence.

    PubMed

    Li, X; Zhang, G; Ngo, N; Zhao, X; Kain, S R; Huang, C C

    1997-11-07

    The Green Fluorescent Protein (GFP) from the jellyfish Aequorea victoria is a widely used marker for gene expression and protein localization studies. Dissection of the structure of the protein would be expected to shed light on its potential applications to other fields such as the detection of protease activity. Using deletion analysis, we have defined the minimal domain in GFP required for fluorescence to amino acids 7-229. This domain starts at the middle of the first small alpha helix at the N terminus of GFP and ends immediately following the last beta sheet. Studies of the amino acids at both termini of the minimal domain revealed that positions 6 and 7 at the N terminus are Glu-specific. Change of the Glu residues to other amino acids results in reduction of GFP fluorescence. Position 229 at the C terminus of GFP, however, is nonspecific: the Ile can be replaced with other amino acids with no measurable loss of fluorescence. A total of only 15 terminal amino acids can be deleted from GFP without disrupting fluorescence, consistent with findings of a previous study of GFP crystal structure (Ormo, M., Cubitt, A. B., Kallio, K., Gross, L. A., Tsien, R. Y., Remington, S. J. (1996) Science 273, 1392-1395 and Yang, F., Moss, L. G., and Phillips, G. N., Jr. (1996) Nat. Biotechnol. 14, 1246-1251) that a tightly packed structure exists in the protein. We also generated internal deletions within the loop regions of GFP according to its crystal structure and found that all such deletions eliminated GFP fluorescence.

  19. Linkage and linkage disequilibrium in chromosome band 1p36 in American Chaldeans with inflammatory bowel disease.

    PubMed

    Cho, J H; Nicolae, D L; Ramos, R; Fields, C T; Rabenau, K; Corradino, S; Brant, S R; Espinosa, R; LeBeau, M; Hanauer, S B; Bodzin, J; Bonen, D K

    2000-05-22

    The idiopathic inflammatory bowel diseases (IBDs), consisting of Crohn's disease and ulcerative colitis, are complex genetic disorders involving chronic inflammation of the intestines. Multiple genetic loci have been implicated through genome-wide searches, but refinement of localization sufficient to undertake positional cloning efforts has been problematic. This difficulty can be obviated through identification of ancestrally shared regions in genetic isolates, such as the Chaldean population, a Roman Catholic group from Iraq. We analyzed four multiply affected American Chaldean families with inflammatory bowel disease not known to be related. We observed evidence for linkage and linkage disequilibrium in precisely the same region of chromosome band 1p36 reported previously in an outbred population. Maximal evidence for linkage was observed near D1S1597 by multipoint analysis (MLOD = 3.01, P = 6.1 x 10(-5)). A shared haplotype (D1S507 to D1S1628) was observed over 27 cM between two families. There was homozygous sharing of a 5 cM portion of that haplotype in one family and over a <1 cM region in the second family. Homozygous sharing of this haplotype near D1S2697 and D1S3669 was observed in one individual in a third multiply affected family, with heterozygous sharing in a fourth family. Linkage in outbred families as well as in this genetic isolate indicates that a pathophysiologically crucial IBD susceptibility gene is located in 1p36. These findings provide a unique opportunity to refine the localization and identify a major susceptibility gene for a complex genetic disorder.

  20. Insertion and deletion events that define the pathogen Mycobacterium avium subsp. paratuberculosis.

    PubMed

    Alexander, David C; Turenne, Christine Y; Behr, Marcel A

    2009-02-01

    Mycobacterium avium comprises genetically related yet phenotypically distinct subspecies. Consistent with their common origin, whole-genome sequence comparisons have revealed extensive synteny among M. avium organisms. However, the sequenced strains also display numerous regions of heterogeneity that likely contribute to the diversity of the individual subspecies. Starting from a phylogenetic framework derived by multilocus sequence analysis, we examined the distribution of 25 large sequence polymorphisms across a panel of genetically defined M. avium strains. This distribution was most variable among M. avium subsp. hominissuis isolates. In contrast, M. avium subsp. paratuberculosis strains exhibited a characteristic profile, with all isolates containing a set of genomic insertions absent from other M. avium strains. The emergence of the pathogen from its putative M. avium subsp. hominissuis ancestor entailed the acquisition of approximately 125 kb of novel genetic material, followed by a second phase, characterized by reductive genomics. One genomic deletion is common to all isolates while additional deletions distinguish two major lineages of M. avium subsp. paratuberculosis. For the average strain, these losses total at least 38 kb (sheep lineage) to 90 kb (cattle lineage). This biphasic pattern of evolution, characterized by chromosomal gene acquisition with subsequent gene loss, describes the emergence of M. avium subsp. paratuberculosis and may serve as a general model for the origin of pathogenic mycobacteria.

  1. Deletions in herpes simplex virus glycoprotein D define nonessential and essential domains.

    PubMed Central

    Feenstra, V; Hodaie, M; Johnson, D C

    1990-01-01

    Herpes simplex virus glycoprotein D (gD) is a major component of the virion envelope and infected cell membranes and is essential for virus entry into cells. We have recently shown that gD interacts with a limited number of cell surface receptors which are required for virus penetration into cells. To define domains of gD which are required for aspects of virus replication including receptor binding, deletion mutations of 5 to 14 amino acids were constructed by using oligonucleotide-directed mutagenesis. Plasmids containing mutant genes for gD were assayed for the ability to rescue a recombinant virus, F-gD beta, in which beta-galactosidase sequences replace gD-coding sequences. Effects on global folding and posttranslational processing of the molecules were assessed by using a panel of monoclonal antibodies which recognize both continuous and discontinuous epitopes. A region near the amino terminus (residues 7 to 21) of gD which is recognized by monoclonal antibodies able to neutralize herpes simplex virus in the absence of complement was not essential for function. In addition, virtually all of the cytoplasmic domain of gD and an extracellular domain close to the membrane were dispensable. In contrast, deletion mutations in the central region of the molecule, save for one exception, led to alterations in global folding of the molecule and maturation of the protein was inhibited. Images PMID:2157872

  2. Monosomy 1p36.31-33{yields}pter due to a paternal reciprocal translocation: Prognostic significance of FISH analysis

    SciTech Connect

    Blennow, E.; Bui, The-Hung; Wallin, A.

    1996-10-02

    A rare monosomy 1p36.31-33{r_arrow}pter was found in a child with physical anomalies, psycho-motor retardation, and seizures. Cytogenetic investigation suggested an unbalanced translocation between 1p and an acrocentric chromosome, but the rearrangement was difficult to assess accurately using conventional chromosome banding techniques. The half-cryptic translocation was further characterized using fluorescence in situ hybridization, and the aberrant chromosome 1 was shown to be a derivate of a paternal reciprocal translocation t(1;15)(p36.31-33;p11.2-12). The breakpoints on chromosome 1 and 15 were defined in detail using locus specific probes. The rearrangement did not include the region on chromosome 1p which previously has been suggested to predispose to the development of neuroblastoma in a case with a constitutional translocation. At 3 6/12 years, the patient has no clinical signs of this disease, which illustrates the prognostic significance of this investigation. 30 refs., 4 figs., 1 tab.

  3. Deletions of the long arm of chromosome 5 define subgroups of T-cell acute lymphoblastic leukemia.

    PubMed

    La Starza, Roberta; Barba, Gianluca; Demeyer, Sofie; Pierini, Valentina; Di Giacomo, Danika; Gianfelici, Valentina; Schwab, Claire; Matteucci, Caterina; Vicente, Carmen; Cools, Jan; Messina, Monica; Crescenzi, Barbara; Chiaretti, Sabina; Foà, Robin; Basso, Giuseppe; Harrison, Christine J; Mecucci, Cristina

    2016-08-01

    Recurrent deletions of the long arm of chromosome 5 were detected in 23/200 cases of T-cell acute lymphoblastic leukemia. Genomic studies identified two types of deletions: interstitial and terminal. Interstitial 5q deletions, found in five cases, were present in both adults and children with a female predominance (chi-square, P=0.012). Interestingly, these cases resembled immature/early T-cell precursor acute lymphoblastic leukemia showing significant down-regulation of five out of the ten top differentially expressed genes in this leukemia group, including TCF7 which maps within the 5q31 common deleted region. Mutations of genes known to be associated with immature/early T-cell precursor acute lymphoblastic leukemia, i.e. WT1, ETV6, JAK1, JAK3, and RUNX1, were present, while CDKN2A/B deletions/mutations were never detected. All patients had relapsed/resistant disease and blasts showed an early differentiation arrest with expression of myeloid markers. Terminal 5q deletions, found in 18 of patients, were more prevalent in adults (chi-square, P=0.010) and defined a subgroup of HOXA-positive T-cell acute lymphoblastic leukemia characterized by 130 up- and 197 down-regulated genes. Down-regulated genes included TRIM41, ZFP62, MAPK9, MGAT1, and CNOT6, all mapping within the 1.4 Mb common deleted region at 5q35.3. Of interest, besides CNOT6 down-regulation, these cases also showed low BTG1 expression and a high incidence of CNOT3 mutations, suggesting that the CCR4-NOT complex plays a crucial role in the pathogenesis of HOXA-positive T-cell acute lymphoblastic leukemia with terminal 5q deletions. In conclusion, interstitial and terminal 5q deletions are recurrent genomic losses identifying distinct subtypes of T-cell acute lymphoblastic leukemia. Copyright© Ferrata Storti Foundation.

  4. Deletions of the long arm of chromosome 5 define subgroups of T-cell acute lymphoblastic leukemia

    PubMed Central

    La Starza, Roberta; Barba, Gianluca; Demeyer, Sofie; Pierini, Valentina; Di Giacomo, Danika; Gianfelici, Valentina; Schwab, Claire; Matteucci, Caterina; Vicente, Carmen; Cools, Jan; Messina, Monica; Crescenzi, Barbara; Chiaretti, Sabina; Foà, Robin; Basso, Giuseppe; Harrison, Christine J.; Mecucci, Cristina

    2016-01-01

    Recurrent deletions of the long arm of chromosome 5 were detected in 23/200 cases of T-cell acute lymphoblastic leukemia. Genomic studies identified two types of deletions: interstitial and terminal. Interstitial 5q deletions, found in five cases, were present in both adults and children with a female predominance (chi-square, P=0.012). Interestingly, these cases resembled immature/early T-cell precursor acute lymphoblastic leukemia showing significant down-regulation of five out of the ten top differentially expressed genes in this leukemia group, including TCF7 which maps within the 5q31 common deleted region. Mutations of genes known to be associated with immature/early T-cell precursor acute lymphoblastic leukemia, i.e. WT1, ETV6, JAK1, JAK3, and RUNX1, were present, while CDKN2A/B deletions/mutations were never detected. All patients had relapsed/resistant disease and blasts showed an early differentiation arrest with expression of myeloid markers. Terminal 5q deletions, found in 18 of patients, were more prevalent in adults (chi-square, P=0.010) and defined a subgroup of HOXA-positive T-cell acute lymphoblastic leukemia characterized by 130 up- and 197 down-regulated genes. Down-regulated genes included TRIM41, ZFP62, MAPK9, MGAT1, and CNOT6, all mapping within the 1.4 Mb common deleted region at 5q35.3. Of interest, besides CNOT6 down-regulation, these cases also showed low BTG1 expression and a high incidence of CNOT3 mutations, suggesting that the CCR4-NOT complex plays a crucial role in the pathogenesis of HOXA-positive T-cell acute lymphoblastic leukemia with terminal 5q deletions. In conclusion, interstitial and terminal 5q deletions are recurrent genomic losses identifying distinct subtypes of T-cell acute lymphoblastic leukemia. PMID:27151989

  5. Defining the region(s) of deletion at 6q16-q22 in human prostate cancer.

    PubMed

    Hyytinen, Eija-Riitta; Saadut, Rega; Chen, Ceshi; Paull, Lindsay; Koivisto, Pasi A; Vessella, Robert L; Frierson, Henry F; Dong, Jin-Tang

    2002-07-01

    Deletion of the long arm of chromosome 6 (6q) frequently occurs in many neoplasms, including carcinomas of the prostate and breast and melanoma, suggesting the location of a tumor-suppressor gene or genes at 6q. At present, however, the region of deletion has not been well defined, and the target gene of deletion remains to be identified. In this study, we analyzed 44 primary prostate cancers with 16 polymorphic markers for loss of heterozygosity (LOH) by using PCR-based techniques. We also examined 23 cell lines/xenografts of prostate cancer with 38 markers for LOH by the method of homozygosity mapping of deletion. LOH at 6q16 - q22 was detected in 21 of 44 (48%) primary tumors and in 12 of 23 (52%) cell lines/xenografts. Two regions of LOH were defined. One was 7.5 cM at 6q16 - q21 between markers D6S1716 and D6S1580, and the other was 4.3 cM at 6q22 between D6S261 and D6S1702. Whereas no correlation was found between LOH at 6q16-q22 and patient age at diagnosis or Gleason score, tumors at higher stage appear to have more frequent LOH. These findings suggest that deletion of 6q16 - q22 is a frequent event in prostate cancer, and that the deletion originates from two distinct regions. These results should be useful in identifying the target gene(s) of deletion at 6q.

  6. Mutants deleted in the agnogene of simian virus 40 define a new complementation group.

    PubMed Central

    Mertz, J E; Murphy, A; Barkan, A

    1983-01-01

    Analysis of the DNA sequence of the late leader region of simian virus 40 indicates that it might encode a 61-amino acid, highly basic protein, LP-1. Mutants deleted in this region are viable, but they produce infectious progeny more slowly than wild-type virus in established monkey cells. On the basis of the rates of appearance and the sizes of mixed plaques formed after cotransfections with pairs of mutants, we found that mutants defective in the synthesis of LP-1 complementation was also observed in infections with virions and was bidirectional. Therefore, these mutants define a new complementation group, group G. In addition, a protein of the appropriate molecular weight for LP-1 (approximately 8 X 10(3) ) was synthesized by wild-type virus-infected cells but not by mock-infected or group G gene mutant-infected cells. This protein, whose identity has been established definitively by Jay et al. (Nature (London) 291:346-349, 1981), was synthesized at a high rate at late times after infection, was present predominantly in the cytoplasmic fraction of cells, possessed a fairly short half-life, and was absent from mature virions. Once formed, virions of group G gene mutants behaved biologically and physically like virions of wild-type virus. On the basis of these findings and other known properties of LP-1 and mutants defective in LP-1 synthesis, we hypothesize that LP-1 functions to facilitate virion assembly, possibly by serving as a nonreusable scaffolding protein. Images PMID:6296443

  7. Defining the ends of Parkin exon 4 deletions in two different families with Parkinson's disease.

    PubMed

    Clarimon, Jordi; Johnson, Janel; Dogu, Okan; Horta, Wagner; Khan, Naheed; Lees, Andrew J; Hardy, John; Singleton, Andrew

    2005-02-05

    Autosomal recessive juvenile parkinsonism (AR-JP, PARK2) is characterized by an early onset parkinsonism, often presenting with dystonia as an early feature. Mutations in Parkin are a relatively common cause of AR-JP and are estimated to be present in approximately 30% of familial young onset Parkinson disease (PD) [Abbas et al. (1999); Hum Mol Genet 8:567-574]. These mutations include exon rearrangements (deletions and duplications), point mutations, and small deletions. Similar genomic mutations have been described in unrelated patients, thereby indicating independent mutational events or ancient founder effects. We have identified homozygous deletion mutations of exon 4 in Parkin in two unrelated families, one from Brazil and the other from Turkey [Dogu et al. (2004); Mov Dis 9:812-816; Khan et al., Mov Dis, in press]. We have performed molecular analysis of the deletion breakpoints and this data indicates these mutations originated independently. We present here data demonstrating that the mutation responsible for disease in the Brazilian kindred consists of two separate deletions (1,069 and 1,750 bp) surrounding and including exon 4. The deletion removing parkin exon 4 identified in the Turkish family extended 156,203 bp. In addition to demonstrating that disease in these families is not caused by a single founder mutation, these data show that there is no common fragile site between these mutational events.

  8. Defined single-gene and multi-gene deletion mutant collections in Salmonella enterica sv Typhimurium.

    PubMed

    Porwollik, Steffen; Santiviago, Carlos A; Cheng, Pui; Long, Fred; Desai, Prerak; Fredlund, Jennifer; Srikumar, Shabarinath; Silva, Cecilia A; Chu, Weiping; Chen, Xin; Canals, Rocío; Reynolds, M Megan; Bogomolnaya, Lydia; Shields, Christine; Cui, Ping; Guo, Jinbai; Zheng, Yi; Endicott-Yazdani, Tiana; Yang, Hee-Jeong; Maple, Aimee; Ragoza, Yury; Blondel, Carlos J; Valenzuela, Camila; Andrews-Polymenis, Helene; McClelland, Michael

    2014-01-01

    We constructed two collections of targeted single gene deletion (SGD) mutants and two collections of targeted multi-gene deletion (MGD) mutants in Salmonella enterica sv Typhimurium 14028s. The SGD mutant collections contain (1), 3517 mutants in which a single gene is replaced by a cassette containing a kanamycin resistance (KanR) gene oriented in the sense direction (SGD-K), and (2), 3376 mutants with a chloramphenicol resistance gene (CamR) oriented in the antisense direction (SGD-C). A combined total of 3773 individual genes were deleted across these SGD collections. The MGD collections contain mutants bearing deletions of contiguous regions of three or more genes and include (3), 198 mutants spanning 2543 genes replaced by a KanR cassette (MGD-K), and (4), 251 mutants spanning 2799 genes replaced by a CamR cassette (MGD-C). Overall, 3476 genes were deleted in at least one MGD collection. The collections with different antibiotic markers permit construction of all viable combinations of mutants in the same background. Together, the libraries allow hierarchical screening of MGDs for different phenotypic followed by screening of SGDs within the target MGD regions. The mutants of these collections are stored at BEI Resources (www.beiresources.org) and publicly available.

  9. Assignment of the human amiloride-sensitive Na{sup +} channel {delta} isoform to chromosome 1p36.3-p36.2

    SciTech Connect

    Waldmann, R.; Bassilana, F.; Voilley, N.

    1996-06-01

    This report describes the localization of the human amiloride-sensitive Na{sup +} channel {delta} isoform to human chromosome 1p36.3-p36.2 using in situ hybridization. Mutations in this group of ion channels have been implicated in various hereditary diseases. 18 refs., 1 fig.

  10. Amelogenesis Imperfecta in Two Families with Defined AMELX Deletions in ARHGAP6

    PubMed Central

    Hu, Jan C.-C.; Chan, Hui-Chen; Simmer, Stephen G.; Seymen, Figen; Richardson, Amelia S.; Hu, Yuanyuan; Milkovich, Rachel N.; Estrella, Ninna M. R. P.; Yildirim, Mine; Bayram, Merve; Chen, Chiung-Fen; Simmer, James P.

    2012-01-01

    Amelogenesis imperfecta (AI) is a group of inherited conditions featuring isolated enamel malformations. About 5% of AI cases show an X-linked pattern of inheritance, which are caused by mutations in AMELX. In humans there are two, non-allelic amelogenin genes: AMELX (Xp22.3) and AMELY (Yp11.2). About 90% of amelogenin expression is from AMELX, which is nested within intron 1 of the gene encoding Rho GTPase activating protein 6 (ARHGAP6). We recruited two AI families and determined that their disease-causing mutations were partial deletions in ARHGAP6 that completely deleted AMELX. Affected males in both families had a distinctive enamel phenotype resembling “snow-capped” teeth. The 96,240 bp deletion in family 1 was confined to intron 1 of ARHGAP6 (g.302534_398773del96240), but removed alternative ARHGAP6 promoters 1c and 1d. Analyses of developing teeth in mice showed that ARHGAP6 is not expressed from these promoters in ameloblasts. The 52,654 bp deletion in family 2 (g.363924_416577del52654insA) removed ARHGAP6 promoter 1d and exon 2, precluding normal expression of ARHGAP6. The male proband of family 2 had slightly thinner enamel with greater surface roughness, but exhibited the same pattern of enamel malformations characteristic of males in family 1, which themselves showed minor variations in their enamel phenotypes. We conclude that the enamel defects in both families were caused by amelogenin insufficiency, that deletion of AMELX results in males with a characteristic snow-capped enamel phenotype, and failed ARHGAP6 expression did not appreciably alter the severity of enamel defects when AMELX was absent. PMID:23251683

  11. [First two Mexican cases of monosomy 1p36: possible diagnosis in patients with mental retardation and dysmorphism].

    PubMed

    Villarroel, Camilo E; Álvarez, Rosa M; Gómez-Laguna, Laura; Ramos, Sandra; González-Del Ángel, Ariadna

    2011-06-01

    It is calculated that distal deletion of the short arm of chromosome 1 occurs in one out of every 5000 live births and causes approximately 1.2% of cases of mental retardation of unknown origin. This alteration usually cannot be detected in the standard karyotype, requiring molecular cytogenetic techniques for the diagnosis. In addition to the neurological manifestations, it may cause internal organs malformations, such as congenital heart disease, and a characteristic facial phenotype. This report describes the clinical and cytogenetic findings from the first two cases diagnosed in Mexico, confirmed by fluorescence in situ hybridization test, and compares them to those described in the literature. The probable subdiagnosis of this entity, the importance of improves its recognition and the useful data for the clinical suspicion are also discussed.

  12. Deletions of a differentially methylated CpG island at SNRPN define a putative imprinting control region

    SciTech Connect

    Sutcliffe, J.S.,; Nakao, M.; Beaudet, A.L.

    1994-09-01

    Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are associated with paternal and maternal deficiencies, respectively, of gene expression within human chromosome 15q11-q13, and are caused by deletion, uniparental disomy, or other mutations. Four transcripts designated PAR-5, PAR-7, PAR-1 and PAR-4 were isolated and localized to a region within 300 kb telomeric to the gene encoding small nuclear ribonucleoprotein-associated polypeptide N (SNRPN). Analysis of the transcripts in cultured fibroblasts and lymphoblasts from deletion patients demonstrated that SNRPN, PAR-5 and PAR-1 are expressed exclusively from the paternal chromosome, defining an imprinted domain that spans at least 200 kb. All three imprinted transcripts were absent in cells from three PWS patients (one pair of sibs and one sporadic case) with small deletions that involve a differentially methylated CpG island containing a previously undescribed 5{prime} untranslated exon ({alpha}) of SNRPN. Methylation of the CpG island is specific for the maternal chromosome consistent with paternal expression of the imprinted domain. One deletion, which is benign when maternally transmitted, extends upstream <30 kb from the CpG island, and is associated with altered methylation centromeric to SNRPN, and loss of transcription telomeric to SNRPN, implying the presence of an imprinting control region around the CpG island containing exon {alpha}.

  13. Constitutional Ip36 deletion in a child with neuroblastoma

    SciTech Connect

    Biegel, J.A.; Zackai, E.H.; Scher, C.D.; Emanuel, B.S. Univ. of Pennsylvania, Philadelphia ); White, P.S.; Marshall, H.N.; Fujimori, Minoru; Brodeur, G.M. )

    1993-01-01

    The authors describe a child with dysmorphic features, as well as developmental and growth delay, who developed neuroblastoma at 5 mo of age. Cytogenetic analysis of blood lymphocytes revealed an interstitial deletion of 1p36.1 [r arrow] 1p36.2, which was apparent only with high-resolution banding. Molecular analysis with a collection of polymorphic DNA probes for 1p confirmed an interstitial deletion involving subbands of 1p36. Deletions of this region are a common finding in neuroblastoma cells from patients with advanced stages of disease. Therefore, these results (a) suggest that constitutional deletion of this region predisposed the patient to the development of neuroblastoma and (b) support the localization of a neuroblastoma tumor-suppressor locus to 1p36. 48 refs., 2 figs.

  14. MHC Class II tetramers and the pursuit of antigen-specific T cells: define, deviate, delete.

    PubMed

    Mallone, Roberto; Nepom, Gerald T

    2004-03-01

    Selective expansion and activation of a very small number of antigen-specific CD4(+) T cells is a remarkable and essential property of the adaptive immune response. Antigen-specific T cells were until recently identified only indirectly by functional assays, such as antigen-induced cytokine secretion and proliferation. The advent of MHC Class II tetramers has added a pivotal tool to our research armamentarium, allowing the definition of allo- and autoimmune responses in deeper detail. Rare antigen-specific CD4(+) cells can now be selectively identified, isolated and characterized. The same tetramer reagents also provide a new mean of stimulating T cells, more closely reproducing the MHC-peptide/TCR interaction. This property allows the use of tetramers to direct T cells toward the more desirable outcome, that is, activation (in malignancies and infectious diseases) or Th2/T regulatory cell deviation, anergy and deletion (in autoimmune diseases). These experimental approaches hold promise for diagnostic, prognostic and therapeutic applications.

  15. Incomplete and delayed Sox2 deletion defines residual ear neurosensory development and maintenance

    PubMed Central

    Dvorakova, Martina; Jahan, Israt; Macova, Iva; Chumak, Tetyana; Bohuslavova, Romana; Syka, Josef; Fritzsch, Bernd; Pavlinkova, Gabriela

    2016-01-01

    The role of Sox2 in neurosensory development is not yet fully understood. Using mice with conditional Islet1-cre mediated deletion of Sox2, we explored the function of Sox2 in neurosensory development in a model with limited cell type diversification, the inner ear. In Sox2 conditional mutants, neurons initially appear to form normally, whereas late- differentiating neurons of the cochlear apex never form. Variable numbers of hair cells differentiate in the utricle, saccule, and cochlear base but sensory epithelium formation is completely absent in the apex and all three cristae of the semicircular canal ampullae. Hair cells differentiate only in sensory epithelia known or proposed to have a lineage relationship of neurons and hair cells. All initially formed neurons lacking hair cell targets die by apoptosis days after they project toward non-existing epithelia. Therefore, late neuronal development depends directly on Sox2 for differentiation and on the survival of hair cells, possibly derived from common neurosensory precursors. PMID:27917898

  16. Genome-wide scan for serum ghrelin detects linkage on chromosome 1p36 in Hispanic children: results from the Viva La Familia study.

    PubMed

    Voruganti, V Saroja; Göring, Harald H H; Diego, Vincent P; Cai, Guowen; Mehta, Nitesh R; Haack, Karin; Cole, Shelley A; Butte, Nancy F; Comuzzie, Anthony G

    2007-10-01

    This study was conducted to investigate genetic influence on serum ghrelin and its relationship with adiposity-related phenotypes in Hispanic children (n=1030) from the Viva La Familia study (VFS). Anthropometric measurements and levels of serum ghrelin were estimated and genetic analyses conducted according to standard procedures. Mean age, body mass index (BMI), and serum ghrelin were 11+/-0.13 y, 25+/-0.24 kg/m2 and 38+/-0.5 ng/mL, respectively. Significant heritabilities (p<0.001) were obtained for BMI, weight, fat mass, percent fat, waist circumference, waist-to-height ratio, and ghrelin. Bivariate analyses of ghrelin with adiposity traits showed significant negative genetic correlations (p<0.0001) with weight, BMI, fat mass, percent fat, waist circumference, and waist-to-height ratio. A genome-wide scan for ghrelin detected significant linkage on chromosome 1p36.2 between STR markers D1S2697 and D1S199 (LOD=3.2). The same region on chromosome 1 was the site of linkage for insulin (LOD=3.3), insulinlike growth factor binding protein 1 (IGFBP1) (LOD=3.4), homeostatic model assessment method (HOMA) (LOD=2.9), and C-peptide (LOD=2.0). Several family-based studies have reported linkages for obesity-related phenotypes in the region of 1p36. These results indicate the importance of this region in relation to adiposity in children from the VFS.

  17. Characterization of the human gene for microfibril-associated glycoprotein (MFAP2), assignment to chromosome 1p36.1-p35, and linkage to D1S170

    SciTech Connect

    Faraco, J.; Bashir, M.; Rosenbloom, J.

    1995-02-10

    Microfibril-associated glycoprotein, MAGP (gene symbol MFAP2), is a component of connective tissue microfibrils and a candidate for involvement in the etiology of inherited connective tissue diseases. We have cloned a human MAGP cDNA that is highly homologous to the previously characterized bovine and murine genes. Like the bovine and murine loci, the human gene has eight coding exons, but it contains two alternatively used 5{prime} untranslated exons, whereas only one untranslated exon was described in the bovine and murine Magp genes. By using rodent x human somatic cell hybrid panels and fluorescence chromosomal in situ hybridization, we have assigned the locus to human chromosome 1p36.1-p35. An insertion/ deletion polymorphism has been identified within intron 7. Linkage analysis between this polymorphism and markers on distal chromosome 1 revealed that MAGP is tightly linked to the anonymous marker D1S170. Physical mapping revealed a distance of <100 kb between the two markers. This information can be used to screen for linkage in families with microfibrillar abnormalities that are not linked to the fibrillin genes on chromosomes 15 or 5. 24 refs., 5 figs., 1 tab.

  18. Genomewide scan in Ashkenazi Jewish families demonstrates evidence of linkage of ocular refraction to a QTL on chromosome 1p36.

    PubMed

    Wojciechowski, Robert; Moy, Chris; Ciner, Elise; Ibay, Grace; Reider, Lauren; Bailey-Wilson, Joan E; Stambolian, Dwight

    2006-05-01

    The development of refractive error is mediated by both environmental and genetic factors. We performed regression-based quantitative trait locus (QTL) linkage analysis on Ashkenazi Jewish families to identify regions in the genome responsible for ocular refraction. We measured refractive error on individuals in 49 multi-generational American families of Ashkenazi Jewish descent. The average family size was 11.1 individuals and was composed of 2.7 generations. Recruitment criteria specified that each family contain at least two myopic members. The mean spherical equivalent refractive error in the sample was -3.46D (SD=3.29) and 87% of individuals were myopic. Microsatellite genotyping with 387 markers was performed on 411 individuals. We performed multipoint regression-based linkage analysis for ocular refraction and a log transformation of the trait using the statistical package Merlin-Regress. Empirical genomewide significance levels were estimated through gene-dropping simulations by generating random genotypes at each of the 387 markers in 200 replicates of our pedigrees. Maximum LOD scores of 9.5 for ocular refraction and 8.7 for log-transformed refraction (LTR) were observed at 49.1 cM on chromosome 1p36 between markers D1S552 and D1S1622. The empirical genomewide significance levels were P=0.065 for ocular refraction and P<0.005 for LTR, providing strong evidence for linkage of refraction to this locus. The inter-marker region containing the peak spans 11 Mb and contains approximately 189 genes. We found genomewide significant evidence for linkage of refractive error to a novel QTL on chromosome 1p36 in an Ashkenazi Jewish population.

  19. Murine fumarylacetoacetate hydrolase (Fah) gene is disrupted by a neonatally lethal albino deletion that defines the hepatocyte-specific developmental regulation 1 (hsdr-1) locus

    SciTech Connect

    Klebig, M.L. Oak Ridge National Lab., TN ); Russell, L.B.; Rinchik, E.M. )

    1992-02-15

    Homozygous deletion of the hepatocyte-specific developmental regulation 1 (hsdr-1) locus in mouse chromosome 7 results in perinatal death and a pleiotropic syndrome characterized by ultrastructural abnormalities of the liver and kidney, failure of induction of a number of specific transcription units in the liver and kidney during late gestation, and marked overexpression of an enzyme that defends against oxidative stress. Previously, the breakpoints of two albino (c) deletions (c{sup 14CoS} and c{sup IFAFyh}) that genetically define hsdr-1 were localized, on a long-range map, in the vicinity of the distal breakpoint of a viable albino deletion (c{sup 24R75M}) that breaks proximally within the c locus. Here the authors report the use of a probe derived from a deletion breakpoint fusion fragment cloned from c{sup 24R75M}/c{sup 24R75M} DNA to clone a breakpoint fusion fragment caused by the c{sup 14CoS} deletion. The proximal breakpoint of the c{sup 14CoS} deletion was discovered to disrupt a gene (Fah) encoding fumarylacetoacetate hydrolase, the last enzyme in the tyrosine degradation pathway. These mouse mutants may also provide models for the human genetic disorder hereditary tyrosinemia, which is associated with fumarylacetoacetate hydrolase deficiency and liver and kidney dysfunction.

  20. Deletion mapping of four loci defined by N-ethyl-N-nitrosourea-induced postimplantation-lethal mutations within the pid-Hbb region of mouse chromosome 7

    SciTech Connect

    Rinchik, E.M.; Carpenter, D.A.; Long, C.L. )

    1993-12-01

    As part of a long-term effort to refine the physical and functional maps of the Fes-Hbb region of mouse chromosome 7, four loci [l(7)1Rn, l(7)2Rn, l(7)3Rn, l(7)4Rn] defined by N-ethyl-N-nitrosourea (ENU)-induced, prenatally lethal mutations were mapped by means of trans complementation crosses to mice carrying lethal deletions of the mouse chromosome-7 albino (c) locus. Each locus was assigned to a defined subregion of the deletions map at the distal end of the Fes-Hbb interval. Of particular use for this mapping were preimplantation-lethal deletions having distal breakpoints localized between pid and Omp. Hemizygosity or homozygosity for each of the ENU-induced lethals was found to arrest development after uterine implantation; the specific time of postimplantation death varied, and depended on both the mutation itself and on whether it was hemizygous or homozygous. Based on their map positions outside of and distal to deletions that cause death at preimplantation stages, these ENU-induced mutations identify loci, necessary for postimplantation development, that could not have been discovered by phenotypic analyses of mice homozygous for any albino deletion. The mapping of these loci to specific genetic intervals defined by deletion breakpoints suggests a number of positional-cloning strategies for the molecular isolation of these genes. Phenotypic and genetic analyses of these mutations should provide useful information on the functional composition of the corresponding segment of the human genome (perhaps human 11q13.5). 28 refs., 1 fig., 3 tabs.

  1. Deletion mapping of four loci defined by N-ethyl-N-nitrosourea-induced postimplantation-lethal mutations within the pid-Hbb region of mouse chromosome 7.

    PubMed

    Rinchik, E M; Carpenter, D A; Long, C L

    1993-12-01

    As part of a long-term effort to refine the physical and functional maps of the Fes-Hbb region of mouse chromosome 7, four loci [l(7)1Rn, l(7)2Rn, l(7)3Rn, l(7)4Rn] defined by N-ethyl-N-nitrosourea (ENU)-induced, prenatally lethal mutations were mapped by means of trans complementation crosses to mice carrying lethal deletions of the mouse chromosome-7 albino (c) locus. Each locus was assigned to a defined subregion of the deletion map at the distal end of the Fes-Hbb interval. Of particular use for this mapping were preimplantation-lethal deletions having distal breakpoints localized between pid and Omp. Hemizygosity or homozygosity for each of the ENU-induced lethals was found to arrest development after uterine implantation; the specific time of postimplantation death varied, and depended on both the mutation itself and on whether it was hemizygous or homozygous. Based on their map positions outside of and distal to deletions that cause death at preimplantation stages, these ENU-induced mutations identify loci, necessary for postimplantation development, that could not have been discovered by phenotypic analyses of mice homozygous for any albino deletion. The mapping of these loci to specific genetic intervals defined by deletion breakpoints suggests a number of positional-cloning strategies for the molecular isolation of these genes. Phenotypic and genetic analyses of these mutations should provide useful information on the functional composition of the corresponding segment of the human genome (perhaps human 11q13.5).

  2. Assignment of the genes encoding the human chloride channels, CLCNKA and CLCNKB, to 1p36 and of CLCN3 to 4q32-q33 by in situ hybridization

    SciTech Connect

    Saito-Ohara, Fumiko; Uchida, Shinichi; Takeuchi, Yasuo

    1996-09-01

    This report describes the localization of the genes encoding the human chloride channels, CLCNKA and CLCNKB, to human chromosome 1p36 and of CLCN3 to human chromosome 4q32-33 using fluorescence in situ hybridization. Mutations in these voltage-gated chloride channel genes have been implicated in various hereditary diseases. 18 refs., 1 fig.

  3. Jumping translocations of 1q12 in multiple myeloma: a novel mechanism for deletion of 17p in cytogenetically defined high-risk disease

    PubMed Central

    Tian, Erming; Heuck, Christoph J.; Epstein, Joshua; Johann, Donald J.; Swanson, Charles M.; Lukacs, Janet L.; Johnson, Marian; Binz, Regina; Boast, Angela; Sammartino, Gael; Usmani, Saad; Zangari, Maurizio; Waheed, Sarah; van Rhee, Frits; Barlogie, Bart

    2014-01-01

    Multiple myeloma (MM) is a B-cell malignancy driven in part by increasing copy number alterations (CNAs) during disease progression. Prognostically significant CNAs accumulate during clonal evolution and include gains of 1q21 and deletions of 17p, among others. Unfortunately, the mechanisms underlying the accumulation of CNAs and resulting subclonal heterogeneity in high-risk MM are poorly understood. To investigate the impact of jumping translocations of 1q12 (JT1q12) on receptor chromosomes (RCs) and subsequent clonal evolution, we analyzed specimens from 86 patients selected for unbalanced 1q12 aberrations by G-banding. Utilizing spectral karyotyping and locus-specific fluorescence in situ hybridization, we identified 10 patients with unexpected focal amplifications of an RC that subsequently translocated as part of a sequential JT1q12 to one or more additional RCs. Four patients exhibited amplification and translocation of 8q24 (MYC), 3 showed amplification of 16q11, and 1 each displayed amplification of 18q21.3 (BCL2), 18q23, or 4p16 (FGFR3). Unexpectedly, in 6 of 14 patients with the combination of the t(4;14) and deletion of 17p, we identified the loss of 17p as resulting from a JT1q12. Here, we provide evidence that the JT1q12 is a mechanism for the simultaneous gain of 1q21 and deletion of 17p in cytogenetically defined high-risk disease. PMID:24497533

  4. Activity, reconstitution, and accumulation of nitrogenase components in Azotobacter vinelandii mutant strains containing defined deletions within the nitrogenase structural gene cluster.

    PubMed Central

    Robinson, A C; Burgess, B K; Dean, D R

    1986-01-01

    The Azotobacter vinelandii genes encoding the nitrogenase structural components are clustered and ordered: nifH (Fe protein)-nifD (MoFe protein alpha subunit)-nifK (MoFe protein beta subunit). In this study various A. vinelandii mutant strains which contain defined deletions within the nitrogenase structural genes were isolated and studied. Mutants deleted for the nifD or nifK genes were still able to accumulate significant amounts of the unaltered MoFe protein subunit as well as active Fe protein. Extracts of such nifD or nifK deletion strains had no MoFe protein activity. However, active MoFe protein could be reconstituted by mixing extracts of the mutant strains. These results establish an approach for the purification of the individual MoFe protein subunits. Mutants lacking either or both of the MoFe protein subunits were still able to synthesize the iron-molybdenum cofactor (FeMo-cofactor), indicating that in A. vinelandii the FeMo-cofactor is preassembled and inserted into the MoFe protein. In contrast, a mutant strain lacking both the Fe protein and the MoFe protein failed to accumulate any detectable FeMo-cofactor. The further utility of specifically altered A. vinelandii strains for the study of the assembly, structure, and reactivity of nitrogenase is discussed. Images PMID:3457004

  5. Tumor cells with neuronal intermediate progenitor features define a subgroup of 1p/19q co-deleted anaplastic gliomas.

    PubMed

    Bielle, Franck; Ducray, François; Mokhtari, Karima; Dehais, Caroline; Adle-Biassette, Homa; Carpentier, Catherine; Chanut, Anaïs; Polivka, Marc; Poggioli, Sylvie; Rosenberg, Shai; Giry, Marine; Marie, Yannick; Duyckaerts, Charles; Sanson, Marc; Figarella-Branger, Dominique; Idbaih, Ahmed

    2016-08-20

    The integrated diagnosis of anaplastic oligodendroglioma, IDH mutant and 1p/19q co-deleted, grade III (O3(id) ) is a histomolecular entity that WHO 2016 classification distinguished from other diffuse gliomas by specific molecular alterations. In contrast, its cell portrait is less well known. The present study is focused on intertumor and intratumor, cell lineage-oriented, heterogeneity in O3(id) . Based on pathological, transcriptomic and immunophenotypic studies, a novel subgroup of newly diagnosed O3(id) overexpressing neuronal intermediate progenitor (NIP) genes was identified. This NIP overexpression pattern in O3(id) is associated with: (i) morphological and immunohistochemical similarities with embryonic subventricular zone, (ii) proliferating tumor cell subpopulation with NIP features including expression of INSM1 and no expression of SOX9, (iii) mutations in critical genes involved in NIP biology and, (iv) increased tumor necrosis. Interestingly, NIP tumor cell subpopulation increases in O3(id) recurrence compared with paired newly diagnosed tumors. Our results, validated in an independent cohort, emphasize intertumor and intratumor heterogeneity in O3(id) and identified a tumor cell subpopulation exhibiting NIP characteristics that is potentially critical in oncogenesis of O3(id) . A better understanding of spatial and temporal intratumor cell heterogeneity in O3(id) will open new therapeutic avenues overcoming resistance to current antitumor treatments.

  6. Passenger Deletions Generate Therapeutic Vulnerabilities in Cancer

    PubMed Central

    Muller, Florian L.; Colla, Simona; Aquilanti, Elisa; Manzo, Veronica; Genovese, Giannicola; Lee, Jaclyn; Eisenson, Dan; Narurkar, Rujuta; Deng, Pingna; Nezi, Luigi; Lee, Michelle; Hu, Baoli; Hu, Jian; Sahin, Ergun; Ong, Derrick; Fletcher-Sananikone, Eliot; Ho, Dennis; Kwong, Lawrence; Brennan, Cameron; Wang, Y. Alan; Chin, Lynda; DePinho, Ronald A.

    2013-01-01

    Inactivation of tumor suppressor genes via homozygous deletion is a prototypic event in the cancer genome, yet such deletions often encompass neighboring genes. We hypothesized that homozygous deletions in such passenger genes can expose cancer-specific therapeutic vulnerabilities in the case where the collaterally deleted gene is a member of a functionally redundant family of genes exercising an essential function. The glycolytic gene Enolase 1 (ENO1) in the 1p36 locus is deleted in Glioblastoma (GBM), which is tolerated by expression of ENO2. We demonstrate that shRNA-mediated extinction of ENO2 selectively inhibits growth, survival, and tumorigenic potential of ENO1-deleted GBM cells and that the enolase inhibitor phosphonoacetohydroxamate (PhAH) is selectively toxic to ENO1-deleted GBM cells relative to ENO1-intact GBM cells or normal astrocytes. The principle of collateral vulnerability should be applicable to other passenger deleted genes encoding functionally-redundant essential activities and provide an effective treatment strategy for cancers harboring such genomic events. PMID:22895339

  7. Linkage Analyses at the Chromosome 1 Loci 1q24-25 (HPC1), 1q42.2-43 (PCAP), and 1p36 (CAPB) in Families with Hereditary Prostate Cancer

    PubMed Central

    Berry, Rebecca; Schaid, Daniel J.; Smith, Jeffrey R.; French, Amy J.; Schroeder, Jennifer J.; McDonnell, Shannon K.; Peterson, Brett J.; Wang, Zheng-Yuan; Carpten, John D.; Roberts, Steven G.; Tester, David J.; Blute, Michael L.; Trent, Jeffrey M.; Thibodeau, Stephen N.

    2000-01-01

    Summary Recent studies suggest that hereditary prostate cancer (PRCA) is a complex disease, involving multiple susceptibility genes and variable phenotypic expression. Through linkage analysis, potential prostate cancer susceptibility loci have been mapped to 3 regions on chromosome 1. To investigate the reported linkage to these regions, we conducted linkage studies on 144 PRCA families by using microsatellite markers in regions 1q24-25 (HPC1) and 1q42.2-43 (PCAP). We also examined the 1p36 (CAPB) region in 13 PRCA families with at least one case of brain cancer. No significant evidence of linkage to the HPC1 or PCAP region was found when the entire data set was analyzed. However, weak evidence for linkage to HPC1 was observed in the subset of families with male-to-male transmission (n=102; maximum multipoint nonparametric linkage [NPL] 1.99, P=.03). Weak evidence for linkage with heterogeneity within this subset was also observed (HLOD 1.21, P=.02), with ∼20% of families linked. Although not statistically significant, suggestive evidence for linkage to PCAP was observed for the families (n=21) that met the three criteria of male-to-male transmission, average age of diagnosis <66 years, and ⩾5 affected individuals (maximum multipoint NPL 1.45, P=.08). There was no evidence for linkage to CAPB in the brain cancer–prostate cancer subset. These results strengthen the argument that prostate cancer is a heterogeneous disease and that multiple genetic and environmental factors may be important for its etiology. PMID:10677314

  8. Targeted deletion of the Nesp55 DMR defines another Gnas imprinting control region and provides a mouse model of autosomal dominant PHP-Ib.

    PubMed

    Fröhlich, Leopold F; Mrakovcic, Maria; Steinborn, Ralf; Chung, Ung-Il; Bastepe, Murat; Jüppner, Harald

    2010-05-18

    Approximately 100 genes undergo genomic imprinting. Mutations in fewer than 10 imprinted genetic loci, including GNAS, are associated with complex human diseases that differ phenotypically based on the parent transmitting the mutation. Besides the ubiquitously expressed Gsalpha, which is of broad biological importance, GNAS gives rise to an antisense transcript and to several Gsalpha variants that are transcribed from the nonmethylated parental allele. We previously identified two almost identical GNAS microdeletions extending from exon NESP55 to antisense (AS) exon 3 (delNESP55/delAS3-4). When inherited maternally, both deletions are associated with erasure of all maternal GNAS methylation imprints and autosomal-dominant pseudohypoparathyroidism type Ib, a disorder characterized by parathyroid hormone-resistant hypocalcemia and hyperphosphatemia. As for other imprinting disorders, the mechanisms resulting in abnormal GNAS methylation are largely unknown, in part because of a paucity of suitable animal models. We now showed in mice that deletion of the region equivalent to delNESP55/delAS3-4 on the paternal allele (DeltaNesp55(p)) leads to healthy animals without Gnas methylation changes. In contrast, mice carrying the deletion on the maternal allele (DeltaNesp55(m)) showed loss of all maternal Gnas methylation imprints, leading in kidney to increased 1A transcription and decreased Gsalpha mRNA levels, and to associated hypocalcemia, hyperphosphatemia, and secondary hyperparathyroidism. Besides representing a murine autosomal-dominant pseudohypoparathyroidism type Ib model and one of only few animal models for imprinted human disorders, our findings suggest that the Nesp55 differentially methylated region is an additional principal imprinting control region, which directs Gnas methylation and thereby affects expression of all maternal Gnas-derived transcripts.

  9. AluY-mediated germline deletion, duplication and somatic stem cell reversion in UBE2T defines a new subtype of Fanconi anemia.

    PubMed

    Virts, Elizabeth L; Jankowska, Anna; Mackay, Craig; Glaas, Marcel F; Wiek, Constanze; Kelich, Stephanie L; Lottmann, Nadine; Kennedy, Felicia M; Marchal, Christophe; Lehnert, Erik; Scharf, Rüdiger E; Dufour, Carlo; Lanciotti, Marina; Farruggia, Piero; Santoro, Alessandra; Savasan, Süreyya; Scheckenbach, Kathrin; Schipper, Jörg; Wagenmann, Martin; Lewis, Todd; Leffak, Michael; Farlow, Janice L; Foroud, Tatiana M; Honisch, Ellen; Niederacher, Dieter; Chakraborty, Sujata C; Vance, Gail H; Pruss, Dmitry; Timms, Kirsten M; Lanchbury, Jerry S; Alpi, Arno F; Hanenberg, Helmut

    2015-09-15

    Fanconi anemia (FA) is a rare inherited disorder clinically characterized by congenital malformations, progressive bone marrow failure and cancer susceptibility. At the cellular level, FA is associated with hypersensitivity to DNA-crosslinking genotoxins. Eight of 17 known FA genes assemble the FA E3 ligase complex, which catalyzes monoubiquitination of FANCD2 and is essential for replicative DNA crosslink repair. Here, we identify the first FA patient with biallelic germline mutations in the ubiquitin E2 conjugase UBE2T. Both mutations were aluY-mediated: a paternal deletion and maternal duplication of exons 2-6. These loss-of-function mutations in UBE2T induced a cellular phenotype similar to biallelic defects in early FA genes with the absence of FANCD2 monoubiquitination. The maternal duplication produced a mutant mRNA that could encode a functional protein but was degraded by nonsense-mediated mRNA decay. In the patient's hematopoietic stem cells, the maternal allele with the duplication of exons 2-6 spontaneously reverted to a wild-type allele by monoallelic recombination at the duplicated aluY repeat, thereby preventing bone marrow failure. Analysis of germline DNA of 814 normal individuals and 850 breast cancer patients for deletion or duplication of UBE2T exons 2-6 identified the deletion in only two controls, suggesting aluY-mediated recombinations within the UBE2T locus are rare and not associated with an increased breast cancer risk. Finally, a loss-of-function germline mutation in UBE2T was detected in a high-risk breast cancer patient with wild-type BRCA1/2. Cumulatively, we identified UBE2T as a bona fide FA gene (FANCT) that also may be a rare cancer susceptibility gene.

  10. AluY-mediated germline deletion, duplication and somatic stem cell reversion in UBE2T defines a new subtype of Fanconi anemia

    PubMed Central

    Virts, Elizabeth L.; Jankowska, Anna; Mackay, Craig; Glaas, Marcel F.; Wiek, Constanze; Kelich, Stephanie L.; Lottmann, Nadine; Kennedy, Felicia M.; Marchal, Christophe; Lehnert, Erik; Scharf, Rüdiger E.; Dufour, Carlo; Lanciotti, Marina; Farruggia, Piero; Santoro, Alessandra; Savasan, Süreyya; Scheckenbach, Kathrin; Schipper, Jörg; Wagenmann, Martin; Lewis, Todd; Leffak, Michael; Farlow, Janice L.; Foroud, Tatiana M.; Honisch, Ellen; Niederacher, Dieter; Chakraborty, Sujata C.; Vance, Gail H.; Pruss, Dmitry; Timms, Kirsten M.; Lanchbury, Jerry S.; Alpi, Arno F.; Hanenberg, Helmut

    2015-01-01

    Fanconi anemia (FA) is a rare inherited disorder clinically characterized by congenital malformations, progressive bone marrow failure and cancer susceptibility. At the cellular level, FA is associated with hypersensitivity to DNA-crosslinking genotoxins. Eight of 17 known FA genes assemble the FA E3 ligase complex, which catalyzes monoubiquitination of FANCD2 and is essential for replicative DNA crosslink repair. Here, we identify the first FA patient with biallelic germline mutations in the ubiquitin E2 conjugase UBE2T. Both mutations were aluY-mediated: a paternal deletion and maternal duplication of exons 2–6. These loss-of-function mutations in UBE2T induced a cellular phenotype similar to biallelic defects in early FA genes with the absence of FANCD2 monoubiquitination. The maternal duplication produced a mutant mRNA that could encode a functional protein but was degraded by nonsense-mediated mRNA decay. In the patient's hematopoietic stem cells, the maternal allele with the duplication of exons 2–6 spontaneously reverted to a wild-type allele by monoallelic recombination at the duplicated aluY repeat, thereby preventing bone marrow failure. Analysis of germline DNA of 814 normal individuals and 850 breast cancer patients for deletion or duplication of UBE2T exons 2–6 identified the deletion in only two controls, suggesting aluY-mediated recombinations within the UBE2T locus are rare and not associated with an increased breast cancer risk. Finally, a loss-of-function germline mutation in UBE2T was detected in a high-risk breast cancer patient with wild-type BRCA1/2. Cumulatively, we identified UBE2T as a bona fide FA gene (FANCT) that also may be a rare cancer susceptibility gene. PMID:26085575

  11. A deletion in the PHYD gene of the Arabidopsis Wassilewskija ecotype defines a role for phytochrome D in red/far-red light sensing.

    PubMed

    Aukerman, M J; Hirschfeld, M; Wester, L; Weaver, M; Clack, T; Amasino, R M; Sharrock, R A

    1997-08-01

    The PHYD gene of the Wassilewskija (Ws) ecotype of Arabidopsis contains a 14-bp deletion (the phyD-1 mutation) beginning at amino acid 29 of the reading frame, resulting in translation termination at a nonsense codon 138 nucleotides downstream of the deletion end point. Immunoblot analyses showed that Ws lacks phyD but contains normal levels of phyA, phyB, and phyC. By backcrossing into the Ws and Landsberg erecta genetic backgrounds, we constructed sibling pairs of PHYD+ and phyD-1 lines and of phyB- PHYD+ and phyB- phyD- lines. Hypocotyl lengths after growth under white or red light increased sequentially in strains that were B+D+, B+D-, B-D+, and B-D-. In the Ws genetic background, an increase in petiole length, a reduction in cotyledon area and in anthocyanin accumulation in seedling stems, a diminished effect of an end-of-day pulse of far-red light on hypocotyl elongation, and a decrease in the number of rosette leaves at the onset of flowering were also seen sequentially in these lines. Thus, phyD, which is approximately 80% identical in amino acid sequence to phyB, acts in conjunction with phyB in regulating many shade avoidance responses. The existence of the apparently naturally occurring phyD-1 mutation indicates that phyD is not essential in some natural environments.

  12. Structural Analysis and Deletion Mutagenesis Define Regions of QUIVER/SLEEPLESS that Are Responsible for Interactions with Shaker-Type Potassium Channels and Nicotinic Acetylcholine Receptors

    PubMed Central

    Wu, Meilin; Liu, Clifford Z.; Joiner, William J.

    2016-01-01

    Ly6 proteins are endogenous prototoxins found in most animals. They show striking structural and functional parallels to snake α-neurotoxins, including regulation of ion channels and cholinergic signaling. However, the structural contributions of Ly6 proteins to regulation of effector molecules is poorly understood. This question is particularly relevant to the Ly6 protein QUIVER/SLEEPLESS (QVR/SSS), which has previously been shown to suppress excitability and synaptic transmission by upregulating potassium (K) channels and downregulating nicotinic acetylcholine receptors (nAChRs) in wake-promoting neurons to facilitate sleep in Drosophila. Using deletion mutagenesis, co-immunoprecipitations, ion flux assays, surface labeling and confocal microscopy, we demonstrate that only loop 2 is required for many of the previously described properties of SSS in transfected cells, including interactions with K channels and nAChRs. Collectively our data suggest that QVR/SSS, and by extension perhaps other Ly6 proteins, target effector molecules using limited protein motifs. Mapping these motifs may be useful in rational design of drugs that mimic or suppress Ly6-effector interactions to modulate nervous system function. PMID:26828958

  13. Regional deletion and amplification on chromosome 6 in a uveal melanoma case without abnormalities on chromosomes 1p, 3 and 8.

    PubMed

    van Gils, Walter; Kilic, Emine; Brüggenwirth, Hennie T; Vaarwater, Jolanda; Verbiest, Michael M; Beverloo, Berna; van Til-Berg, Marjan E; Paridaens, Dion; Luyten, Gregorius P; de Klein, Annelies

    2008-02-01

    Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Loss of the long arm and gain of the short arm of chromosome 6 are frequently observed chromosomal aberrations in UM, together with loss of chromosome 1p36, loss of chromosome 3 and gain of chromosome 8. This suggests the presence of one or more oncogenes on 6p and tumor suppressor genes at 6q that are involved in UM development. Both regions, however, have not been well defined yet. Furthermore in other neoplasms gain of 6p and loss of 6q are frequently occurring events. In this case report, we describe the delineation of a partial gain on chromosome 6p and a partial deletion on 6q in a UM with the objective to pinpoint smaller candidate regions on chromosome 6 involved in UM development. Conventional cytogenetics, comparative genomic hybridization (CGH) and fluorescence in-situ hybridization (FISH) were used to delineate regions of loss and gain on chromosome 6 in this UM patient. With conventional cytogenetics a deleted region was found on chromosome 6q that was further delineated to a region ranging from 6q16.1 to 6q22 using CGH and FISH. A region of gain from 6pter to 6p21.2 was also demarcated with CGH and FISH. No other deletions or amplifications on recurrently involved chromosomes were found in this patient. This study indicates the presence of one or more tumor suppressor genes on chromosomal region 6q16.1-6q22 and the presence of one or more oncogenes on chromosomal region 6pter-6p21.2, which are likely to be important in UM and other tumors.

  14. Prevalence of selected genomic deletions and duplications in a French–Canadian population-based sample of newborns

    PubMed Central

    Tucker, Tracy; Giroux, Sylvie; Clément, Valérie; Langlois, Sylvie; Friedman, Jan M; Rousseau, François

    2013-01-01

    Chromosomal microarray analysis has identified many novel microdeletions or microduplications that produce neurodevelopmental disorders with a recognizable clinical phenotype and that are not observed in normal individuals. However, imbalance of other genomic regions is associated with a variable phenotype with intellectual disability (ID) or autism in some individuals but are also observed in completely normal individuals. Several large studies have reported the prevalence of copy number (CN) variants in people with particular features (e.g., ID, autism, schizophrenia, or epilepsy); few studies have investigated the prevalence of genomic CN changes in the general population. We used a high-throughput method to screen 6813 consecutive cord blood samples from a predominantly French–Canadian population to assess genomic CN in five genomic regions: 1p36, 15q11-q13, 16p11.2, 16p11.2-p12.2, and 22q11.2. We identified one deletion and one duplication within 1p36, two deletions of 15q11-q13, eight deletions of 16p11.2-p12.2, two deletions and five duplications of 16p11.2, and six duplications of 22q11.2. This study provides estimates of the frequency of CN variants in an unselected population. Our findings have important implications for genetic counseling. PMID:24498606

  15. Schizophrenia and chromosomal deletions

    SciTech Connect

    Lindsay, E.A.; Baldini, A.; Morris, M. A.

    1995-06-01

    Recent genetic linkage analysis studies have suggested the presence of a schizophrenia locus on the chromosomal region 22q11-q13. Schizophrenia has also been frequently observed in patients affected with velo-cardio-facial syndrome (VCFS), a disorder frequently associated with deletions within 22q11.1. It has been hypothesized that psychosis in VCFS may be due to deletion of the catechol-o-methyl transferase gene. Prompted by these observations, we screened for 22q11 deletions in a population of 100 schizophrenics selected from the Maryland Epidemiological Sample. Our results show that there are schizophrenic patients carrying a deletion of 22q11.1 and a mild VCFS phenotype that might remain unrecognized. These findings should encourage a search for a schizophrenia-susceptibility gene within the deleted region and alert those in clinical practice to the possible presence of a mild VCFS phenotype associated with schizophrenia. 9 refs.

  16. Correlation between array-comparative genomic hybridization-defined genomic gains and losses and survival: identification of 1p31-32 deletion as a prognostic factor in myeloma

    PubMed Central

    Chng, WJ; Gertz, MA; Chung, T-H; Van Wier, S; Keats, JJ; Baker, A; Bergsagel, PL; Carpten, J; Fonseca, R

    2010-01-01

    In this study, we correlated array-comparative genomic hybridization-defined abnormalities with survival in two different cohorts of patients treated with therapy based on high-dose melphalan with autologous stem-cell transplantation (64 from the Mayo Clinic and 67 from the University of Arkansas Medical School) and identified that several regions of genomic gains and losses were significantly associated with poorer survival. Three noncontiguous survival relevant regions covering 1p31-33 and two noncontiguous regions covering 20p12.3-12.1 were common between the two datasets. The prognostic relevance of these hotspots was validated in an independent cohort using fluorescent in situ hybridization, which showed that 1p31-32 loss is significantly associated with shorter survival (24.5 months versus 40 months, log-rank P-value=0.01), whereas 20p12 loss has a trend toward shorter survival (26.3 months versus 40 months, log-rank P-value=0.06). On multivariate analysis, 1p31-32 loss is an independent prognostic factor. On further analysis, the prognostic impact of 1p31-32 loss is due to shortening of post-relapse survival as there is no impact on complete response rates and progression-free survival. PMID:20220778

  17. Quantum deletion: Beyond the no-deletion principle

    SciTech Connect

    Adhikari, Satyabrata

    2005-11-15

    Suppose we are given two identical copies of an unknown quantum state and we wish to delete one copy from among the given two copies. The quantum no-deletion principle restricts us from perfectly deleting a copy but it does not prohibit us from deleting a copy approximately. Here we construct two types of a 'universal quantum deletion machine' which approximately deletes a copy such that the fidelity of deletion does not depend on the input state. The two types of universal quantum deletion machines are (1) a conventional deletion machine described by one unitary operator and (2) a modified deletion machine described by two unitary operators. Here it is shown that the modified deletion machine deletes a qubit with fidelity 3/4, which is the maximum limit for deleting an unknown quantum state. In addition to this we also show that the modified deletion machine retains the qubit in the first mode with average fidelity 0.77 (approx.) which is slightly greater than the fidelity of measurement for two given identical states, showing how precisely one can determine its state [S. Massar and S. Popescu, Phys. Rev. Lett. 74, 1259 (1995)]. We also show that the deletion machine itself is input state independent, i.e., the information is not hidden in the deleting machine, and hence we can delete the information completely from the deletion machine.

  18. Phenotypic characterization of rare interstitial deletion of chromosome 4

    PubMed Central

    Ismail, Samira; Helmy, Nivine A.; Mahmoud, Wael M.; El-Ruby, Mona O.

    2012-01-01

    Interstitial deletion of the long arm of chromosome 4 is rare. Patients with interstitial deletion of the long arm of chromosome 4 differ from those with terminal deletions. Phenotypes may be variable, depending upon the specific length and location of the deleted portion. Here, we report on a boy exhibiting most of the congenital malformations encountered in terminal 4q syndrome. The conventional karyotyping and Fluorescence in-situ hybridization revealed a de novo interstitial del (4)(q31q32). The current report is a further document highlighting that deletion of segment q31 could be contributing to the expression of most of the phenotype of 4q deletion syndrome. Using array comparative genome hybridization methodology is recommended for investigating further cases with similar segmental interstitial deletions to support and delineate findings and to define genes implicated in the pathogenesis of the disorder. PMID:27625821

  19. Genomic findings in patients with clinical suspicion of 22q11.2 deletion syndrome.

    PubMed

    Koczkowska, Magdalena; Wierzba, Jolanta; Śmigiel, Robert; Sąsiadek, Maria; Cabała, Magdalena; Ślężak, Ryszard; Iliszko, Mariola; Kardaś, Iwona; Limon, Janusz; Lipska-Ziętkiewicz, Beata S

    2017-02-01

    Chromosome 22q11.2 deletion syndrome, one of the most common human genomic syndromes, has highly heterogeneous clinical presentation. Patients usually harbor a 1.5 to 3 Mb hemizygous deletion at chromosome 22q11.2, resulting in pathognomic TBX1, CRKL and/or MAPK1 haploinsufficiency. However, there are some individuals with clinical features resembling the syndrome who are eventually diagnosed with genomic disorders affecting other chromosomal regions. The objective of this study was to evaluate the additive value of high-resolution array-CGH testing in the cohort of 41 patients with clinical features of 22q11.2 deletion syndrome and negative results of standard cytogenetic diagnostic testing (karyotype and FISH for 22q11.2 locus). Array-CGH analysis revealed no aberrations at chromosomes 22 or 10 allegedly related to the syndrome. Five (12.2 %) patients were found to have other genomic imbalances, namely 17q21.31 microdeletion syndrome (MIM#610443), 1p36 deletion syndrome (MIM#607872), NF1 microduplication syndrome (MIM#613675), chromosome 6pter-p24 deletion syndrome (MIM#612582) and a novel interstitial deletion at 3q26.31 of 0.65 Mb encompassing a dosage-dependent gene NAALADL2. Our study demonstrates that the implementation of array-CGH into the panel of classic diagnostic procedures adds significantly to their efficacy. It allows for detection of constitutional genomic imbalances in 12 % of subjects with negative result of karyotype and FISH targeted for 22q11.2 region. Moreover, if used as first-tier genetic test, the method would provide immediate diagnosis in ∼40 % phenotypic 22q11.2 deletion subjects.

  20. Submicroscopic deletions at 22q11.2: Variability of the clinical picture and delineation of a commonly deleted region

    SciTech Connect

    Lindsay, E.A.; Shaffer, L.G.; Greenberg, F.

    1995-03-27

    DiGeorge anomaly (DGA) and velo-cardio-facial syndrome (VCFS) are frequently associated with monosomy of chromosome region 22q11. Most patients have a submicroscopic deletion, recently estimated to be at least 1-2 Mb. It is not clear whether individuals who present with only some of the features of these conditions have the deletion, and if so, whether the size of the deletion varies from those with more classic phenotypes. We have used fluorescence in situ hybridization (FISH) to assess the deletion status of 85 individuals referred to us for molecular analysis, with a wide range of DGA-like or VCFS-like clinical features. The test probe used was the cosmid sc11.1, which detects two loci about 2 Mb apart in 22q11.2. Twenty-four patients carried the deletion. Of the deleted patients, most had classic DGA or VCFS phenotypes, but 6 deleted patients had mild phenotypes, including 2 with minor facial anomalies and velopharyngeal incompetence as the only presenting signs. Despite the great phenotypic variability among the deleted patients, none had a deletion smaller than the 2-Mb region defined by sc11.1. Smaller deletions were not detected in patients with particularly suggestive phenotypes who were not deleted for sc11.1, even when tested with two other probes from the DGA/VCFS region. 24 refs., 2 figs., 2 tabs.

  1. Hydrocephalus Defined

    MedlinePlus

    ... narrow pathways. CSF is in constant production and absorption; it has a defined pathway from the lateral ... there is an imbalance of production and/or absorption. With most types of hydrocephalus, the fluid gets ...

  2. Adding and Deleting Images

    EPA Pesticide Factsheets

    Images are added via the Drupal WebCMS Editor. Once an image is uploaded onto a page, it is available via the Library and your files. You can edit the metadata, delete the image permanently, and/or replace images on the Files tab.

  3. 17 CFR 145.4 - Public records available with identifying details deleted; nonpublic records available in...

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... identifying details deleted; nonpublic records available in abridged or summary form. 145.4 Section 145.4... § 145.4 Public records available with identifying details deleted; nonpublic records available in... privacy, the Commission may delete identifying details when it makes available “public records” as defined...

  4. 17 CFR 145.4 - Public records available with identifying details deleted; nonpublic records available in...

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... identifying details deleted; nonpublic records available in abridged or summary form. 145.4 Section 145.4... INFORMATION § 145.4 Public records available with identifying details deleted; nonpublic records available in... privacy, the Commission may delete identifying details when it makes available “public records” as defined...

  5. 17 CFR 145.4 - Public records available with identifying details deleted; nonpublic records available in...

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... identifying details deleted; nonpublic records available in abridged or summary form. 145.4 Section 145.4... § 145.4 Public records available with identifying details deleted; nonpublic records available in... privacy, the Commission may delete identifying details when it makes available “public records” as defined...

  6. 17 CFR 145.4 - Public records available with identifying details deleted; nonpublic records available in...

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... identifying details deleted; nonpublic records available in abridged or summary form. 145.4 Section 145.4... § 145.4 Public records available with identifying details deleted; nonpublic records available in... privacy, the Commission may delete identifying details when it makes available “public records” as defined...

  7. 17 CFR 145.4 - Public records available with identifying details deleted; nonpublic records available in...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... identifying details deleted; nonpublic records available in abridged or summary form. 145.4 Section 145.4... § 145.4 Public records available with identifying details deleted; nonpublic records available in... privacy, the Commission may delete identifying details when it makes available “public records” as defined...

  8. Molecular mapping within the mouse albino-deletion complex.

    PubMed

    Johnson, D K; Hand, R E; Rinchik, E M

    1989-11-01

    Induced germ-line deletion mutations in the mouse provide a malleable experimental system for in-depth molecular and functional analysis of large segments of the mammalian genome. To obtain an initial bank of molecular probes for the region of mouse chromosome 7 associated with the albino-deletion complex, random anonymous DNA clones, derived from a library constructed from flow-sorted chromosomes, were screened on DNAs from Mus musculus-Mus spretus F1 hybrids carrying large, multilocus, lethal albino deletions. Clones falling within a given deletion interval can easily be recognized because hybridization bands that represent restriction fragment length polymorphisms specific for the mutant (deleted) chromosome inherited from the M. musculus parent will be absent. Among 72 informative clones used as probes, one, which defines the locus D7OR1, mapped within two deletions that are 6-11 centimorgans in length. Submapping of this anonymous clone across a panel of 27 smaller deletions localized D7OR1 distal to a chromosomal subregion important for survival of the preimplantation embryo, proximal to globin [beta-chain (Hbb)], and near the shaker-1 (sh-1) locus. The results of these deletion-mapping experiments were also confirmed by standard three-point linkage analysis. This strategy for selection and rapid mapping of anonymous DNA probes to chromosomal segments corresponding to germ-line deletion mutations should contribute to the generation of more detailed physical and functional maps of genomic regions associated with mutant developmental phenotypes.

  9. Comprehensive Analysis of Pathogenic Deletion Variants in Fanconi Anemia Genes

    PubMed Central

    Flynn, Elizabeth K.; Kamat, Aparna; Lach, Francis P.; Donovan, Frank X.; Kimble, Danielle C.; Narisu, Narisu; Sanborn, Erica; Boulad, Farid; Davies, Stella M.; Gillio, Alfred P.; Harris, Richard E.; MacMillan, Margaret L.; Wagner, John E.; Smogorzewska, Agata; Auerbach, Arleen D.; Ostrander, Elaine A.; Chandrasekharappa, Settara C.

    2014-01-01

    Fanconi anemia (FA) is a rare recessive disease resulting from mutations in one of at least 16 different genes. Mutation types and phenotypic manifestations of FA are highly heterogeneous and influence the clinical management of the disease. We analyzed 202 FA families for large deletions, using high-resolution Comparative Genome Hybridization arrays (arrayCGH), Single Nucleotide Polymorphism arrays (SNParrays) and DNA sequencing. We found pathogenic deletions in 88 FANCA, seven FANCC, two FANCD2, and one FANCB families. We find 35% of FA families carry large deletions, accounting for 18% of all FA pathogenic variants. Cloning and sequencing across the deletion breakpoints revealed that 52 FANCA deletion ends, and one FANCC deletion end extended beyond the gene boundaries, potentially affecting neighboring genes with phenotypic consequences. Seventy-five percent of the FANCA deletions are Alu-Alu mediated, predominantly by AluY elements, and appear to be caused by Non-Allelic Homologous Recombination. Individual Alu hotspots were identified. Defining the haplotypes of four FANCA deletions shared by multiple families revealed that three share a common ancestry. Knowing the exact molecular changes that lead to the disease may be critical for a better understanding of the FA phenotype, and to gain insight into the mechanisms driving these pathogenic deletion variants. PMID:25168418

  10. Deletion (2)(q37)

    SciTech Connect

    Stratton, R.F.; Tolworthy, J.A.; Young, R.S.

    1994-06-01

    We report on a 5-month-old girl with widely spaced nipples, redundant nuchal skin, coarctation of the aorta, anal atresia with distal fistula, postnatal growth retardation, hypotonia, and sparse scalp hair. Initial clinical assessment suggested the diagnosis of Ullrich-Turner syndrome. Chromosome analysis showed a 46,XX,del(2)(q37) karyotype in peripheral lymphocytes. We compare her findings to those of other reported patients with terminal deletions of 2q. 8 refs., 2 figs., 1 tab.

  11. Defining chaos

    SciTech Connect

    Hunt, Brian R.; Ott, Edward

    2015-09-15

    In this paper, we propose, discuss, and illustrate a computationally feasible definition of chaos which can be applied very generally to situations that are commonly encountered, including attractors, repellers, and non-periodically forced systems. This definition is based on an entropy-like quantity, which we call “expansion entropy,” and we define chaos as occurring when this quantity is positive. We relate and compare expansion entropy to the well-known concept of topological entropy to which it is equivalent under appropriate conditions. We also present example illustrations, discuss computational implementations, and point out issues arising from attempts at giving definitions of chaos that are not entropy-based.

  12. Defining excellence.

    PubMed

    Mehl, B

    1993-05-01

    Excellence in the pharmacy profession, particularly pharmacy management, is defined. Several factors have a significant effect on the ability to reach a given level of excellence. The first is the economic and political climate in which pharmacists practice. Stricter controls, reduced resources, and the velocity of change all necessitate nurturing of values and a work ethic to maintain excellence. Excellence must be measured by the services provided with regard to the resources available; thus, the ability to achieve excellence is a true test of leadership and innovation. Excellence is also time dependent, and today's innovation becomes tomorrow's standard. Programs that raise the level of patient care, not those that aggrandize the profession, are the most important. In addition, basic services must be practiced at a level of excellence. Quality assessment is a way to improve care and bring medical treatment to a higher plane of excellence. For such assessment to be effective and not punitive, the philosophy of the program must be known, and the goal must be clear. Excellence in practice is dependent on factors such as political and social norms, standards of practice, available resources; perceptions, time, the motivation to progress to a higher level, and the continuous innovation required to reshape the profession to meet the needs of society.

  13. Velo-cardio-facial syndrome: Frequency and textent of 22q11 deletions

    SciTech Connect

    Lindsay, E.A.; Goldberg, R.; Jurecic, V.

    1995-07-03

    Velo-cardio-facial (VCFS) or Shprintzen syndrome is associated with deletions in a region of chromosome 22q11.2 also deleted in DiGeorge anomaly and some forms of congenital heart disease. Due to the variability of phenotype, the evaluation of the incidence of deletions has been hampered by uncertainty of diagnosis. In this study, 54 patients were diagnosed with VCFS by a single group of clinicians using homogeneous clinical criteria independent of the deletion status. Cell lines of these patients were established and the deletion status evaluated for three loci within the commonly deleted region at 22q11.2 using fluorescence in situ hybridization (FISH). In 81% of the patients all three loci were hemizygous. In one patient we observed a smaller interstitial deletion than that defined by the three loci. The phenotype of this patient was not different from that observed in patients with larger deletions. 22 refs., 2 figs., 1 tab.

  14. Subtelomeric Copy Number Variations: The Importance of 4p/4q Deletions in Patients with Congenital Anomalies and Developmental Disability.

    PubMed

    Novo-Filho, Gil M; Montenegro, Marília M; Zanardo, Évelin A; Dutra, Roberta L; Dias, Alexandre T; Piazzon, Flavia B; Costa, Taís V M M; Nascimento, Amom M; Honjo, Rachel S; Kim, Chong A; Kulikowski, Leslie D

    2016-01-01

    The most prevalent structural variations in the human genome are copy number variations (CNVs), which appear predominantly in the subtelomeric regions. Variable sizes of 4p/4q CNVs have been associated with several different psychiatric findings and developmental disability (DD). We analyzed 105 patients with congenital anomalies (CA) and developmental and/or intellectual disabilities (DD/ID) using MLPA subtelomeric specific kits (P036 /P070) and 4 of them using microarrays. We found abnormal subtelomeric CNVs in 15 patients (14.3%), including 8 patients with subtelomeric deletions at 4p/4q (53.3%). Additional genomic changes were observed at 1p36, 2q37.3, 5p15.3, 5q35.3, 8p23.3, 13q11, 14q32.3, 15q11.2, and Xq28/Yq12. This indicates the prevalence of independent deletions at 4p/4q, involving PIGG, TRIML2, and FRG1. Furthermore, we identified 15 genes with changes in copy number that contribute to neurological development and/or function, among them CRMP1, SORCS2, SLC25A4, and HELT. Our results highlight the association of genes with changes in copy number at 4p and 4q subtelomeric regions and the DD phenotype. Cytogenomic characterization of additional cases with distal deletions should help clarifying the role of subtelomeric CNVs in neurological diseases.

  15. Homozygosity for a null allele of SMIM1 defines the Vel-negative blood group phenotype.

    PubMed

    Storry, Jill R; Jöud, Magnus; Christophersen, Mikael Kronborg; Thuresson, Britt; Åkerström, Bo; Sojka, Birgitta Nilsson; Nilsson, Björn; Olsson, Martin L

    2013-05-01

    The Vel antigen is present on red blood cells (RBCs) from all humans except rare Vel-negative individuals who can form antibodies to Vel in response to transfusion or pregnancy. These antibodies may cause severe hemolytic reactions in blood recipients. We combined SNP profiling and transcriptional network modeling to link the Vel-negative phenotype to SMIM1, located in a 97-kb haplotype block on chromosome 1p36. This gene encodes a previously undiscovered, evolutionarily conserved transmembrane protein expressed on RBCs. Notably, 35 of 35 Vel-negative individuals were homozygous for a frameshift deletion of 17 bp in exon 3. Functional studies using antibodies raised against SMIM1 peptides confirmed a null phenotype in RBC membranes, and SMIM1 overexpression induced Vel expression. Genotype screening estimated that ~1 of 17 Swedish blood donors is a heterozygous deletion carrier and ~1 of 1,200 is a homozygous deletion knockout and enabled identification of Vel-negative donors. Our results establish SMIM1 as a new erythroid gene and Vel as a new blood group system.

  16. Characterization of Deletions of the HBA and HBB Loci by Array Comparative Genomic Hybridization.

    PubMed

    Sabath, Daniel E; Bender, Michael A; Sankaran, Vijay G; Vamos, Esther; Kentsis, Alex; Yi, Hye-Son; Greisman, Harvey A

    2016-01-01

    Thalassemia is among the most common genetic diseases worldwide. α-Thalassemia is usually caused by deletion of one or more of the duplicated HBA genes on chromosome 16. In contrast, most β-thalassemia results from point mutations that decrease or eliminate expression of the HBB gene on chromosome 11. Deletions within the HBB locus result in thalassemia or hereditary persistence of fetal Hb. Although routine diagnostic testing cannot distinguish thalassemia deletions from point mutations, deletional hereditary persistence of fetal Hb is notable for having an elevated HbF level with a normal mean corpuscular volume. A small number of deletions accounts for most α-thalassemias; in contrast, there are no predominant HBB deletions causing β-thalassemia. To facilitate the identification and characterization of deletions of the HBA and HBB globin loci, we performed array-based comparative genomic hybridization using a custom oligonucleotide microarray. We accurately mapped the breakpoints of known and previously uncharacterized HBB deletions defining previously uncharacterized deletion breakpoints by PCR amplification and sequencing. The array also successfully identified the common HBA deletions --(SEA) and --(FIL). In summary, comparative genomic hybridization can be used to characterize deletions of the HBA and HBB loci, allowing high-resolution characterization of novel deletions that are not readily detected by PCR-based methods. Copyright © 2016 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

  17. Characterization of Deletions of the HBA and HBB Loci by Array Comparative Genomic Hybridization

    PubMed Central

    Sabath, Daniel E.; Bender, Michael A.; Sankaran, Vijay G.; Vamos, Esther; Kentsis, Alex; Yi, Hye-Son; Greisman, Harvey A.

    2017-01-01

    Thalassemia is among the most common genetic diseases worldwide. α-Thalassemia is usually caused by deletion of one or more of the duplicated HBA genes on chromosome 16. In contrast, most β-thalassemia results from point mutations that decrease or eliminate expression of the HBB gene on chromosome 11. Deletions within the HBB locus result in thalassemia or hereditary persistence of fetal Hb. Although routine diagnostic testing cannot distinguish thalassemia deletions from point mutations, deletional hereditary persistence of fetal Hb is notable for having an elevated HbF level with a normal mean corpuscular volume. A small number of deletions accounts for most α-thalassemias; in contrast, there are no predominant HBB deletions causing β-thalassemia. To facilitate the identification and characterization of deletions of the HBA and HBB globin loci, we performed array-based comparative genomic hybridization using a custom oligonucleotide microarray. We accurately mapped the breakpoints of known and previously uncharacterized HBB deletions defining previously uncharacterized deletion breakpoints by PCR amplification and sequencing. The array also successfully identified the common HBA deletions --SEA and --FIL. In summary, comparative genomic hybridization can be used to characterize deletions of the HBA and HBB loci, allowing high-resolution characterization of novel deletions that are not readily detected by PCR-based methods. PMID:26612711

  18. Multigenerational autosomal dominant inheritance of 5p chromosomal deletions.

    PubMed

    Zhang, Bin; Willing, Marcia; Grange, Dorothy K; Shinawi, Marwan; Manwaring, Linda; Vineyard, Marisa; Kulkarni, Shashikant; Cottrell, Catherine E

    2016-03-01

    Deletion of the short arm of chromosome 5 (5p-) is associated with phenotypic features including a cat-like cry in infancy, dysmorphic facial features, microcephaly, and intellectual disability, and when encompassing a minimal critical region, may be defined as Cri-du-Chat syndrome (CdCS). Most 5p deletions are de novo in origin, and familial cases are often associated with translocation and inversion. Herein, we report three multigenerational families carrying 5p terminal deletions of different size transmitted in an autosomal dominant manner causing variable clinical findings. Terminal 5p deletions and the mode of inheritance were clinically characterized and molecularly analyzed by a combination of microarray and fluorescence in situ hybridization analyses. Shared phenotypic features documented in this cohort included neuropsychiatric findings, poor growth, and dysmorphic facial features. This study supports newly recognized effects of aberrant SEMA5A and CTNND2 dosage on severity of autistic and cognitive phenotypes. Comparative analysis of the breakpoints narrows the critical region for the cat-like cry down to an interval less than 1 Mb encompassing a candidate gene ICE1, which regulates small nuclear RNA transcription. This study also indicates that familial terminal 5p deletion is a rare presentation displaying intra- and inter-familial phenotypic variability, the latter of which may be attributed to size and gene content of the deletion. The observed intra-familial phenotypic heterogeneity suggests that additional modifying elements including genetic and environmental factors may have an impact on the clinical manifestations observed in 5p deletion carriers, and in time, further high resolution studies of 5p deletion breakpoints will continue to aid in defining genotype-phenotype correlations.

  19. Deletion involving D15S113 in a mother and son without Angelman syndrome: Refinement of the Angelman syndrome critical deletion region

    SciTech Connect

    Michaelis, R.C.; Skinner, S.A.; Lethco, B.A.

    1995-01-02

    Deletions of 15q11-q13 typically result in Angelman syndrome when inherited from the mother and Prader-Willi syndrome when inherited from the father. The critical deletion region for Angelman syndrome has recently been restricted by a report of an Angelman syndrome patient with a deletion spanning less than 200 kb around the D15S113 locus. We report here on a mother and son with a deletion of chromosome 15 that includes the D15S113 locus. The son has mild to moderate mental retardation and minor anomalies, while the mother has a borderline intellectual deficit and slightly downslanting palpebral fissures. Neither patient has the seizures, excessive laughter and hand clapping, ataxia or the facial anomalies which are characteristic of Angelman syndrome. The proximal boundary of the deletion in our patients lies between the D15S10 and The D15S113 loci. Our patients do not have Angelman syndrome, despite the deletion of the D15S113 marker. This suggests that the Angelman syndrome critical deletion region is now defined as the overlap between the deletion found in the previously reported Angelman syndrome patient and the region that is intact in our patients. 28 refs., 6 figs.

  20. A constitutional 5q23 deletion.

    PubMed Central

    Rivera, H; Simi, P; Rossi, S; Pardelli, L; Di Paolo, M C

    1990-01-01

    A 14 month old girl was found to have a deletion of the whole of band 5q23. By comparing 19 other cases monosomic for a part of the 5q13-q31 segment, the constitutional 5q interstitial deletions fall into two groups: adult patients with Gardner-like symptoms and mental retardation associated with deletion 5q21-q22, and patients (mostly children) with unspecific signs and symptoms and different deletions. Images PMID:2325108

  1. Molecular definition of the smallest region of deletion overlap in the Wolf-Hirschhorn syndrome

    SciTech Connect

    Gandelman, K.Y.; Gibson, L.; Meyn, M.S.; Yang-Feng, T.L. )

    1992-09-01

    Wolf-Hirschhorn syndrome (WHS), associated with a deletion of chromosome 4p, is characterized by mental and growth retardation and typical dysmorphism. A girl with clinical features of WHS was found to carry a subtle deletion of chromosome 4p. Initially suggested by high-resolution chromosome analysis, her deletion was confirmed by fluorescence in situ hybridization (FISH) with cosmid probes, E13, and Y2, of D4S113. To delineate this 4p deletion, the authors performed a series of FISH and pulsed-field gel electrophoresis analysis by using probes from 4p16.3. A deletion of [approximately]2.5 Mb with the breakpoint at [approximately]80 kb distal to D4S43 was defined in this patient and appears to be the smallest WHS deletion so far identified. To further refine the WHS critical region, they have studied three unrelated patients with presumptive 4p deletions, two resulting from unbalanced segregations of parental chromosomal translocations and one resulting from an apparently de novo unbalanced translocation. Larger deletions were identified in two patients with WHS. One patient who did not clinically present with WHS had a smaller deletion that thus eliminates the distal 100-300 kb from the telomere as being part of the WHS region. This study has localized the WHS region to [approximately]2 MB between D4S43 and D4S142. 37 refs., 4 figs., 1 tab.

  2. Deletion 14q and pericentric inversion 14.

    PubMed Central

    Nielsen, J; Homma, A; Rasmussen, K; Ried, E; Sorensen, K; Saldana-Garcia, P

    1978-01-01

    A woman with deletion 14q as well as inversion 14 is presented, and physical signs are compared with those of patients with deletion long arm 13. No previous case of deletion long arm 14 has been published. Images PMID:671492

  3. Bridging the Gene-Behavior Divide through Neuroimaging Deletion Syndromes: Velocardiofacial (22q11.2 Deletion) and Williams (7q11.23 Deletion) Syndromes

    PubMed Central

    Eisenberg, Daniel Paul; Jabbi, Mbemba; Berman, Karen Faith

    2010-01-01

    Investigating the relationship between genes and the neural substrates of complex human behavior promises to provide essential insight into the pathophysiology of mental disorders. One approach to this inquiry is through neuroimaging of individuals with microdeletion syndromes that manifest in specific neuropsychiatric phenotypes. Both Velocardiofacial Syndrome (VCFS) and Williams Syndrome (WS) involve haploinsufficiency of a relatively small set of identified genes on the one hand and association with distinct, clinically-relevant behavioral and cognitive profiles on the other hand. In VCFS, there is a deletion in chromosomal region 22q11.2 and a resultant predilection toward psychosis, poor arithmetic proficiency, and low performance intelligence quotients. In WS, there is a deletion in chromosomal region 7q11.23 and a resultant predilection toward hypersociability, non-social anxiety, impaired visuospatial construction, and often intellectual impairment. Structural and functional neuroimaging studies have begun not only to map these well-defined genetic alterations to systems-level brain abnormalities, but also to identify relationships between neural phenotypes and particular genes within the critical deletion regions. Though neuroimaging of both VCFS and WS presents specific, formidable methodological challenges, including comparison subject selection and accounting for neuroanatomical and vascular anomalies in patients, and many questions remain, the literature to date on these syndromes, reviewed herein, constitutes a fruitful “bottom-up” approach to defining gene-brain relationships. PMID:20206275

  4. Interstitial deletions are not the main mechanism leading to 18q deletions.

    PubMed Central

    Strathdee, G.; Harrison, W.; Riethman, H. C.; Goodart, S. A.; Overhauser, J.

    1994-01-01

    Most patients who present with the 18q- syndrome have an apparent terminal deletion of the long arm of chromosome 18. For precise phenotypic mapping of this syndrome, it is important to determine whether the deletions are terminal deletions or interstitial deletions. A human telomeric YAC clone has been identified that hybridizes specifically to the telomeric end of 18q. This clone was characterized and used to analyze seven patients with 18q deletions. By FISH and Southern blotting analysis, all patients were found to lack this chromosomal region on their deleted chromosome, demonstrating that the patients do not have cryptic interstitial deletions. Images Figure 2 Figure 1 Figure 3 PMID:8198131

  5. Deletion mapping of the Aequorea victoria green fluorescent protein.

    PubMed

    Dopf, J; Horiagon, T M

    1996-01-01

    Aequorea victoria green fluorescent protein (GFP) is a promising fluorescent marker which is active in a diverse array of prokaryotic and eukaryotic organisms. A key feature underlying the versatility of GFP is its capacity to undergo heterocyclic chromophore formation by cyclization of a tripeptide present in its primary sequence and thereby acquiring fluorescent activity in a variety of intracellular environments. In order to define further the primary structure requirements for chromophore formation and fluorescence in GFP, a series of N- and C-terminal GFP deletion variant expression vectors were created using the polymerase chain reaction. Scanning spectrofluorometric analyses of crude soluble protein extracts derived from eleven GFP expression constructs revealed that amino acid (aa) residues 2-232, of a total of 238 aa in the native protein, were required for the characteristic emission and absorption spectra of native GFP. Heterocyclic chromophore formation was assayed by comparing the absorption spectrum of GFP deletion variants over the 300-500-nm range to the absorption spectra of full-length GFP and GFP deletion variants missing the chromophore substrate domain from the primary sequence. GFP deletion variants lacking fluorescent activity showed no evidence of heterocyclic ring structure formation when the soluble extracts of their bacterial expression hosts were studied at pH 7.9. These observations suggest that the primary structure requirements for the fluorescent activity of GFP are relatively extensive and are compatible with the view that much of the primary structure serves an autocatalytic function.

  6. Characterization of frequently deleted 6q locus in prostate cancer.

    PubMed

    Sun, Mei; Srikantan, Vasantha; Ma, Lanfeng; Li, Jia; Zhang, Wei; Petrovics, Gyorgy; Makarem, Mazen; Strovel, Jeffrey W; Horrigan, Stephen G; Augustus, Meena; Sesterhenn, Isabell A; Moul, Judd W; Chandrasekharappa, Settara; Zou, Zhiqiang; Srivastava, Shiv

    2006-11-01

    The long arm of chromosome 6 is frequently deleted in diverse human neoplasms. Our previous study showed a minimum deletion region between markers D6S1056 and D6S300 on chromosome 6q in primary prostate cancer (CaP). In this study, we further refined a 200-kb minimal region of deletion (6qTSG1) centered around D6S1013 marker. The 6qTSG1 transcripts contained complex multiple splicing variants with low or absent expression in CaP cells. None of the transcripts identified contained open reading frames that code for a protein in the NCBI database. The expression of 6qTSG transcripts revealed interesting hormonal regulation relevant to CaP biology. Expression of 6q TSG transcript was induced in LNCaP cells that were cultured in charcoal-stripped serum medium suggesting an upregulation of 6qTSG transcript by androgen ablation and cell growth inhibition/apoptosis. Induction of 6qTSG1 expression in response to androgen ablation was abrogated in androgen-independent derivatives of LNCaP cells. In summary, we have defined a candidate CaP suppressor locus on chromosome 6q16.1, and deletions of this locus are frequently associated with prostate tumorigenesis. In the light of emerging role of noncoding RNAs in cancer biology including CaP, future investigations of 6qTSG11 locus is warranted.

  7. A novel 6.3 kb deletion and the Rare 27.6 kb Deletion Causing α(+)-Thalassemia in two Chinese Patients.

    PubMed

    Wang, Xian-Yao; Lin, Ming-Xiang; Lin, Min

    2016-09-01

    We report a novel -α(6.3) deletion and a rare -α(27.6) deletion causing α(+)-thalassemia (α(+)-thal), in two Chinese patients. One patient was a 35-year-old Chinese man with a mild α(+)-thal phenotype [mean corpuscular volume (MCV) 83.6 fL] and the Hb A2 level (2.5%) was close to borderline of the normal range. Multiplex ligation-dependent probe amplification (MLPA) revealed a novel 6344 bp deletion involving the entire HBA1 gene. Mapping by gap-polymerase chain reaction (gap-PCR) defined the exact breakpoint of this deletion to be NG_000006.1: g.31022_37366del6344. It was unique relative to other forms of α-thalassemia (α-thal) reported in the literature, and was designated as -α(6.3) deletion. The other patient, a 41-year-old woman had Hb H (β4) disease [hemoglobin (Hb) level of 8.9 g/dL] with a compound heterozygosity for the - -(SEA) (NG_000006.1: g.26264_45564del19301) deletion. The MLPA and gap-PCR methodologies confirmed the breakpoint (NG_000006.1: g.9079_36718del27640) and identified it as the rare -α(27.6) deletion.

  8. A Method for generating marker-less gene deletions in multidrug-resistant Acinetobacter baumannii

    PubMed Central

    2013-01-01

    Background Acinetobacter baumannii is an important nosocomial pathogen that has become increasingly resistant to multiple antibiotics. Genetic manipulation of MDR A. baumannii is useful especially for defining the contribution of each active efflux mechanism in multidrug resistance. Existing methods rely on the use of an antibiotic selection marker and are not suited for multiple gene deletions. Results A tellurite-resistant (sacB+, xylE+) suicide vector, pMo130-TelR, was created for deleting the adeFGH and adeIJK operons in two clinical MDR A. baumannii, DB and R2 from Singapore. Using a two-step selection, plasmid insertion recombinants (first-crossover) were selected for tellurite resistance and the deletion mutants (second-crossover) were then selected for loss of sacB. The DNA deletions were verified by PCR while loss of gene expression in the ΔadeFGH, ΔadeIJK and ΔadeFGHΔadeIJK deletion mutants was confirmed using qRT-PCR. The contribution of AdeFGH and AdeIJK pumps to MDR was defined by comparing antimicrobial susceptibilities of the isogenic mutants and the parental strains. The deletion of adeIJK produced no more than eight-fold increase in susceptibility to nalidixic acid, tetracycline, minocycline, tigecycline, clindamycin, trimethoprim and chloramphenicol, while the deletion of adeL-adeFGH operon alone had no impact on antimicrobial susceptibility. Dye accumulation assays using H33342 revealed increased dye retention in all deletion mutants, except for the R2ΔadeFGH mutant, where a decrease was observed. Increased accumulation of ethidium bromide was observed in the parental strains and all pump deletion mutants in the presence of efflux inhibitors. The efflux pump deletion mutants in this study revealed that only the AdeIJK, but not the AdeFGH RND pump, contributes to antimicrobial resistance and dye accumulation in MDR A. baumannii DB and R2. Conclusions The marker-less gene deletion method using pMo130-TelR is applicable for creating single and

  9. Deletion of 8p is an independent prognostic parameter in prostate cancer

    PubMed Central

    Galal, Rami; Möller-Koop, Christina; Barrow, Phillipp; Tsourlakis, Maria Christina; Jacobsen, Frank; Hinsch, Andrea; Wittmer, Corinna; Steurer, Stefan; Krech, Till; Büscheck, Franziska; Clauditz, Till Sebastian; Beyer, Burkhard; Wilczak, Waldemar; Graefen, Markus; Huland, Hartwig; Minner, Sarah; Schlomm, Thorsten; Sauter, Guido; Simon, Ronald

    2017-01-01

    Deletion of chromosome 8p is the second most frequent genomic alteration in prostate cancer. To better understand its clinical significance, 8p deletion was analyzed by fluorescence in-situ hybridization on a prostate cancer tissue microarray. 8p deletion was found in 2,581 of 7,017 cancers (36.8%), and was linked to unfavorable tumor phenotype. 8p deletion increased from 29.5% in 4,456 pT2 and 47.8% in 1,598 pT3a to 53.0% in 931 pT3b-pT4 cancers (P < 0,0001). Deletions of 8p were detected in 25.5% of 1,653 Gleason ≤ 3 + 3, 36.6% of 3,880 Gleason 3 + 4, 50.2% of 1,090 Gleason 4 + 3, and 51.1% of 354 Gleason ≥ 4 + 4 tumors (P < 0,0001). 8p deletions were strongly linked to biochemical recurrence (P < 0.0001) independently from established pre- and postoperative prognostic factors (P = 0.0100). However, analysis of morphologically defined subgroups revealed, that 8p deletion lacked prognostic significance in subgroups with very good (Gleason ≤ 3 + 3, 3 + 4 with ≤ 5% Gleason 4) or very poor prognosis (pT3b, Gleason ≥ 8, pN1). 8p deletions were markedly more frequent in cancers with (53.5%) than without PTEN deletions (36.4%; P < 0,0001) and were slightly more frequent in ERG-positive (40.9%) than in ERG-negative cancers (34.7%, P < 0.0001) due to the association with the ERG-associated PTEN deletion. Cancers with 8p/PTEN co-deletions had a strikingly worse prognosis than cancers with deletion of PTEN or 8p alone (P ≤ 0.0003). In summary, 8p deletion is an independent prognostic parameter in prostate cancer that may act synergistically with PTEN deletions. Even statistically independent prognostic biomarkers like 8p may have limited clinical impact in morphologically well defined high or low risk cancers. PMID:27880722

  10. Deletion of 150 kb in the minimal DiGeorge/velocardiofacial syndrome critical region in mouse.

    PubMed

    Kimber, W L; Hsieh, P; Hirotsune, S; Yuva-Paylor, L; Sutherland, H F; Chen, A; Ruiz-Lozano, P; Hoogstraten-Miller, S L; Chien, K R; Paylor, R; Scambler, P J; Wynshaw-Boris, A

    1999-11-01

    Deletions or rearrangements of human chromosome 22q11 lead to a variety of related clinical syndromes such as DiGeorge syndrome (DGS) and velo--cardiofacial syndrome (VCFS). In addition, patients with 22q11 deletions have an increased incidence of schizophrenia and several studies have mapped susceptibility loci for schizophrenia to this region. Human molecular genetic studies have so far failed to identify the crucial genes or disruption mechanisms that result in these disorders. We have used gene targeting in the mouse to delete a defined region within the conserved DGS critical region (DGCR) on mouse chromosome 16 to prospectively investigate the role of the mouse DGCR in 22q11 syndromes. The deletion spans a conserved portion ( approximately 150 kb) of the proximal region of the DGCR, containing at least seven genes ( Znf74l, Idd, Tsk1, Tsk2, Es2, Gscl and Ctp ). Mice heterozygous for this deletion display no findings of DGS/VCFS in either inbred or mixed backgrounds. However, heterozygous mice display an increase in prepulse inhibition of the startle response, a manifestation of sensorimotor gating that is reduced in humans with schizophrenia. Homozygous deleted mice die soon after implantation, demonstrating that the deleted region contains genes essential for early post-implantation embryonic development. These results suggest that heterozygous deletion of this portion of the DGCR is sufficient for sensorimotor gating abnormalities, but not sufficient to produce the common features of DGS/VCFS in the mouse.

  11. Defining needs, defining systems: a critical analysis.

    PubMed

    Dill, A

    1993-08-01

    This article examines the model of need assessment commonly used in social service programs for older adults. Whereas this model defines need as an individual attribute, remediable through programmatic intervention, an alternative formulation suggests that organizational imperatives shape the definition of client need while obscuring their own role in the production of this information. A case study and historical analysis assess the roots of this process and its consequences for clients, staff, and aging programs.

  12. Deletion mapping of the spinal muscular atrophy region

    SciTech Connect

    Burgein, L.; Lefebvre, S.; Buriet, P.

    1994-09-01

    Autosomal recessive childhood spinal muscular atrophies (SMA) are divided into severe (Type I) and mild forms (Types II and III). Using a combination of fine genetic and physical mapping, we constructed a YAC contig of the 5q13 region spanning the disease locus and showed the presence of low copy-repeats in this region. Allele segregation was analyzed at the closest genetic loci detected by markers C212 and C272 in 201 SMA families. Inherited and de novo deletions were observed in 9 unrelated SMA patients. Moreover, deletion events were statistically associated with type I SMA patients as shown by marked heterozygosity deficiency for the loci studied. Genetic analysis with all polymorphic DNA markers derived from the YAC contig has allowed to define the smallest rearrangement between the loci detected by C161 and the C212-C272-C171, covering a 1Mb interval. A large scale physical map of this region has been constructed using pulsed field gel electrophoresis (PFGE) and rare cutter restriction endonucleases. Comparison of the physical map has been established both in patients harboring deletions and unaffected controls using various anonymous probes derived from the YAC contig. This analysis has allowed us to define a physical interval in which at least a portion of the SMA gene must be located. Search for genes within this interval will contribute to the identification of the disease gene or genes.

  13. Parametrically defined differential equations

    NASA Astrophysics Data System (ADS)

    Polyanin, A. D.; Zhurov, A. I.

    2017-01-01

    The paper deals with nonlinear ordinary differential equations defined parametrically by two relations. It proposes techniques to reduce such equations, of the first or second order, to standard systems of ordinary differential equations. It obtains the general solution to some classes of nonlinear parametrically defined ODEs dependent on arbitrary functions. It outlines procedures for the numerical solution of the Cauchy problem for parametrically defined differential equations.

  14. Variable Deletion Strategies in Canonical Correlation Analysis.

    ERIC Educational Resources Information Center

    Tanguma, Jesus

    This paper presents three variable deletion strategies in canonical correlation analysis. All three strategies are illustrated by examples. The first strategy uses the canonical communality (h2) coefficients of the three functions to decide which variable to delete. The second function also uses the canonical communality coefficients, but only…

  15. Partial monosomy 7 with interstitial deletions in two infants with differing congenital abnormalities.

    PubMed Central

    Crawfurd, M D; Kessel, I; Liberman, M; McKeown, J A; Mandalia, P Y; Ridler, M A

    1979-01-01

    Two cases of interstitial deletion of chromosome 7 are presented, one involving the short arm and the other the long arm. The cytogenetic, dermatoglyphic, and clinical findings are compared with previously reported cases of chromosome 7 deletion. The patient with a short arm deletion differs clinically from the previously reported cases but, in common with a least one previous case, has a low total finger ridge count. His interstitial deletion involving the 7p13 leads to 7p21 region also differs from 7p deletions reported in earlier cases. The patient with a long arm deletion has an interstitial loss of the region between 7q11 and 7q21, corresponding to one of three groups of 7q deletion that have been recognised. The phenotypic changes in this group are less well defined than in the other two and the patient presented here differs clinically from the previously reported cases, apart from one phenotypically normal mosaic case, in lacking morphological abnormalities. He shares with one previous case both epilepsy and a high intensity of dermal ridge patterns. Images PMID:537019

  16. Interstitial deletions of chromosome 6q: genotype-phenotype correlation utilizing array CGH.

    PubMed

    Klein, O D; Cotter, P D; Moore, M W; Zanko, A; Gilats, M; Epstein, C J; Conte, F; Rauen, K A

    2007-03-01

    Interstitial deletions of the long arm of chromosome 6 are relatively rare, with fewer than 100 cases reported. Phenotypic variation is in large part due to differences in size and location of the segmental aneuploidy. We report three new patients with interstitial deletions of chromosome 6q defined at the molecular level by array comparative genomic hybridization (array CGH). In two of three cases, the molecular breakpoints differed from those indicated by conventional karyotyping, demonstrating the enhanced resolution of array CGH. Two patients had minimal deletions of 6 and 8.8 Mb involving 6q16.2-->q21, and the third patient had a deletion of 11.3 Mb spanning 6q15-->q21. All three had developmental delay, craniofacial dysmorphology, and functional eye disorders, suggesting that genes affecting brain and craniofacial development are located in 6q16.2-->q21, the deleted region common to all three patients. Furthermore, gene(s) for discordant phenotypic features, such as central diabetes insipidus, may reside at 6q15, the monosomic region unique to patient 3. All three cases described here showed loss of paternal alleles within the deleted segment, providing further evidence of the predominantly paternal origin for 6q deletions and rearrangements.

  17. Molecular genetics of the brown (b)-locus region of mouse chromosome 4. II. Complementation analyses of lethal brown deletions.

    PubMed

    Rinchik, E M

    1994-07-01

    Numerous new mutations at the brown (b) locus in mouse chromosome 4 have been recovered over the years in germ-cell mutagenesis experiments performed at the Oak Ridge National Laboratory. A large series of radiation- and chemical-induced b mutations known to be chromosomal deletions, and also known to be prenatally lethal when homozygous, were analyzed by pairwise complementation crosses as well as by pseudodominance tests involving flanking loci defined by externally visible phenotypes. These crosses were designed to determine the extent of each deletion on the genetic and phenotype map of the chromosomal region surrounding the b locus; the crosses also provided basic data that assigned deletions to complementation groups and defined four new loci associated with aberrancies in normal development. Specifically, the pseudodominance tests identified deletions that include the proximally mapping whirler (wi) and the distally mapping depilated (dep) genes, thereby bracketing these loci defined by visible developmental abnormalities with landmarks (deletion breakpoints) that are easily identified on the physical map. Furthermore, the complementation crosses, which were supplemented with additional crosses that allowed determination of the gross time of lethality of selected deletions, defined four new loci required for normal development. Homozygous deletion of one of these loci (b-associated fitness, baf) results in a runting syndrome evident during postnatal development; deletion of one locus [l(4)2Rn] causes death in the late gestation/neonatal period; and deletion of either of two loci [l(4)1Rn or l(4)3Rn] results in embryonic death, most likely in pre-, peri- or postimplantation stages. The placement of these new functionally defined loci on the evolving molecular map of the b region should be useful for continuing the analysis of the roles played in development by genes in this segment of chromosome 4.

  18. Defining Overweight and Obesity

    MedlinePlus

    ... this? Submit Button Our Division About Us Nutrition Physical Activity Overweight & Obesity Healthy Weight Breastfeeding Micronutrient Malnutrition State and Local Programs Defining Adult Overweight and Obesity Recommend on Facebook ...

  19. Deletions of CDKN2C in Multiple Myeloma: Biological and Clinical Implications

    PubMed Central

    Leone, Paola E.; Walker, Brian A.; Jenner, Matthew W.; Chiecchio, Laura; Dagrada, GianPaolo; Protheroe, Rebecca K.M.; Johnson, David C.; Dickens, Nicholas J.; Brito, Jose Luis; Else, Monica; Gonzalez, David; Ross, Fiona M.; Chen-Kiang, Selina; Davies, Faith E.; Morgan, Gareth J.

    2008-01-01

    Purpose: Deletions of chromosome 1 have been described in 7-40% of cases of myeloma with inconsistent clinical consequences. CDKN2C at 1p32.3 has been identified in myeloma cell lines as the potential target of the deletion. We tested the clinical impact of 1p deletion and used high resolution techniques to define to role of CDKN2C in primary patient material. Experimental Design: We analyzed 515 cases of monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM) and newly diagnosed multiple myeloma (MM) using fluorescence in situ hybridization (FISH) for deletions of CDNK2C. In 78 myeloma cases, we carried out Affymetrix SNP mapping and U133 plus 2.0 expression arrays. In addition, we performed mutation, methylation and western blotting analysis. Results: By FISH we identified deletion of 1p32.3 (CDKN2C) in 3/66 MGUS (4.5%), 4/39 SMM (10.3%) and 55/369 MM cases (15%). We examined the impact of copy number change at CDKN2C on overall survival (OS), and found that the cases with either hemizygous or homozygous deletion of CDKN2C had a worse OS compared to cases which were intact at this region (22 months vs. 38 months; P = 0.003). Using gene mapping we identified three homozygous deletions (HD) at 1p32.3, containing CDKN2C, all of which lacked expression of CDKN2C. Cases with HD of CDKN2C were the most proliferative myelomas, defined by an expression-based proliferation index, consistent with its biological function as a cyclin-dependent kinase inhibitor. Conclusions: Our results suggest that deletions of CDKN2C are important in the progression and clinical outcome of myeloma. PMID:18829482

  20. Targeted chromosomal deletions and inversions in zebrafish.

    PubMed

    Gupta, Ankit; Hall, Victoria L; Kok, Fatma O; Shin, Masahiro; McNulty, Joseph C; Lawson, Nathan D; Wolfe, Scot A

    2013-06-01

    Zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs) provide powerful platforms for genome editing in plants and animals. Typically, a single nuclease is sufficient to disrupt the function of protein-coding genes through the introduction of microdeletions or insertions that cause frameshifts within an early coding exon. However, interrogating the function of cis-regulatory modules or noncoding RNAs in many instances requires the excision of this element from the genome. In human cell lines and invertebrates, two nucleases targeting the same chromosome can promote the deletion of intervening genomic segments with modest efficiencies. We have examined the feasibility of using this approach to delete chromosomal segments within the zebrafish genome, which would facilitate the functional study of large noncoding sequences in a vertebrate model of development. Herein, we demonstrate that segmental deletions within the zebrafish genome can be generated at multiple loci and are efficiently transmitted through the germline. Using two nucleases, we have successfully generated deletions of up to 69 kb at rates sufficient for germline transmission (1%-15%) and have excised an entire lincRNA gene and enhancer element. Larger deletions (5.5 Mb) can be generated in somatic cells, but at lower frequency (0.7%). Segmental inversions have also been generated, but the efficiency of these events is lower than the corresponding deletions. The ability to efficiently delete genomic segments in a vertebrate developmental system will facilitate the study of functional noncoding elements on an organismic level.

  1. Deletion mapping of chr. 16q in breast cancer using dual color FISH with highly efficient cosmid contig probes

    SciTech Connect

    Nakamura, H.; Sakamoto, M.; Kallioniemi, A.; Kallioniemi, O.; Matsumura, K.; Waldman, F.; Pinkel, D.; Gray, I.W. ); Doggett, N. )

    1993-01-01

    Breast cancer is known to have frequent allelic loss on the long arm of chr.16. To facilitate identification of genes from 16q involved in breast cancer progression, the authors performed dual color FISH with chr. 16 centromeric reference probe (detected in red) and locus-specific cosmid contigs (in green) distributed along chr.16q in order to define the region of common deletion. Six breast cancer cell lines and 23 primary breast cancers were examined. Cells were scored as carrying a deletion when the fraction of cells showing fewer locus specific signals than centromeric signals plus the fraction of cells showing less than two locus specific signals was greater than 0.5. Five of 6 breast cancer cell lines showed deletion on chr.16q. The region around 16q24 was deleted in 4 of 5 cell lines. Breast cancer cases were preselected on the basis of p53 deletion by FISH because of the high correlation between p53 deletion and 17q deletion. Chr.16q deletions were found in 13 cases (56%); 10 cases (43%) with the break point between the centromere and 17q12, and 3 cases (13%) with the break point between 16q13 and 16q21. Intriguingly, the common region of deletion in clinical breast cancer, 16q22 to q24, appears to include the locus (16q22.1) for E-cadherin gene encoding cell adhesion protein which might be associated with progression of breast cancer.

  2. Large deletion in the NF1 gene associated with dysmorphism

    SciTech Connect

    Hughes, H.E.; Maynard, J.; Sourour, E.

    1994-09-01

    Neurofibromatosis type 1 is an autosomal dominant disorder with a prevalence of 1 in 3000. The major clinical features of the disease include cafe-au-lait spots, neurofibromas, Lisch nodules and auxillary freckling. Six sporadic NF1 patients with dysmorphism and intellectual impairment have been described to have a large deletion extending beyond the NF1 gene. We report another spordiac NF1 patient with severe developmental delay, early growth failure and dysmorphism (not Noonan-like) associated with a large deletion involving the NF1 gene. A panel of 12 polymorphic DNA markers within 4 cM of the NF1 gene were used to screen for the NF1 gene rearrangements. With all the polymorphic markers, only a single band was ever observed in this affected individual. However, with DNA probe EW301 which maps to 17p, a biparental inheritance was observed. Analysis with several microsatellite markers indicated that this patient had not inherited an allele from the father. A reduction in the hybridization signal was also observed when DNA from this patient was screened with cDNAs AE25, P5, B3A, and an extragenic marker EW206, clearly indicating hemizygosity at these loci. The combined evidence of dosage reduction and biparental inheritance with DNA marker EW301 indictates that this patient has a deletion of paternal origin rather than uniparental disomy. Pulsed-field gel electrophoresis has not, so far, revealed any evidence of an altered band pattern; however, studies are continuing. FISH analysis is currently in progress using YACs and cosmids to define the extent of this deletion.

  3. Defining Risk Drinking

    PubMed Central

    Dawson, Deborah A.

    2011-01-01

    Many efforts to prevent alcohol-related harm are aimed at reducing risk drinking. This article outlines the many conceptual and methodological challenges to defining risk drinking. It summarizes recent evidence regarding associations of various aspects of alcohol consumption with chronic and acute alcohol-related harms, including mortality, morbidity, injury, and alcohol use disorders, and summarizes the study designs most appropriate to defining risk thresholds for these types of harm. In addition, it presents an international overview of low-risk drinking guidelines from more than 20 countries, illustrating the wide range of interpretations of the scientific evidence related to risk drinking. This article also explores the impact of drink size on defining risk drinking and describes variation in what is considered to be a standard drink across populations. Actual and standard drink sizes differ in the United States, and this discrepancy affects definitions of risk drinking and prevention efforts. PMID:22330212

  4. Complex mutations & subpopulations of deletions at exon 19 of EGFR in NSCLC revealed by next generation sequencing: potential clinical implications.

    PubMed

    Marchetti, Antonio; Del Grammastro, Maela; Filice, Giampaolo; Felicioni, Lara; Rossi, Giulio; Graziano, Paolo; Sartori, Giuliana; Leone, Alvaro; Malatesta, Sara; Iacono, Michele; Guetti, Luigi; Viola, Patrizia; Mucilli, Felice; Cuccurullo, Franco; Buttitta, Fiamma

    2012-01-01

    Microdeletions at exon 19 are the most frequent genetic alterations affecting the Epidermal Growth Factor Receptor (EGFR) gene in non-small cell lung cancer (NSCLC) and they are strongly associated with response to treatment with tyrosine kinase inhibitors. A series of 116 NSCLC DNA samples investigated by Sanger Sequencing (SS), including 106 samples carrying exon 19 EGFR deletions and 10 without deletions (control samples), were subjected to deep next generation sequencing (NGS). All samples with deletions at SS showed deletions with NGS. No deletions were seen in control cases. In 93 (88%) cases, deletions detected by NGS were exactly corresponding to those identified by SS. In 13 cases (12%) NGS resolved deletions not accurately characterized by SS. In 21 (20%) cases the NGS showed presence of complex (double/multiple) frameshift deletions producing a net in-frame change. In 5 of these cases the SS could not define the exact sequence of mutant alleles, in the other 16 cases the results obtained by SS were conventionally considered as deletions plus insertions. Different interpretative hypotheses for complex mutations are discussed. In 46 (43%) tumors deep NGS showed, for the first time to our knowledge, subpopulations of DNA molecules carrying EGFR deletions different from the main one. Each of these subpopulations accounted for 0.1% to 17% of the genomic DNA in the different tumors investigated. Our findings suggest that a region in exon 19 is highly unstable in a large proportion of patients carrying EGFR deletions. As a corollary to this study, NGS data were compared with those obtained by immunohistochemistry using the 6B6 anti-mutant EGFR antibody. The immunoreaction was E746-A750del specific. In conclusion, NGS analysis of EGFR exon 19 in NSCLCs allowed us to formulate a new interpretative hypothesis for complex mutations and revealed the presence of subpopulations of deletions with potential pathogenetic and clinical impact.

  5. Defining the Human Microbiome

    PubMed Central

    Ursell, Luke K; Metcalf, Jessica L; Parfrey, Laura Wegener; Knight, Rob

    2012-01-01

    Rapidly developing sequencing methods and analytical techniques are enhancing our ability to understand the human microbiome, and, indeed, how we define the microbiome and its constituents. In this review we highlight recent research that expands our ability to understand the human microbiome on different spatial and temporal scales, including daily timeseries datasets spanning months. Furthermore, we discuss emerging concepts related to defining operational taxonomic units, diversity indices, core versus transient microbiomes and the possibility of enterotypes. Additional advances in sequencing technology and in our understanding of the microbiome will provide exciting prospects for exploiting the microbiota for personalized medicine. PMID:22861806

  6. Clinically relevant single gene or intragenic deletions encompassing critical neurodevelopmental genes in patients with developmental delay, mental retardation, and/or autism spectrum disorders.

    PubMed

    Mikhail, Fady M; Lose, Edward J; Robin, Nathaniel H; Descartes, Maria D; Rutledge, Katherine D; Rutledge, S Lane; Korf, Bruce R; Carroll, Andrew J

    2011-10-01

    Recent studies suggest that copy number variations (CNVs) encompassing several genes involved in neurodevelopmental pathways are associated with a variety of neuropsychiatric phenotypes, including developmental delay (DD), mental retardation (MR), and autism spectrum disorders (ASDs). Here we present eight patients in a cohort of approximately 1,200 patients referred for clinical array CGH testing for various neurodevelopmental phenotypes,whowere identified to carry small (<1.0Mb with the majority <500 kb) either total gene or intragenic deletions encompassing critical synaptic and other neurodevelopmental genes. The presentations of these patients included variable degrees of DD, speech problems, learning disabilities, MR, autistic-like features, and mild non-specific dysmorphic features. These genes belong to four functional categories, including neuronal transcription factor genes (NFIA at 1p31.3, MEF2C at 5q14.3, andCAMAT1at 1p36.23p36.31), neuron-specific splicing factor genes (RBFOX1 at 16p13.2p13.3), genes involved in synapse formation and maintenance (CNTNAP2 at 7q35 and LRFN5 at 14q21.2), and genes involved in neurotransmission (CHRNA7 at 15q13.3 and IL1RAPL1 at Xp21.2p21.3). Our report expands the list of neurodevelopmental genes deleted in various neurobehavioral phenotypes, expands the phenotypes caused by haploinsufficiency of previously reported critical neurodevelopmental genes, and elucidates the clinical relevance and need for careful clinical interpretation of some small CNVs<500 kb. This report also suggests that small clinically relevant deletions encompassing critical synaptic and other neurodevelopmental genes can present clinically with various neurobehavioral phenotypes, which implies the existence of overlapping neuronal pathways in the pathogenesis of these phenotypes.

  7. 78 FR 21916 - Procurement List; Proposed Additions and Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-04-12

    ... Commissaryagency (DECA), Fort Lee, VA Deletions The following products and service are proposed for deletion from... Activity: Defense Commissaryagency (DECA), Fort Lee, VA Barry S. Lineback, Director, Business...

  8. Transition Coordinators: Define Yourselves.

    ERIC Educational Resources Information Center

    Asselin, Susan B.; Todd-Allen, Mary; deFur, Sharon

    1998-01-01

    Describes a technique that was used successfully to identify the changing roles and responsibilities of special educators as transition coordinators. The Developing a Curriculum (DACUM) model uses people who are currently working in the occupation to define job responsibilities. The duties of a transition coordinator are identified. (CR)

  9. Defining Effective Teaching

    ERIC Educational Resources Information Center

    Layne, L.

    2012-01-01

    The author looks at the meaning of specific terminology commonly used in student surveys: "effective teaching." The research seeks to determine if there is a difference in how "effective teaching" is defined by those taking student surveys and those interpreting the results. To investigate this difference, a sample group of professors and students…

  10. Defining Mathematical Giftedness

    ERIC Educational Resources Information Center

    Parish, Linda

    2014-01-01

    This theoretical paper outlines the process of defining "mathematical giftedness" for a present study on how primary school teaching shapes the mindsets of children who are mathematically gifted. Mathematical giftedness is not a badge of honour or some special value attributed to a child who has achieved something exceptional.…

  11. On Defining Mass

    ERIC Educational Resources Information Center

    Hecht, Eugene

    2011-01-01

    Though central to any pedagogical development of physics, the concept of mass is still not well understood. Properly defining mass has proven to be far more daunting than contemporary textbooks would have us believe. And yet today the origin of mass is one of the most aggressively pursued areas of research in all of physics. Much of the excitement…

  12. Defining Supports Geometry

    ERIC Educational Resources Information Center

    Stephan, Michelle L.; McManus, George E.; Dickey, Ashley L.; Arb, Maxwell S.

    2012-01-01

    The process of developing definitions is underemphasized in most mathematics instruction. Investing time in constructing meaning is well worth the return in terms of the knowledge it imparts. In this article, the authors present a third approach to "defining," called "constructive." It involves modifying students' previous understanding of a term…

  13. On Defining Mass

    ERIC Educational Resources Information Center

    Hecht, Eugene

    2011-01-01

    Though central to any pedagogical development of physics, the concept of mass is still not well understood. Properly defining mass has proven to be far more daunting than contemporary textbooks would have us believe. And yet today the origin of mass is one of the most aggressively pursued areas of research in all of physics. Much of the excitement…

  14. Defining the Language Arts.

    ERIC Educational Resources Information Center

    Barth, Patte, Ed.

    1994-01-01

    This issue of "Basic Education" presents articles that discuss, respectively, defining the language arts, an agenda for English, the benefits of two languages, a new teacher (presently teaching English in a foreign country) looking ahead, and the Shaker Fellowships awarded by the school district in Shaker Heights, Ohio. Articles in the…

  15. Defined by Limitations

    ERIC Educational Resources Information Center

    Arriola, Sonya; Murphy, Katy

    2010-01-01

    Undocumented students are a population defined by limitations. Their lack of legal residency and any supporting paperwork (e.g., Social Security number, government issued identification) renders them essentially invisible to the American and state governments. They cannot legally work. In many states, they cannot legally drive. After the age of…

  16. Defining in Classroom Activities.

    ERIC Educational Resources Information Center

    Mariotti, Maria Alessandra; Fischbein, Efraim

    1997-01-01

    Discusses some aspects of the defining process in geometrical context in the reference frame of the theory of "figural concepts." Presents analysis of some examples taken from a teaching experiment at the sixth-grade level. Contains 30 references. (Author/ASK)

  17. Molecular definition of deletions of different segments of distal 5p that result in distinct phenotypic features

    SciTech Connect

    Church, D.M.; Bengtsson, U.; Wasmuth, J.J.; Niebuhr, E.

    1995-05-01

    Cri du chat syndrome (CDC) is a segmental aneusomy associated with deletions of chromosome 5p15. In an effort to define regions that produce the phenotypes associated with CDC, we have analyzed deletions from 17 patients. The majority of these patients had atypical CDC features or were asymptomatic. Using these patients, we have mapped several phenotypes associated with deletions of 5p, including speech delay, catlike cry, newborn facial dysmorphism, and adult facial dysmorphism. This phenotypic map should provide a framework with which to begin identification of genes associated with various phenotypic features associated with deletions of distal 5p. We have also analyzed the parental origin of the de novo deletions, to determine if genomic imprinting could be occurring in this region. In addition, we have isolated cosmids that could be useful for both prenatal and postnatal assessments of del5(p) individuals. 25 refs., 4 figs., 3 tabs.

  18. PRN 91-1: Procedures for Voluntarily Requesting Deletion of Approved Uses from Registered Labels

    EPA Pesticide Factsheets

    This pesticide registration notice defines procedures for registrants to use when they with to request an amendment to delete one or more uses from an approved registration, and it summarizes the actions the Agency will take in response to such requests.

  19. Domain Specific Attentional Impairments in Children with Chromosome 22Q11.2 Deletion Syndrome

    ERIC Educational Resources Information Center

    Bish, Joel P.; Chiodo, Renee; Mattei, Victoria; Simon, Tony J.

    2007-01-01

    One of the defining cognitive characteristics of the chromosome 22q deletion syndrome (DS22q11.2) is visuospatial processing impairments. The purpose of this study was to investigate and extend the specific attentional profile of children with this disorder using both an object-based attention task and an inhibition of return task. A group of…

  20. Defining Dynamic Route Structure

    NASA Technical Reports Server (NTRS)

    Zelinski, Shannon; Jastrzebski, Michael

    2011-01-01

    This poster describes a method for defining route structure from flight tracks. Dynamically generated route structures could be useful in guiding dynamic airspace configuration and helping controllers retain situational awareness under dynamically changing traffic conditions. Individual merge and diverge intersections between pairs of flights are identified, clustered, and grouped into nodes of a route structure network. Links are placed between nodes to represent major traffic flows. A parametric analysis determined the algorithm input parameters producing route structures of current day flight plans that are closest to todays airway structure. These parameters are then used to define and analyze the dynamic route structure over the course of a day for current day flight paths. Route structures are also compared between current day flight paths and more user preferred paths such as great circle and weather avoidance routing.

  1. Defining the fascial system.

    PubMed

    Adstrum, Sue; Hedley, Gil; Schleip, Robert; Stecco, Carla; Yucesoy, Can A

    2017-01-01

    Fascia is a widely used yet indistinctly defined anatomical term that is concurrently applied to the description of soft collagenous connective tissue, distinct sections of membranous tissue, and a body pervading soft connective tissue system. Inconsistent use of this term is causing concern due to its potential to confuse technical communication about fascia in global, multiple discipline- and multiple profession-spanning discourse environments. The Fascia Research Society acted to address this issue by establishing a Fascia Nomenclature Committee (FNC) whose purpose was to clarify the terminology relating to fascia. This committee has since developed and defined the terms a fascia, and, more recently, the fascial system. This article reports on the FNC's proposed definition of the fascial system. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. [To define internet addiction].

    PubMed

    Tonioni, Federico

    2013-01-01

    Internet addiction is a new behavioral disorder difficult to define, especially when referring to young teenagers who make great use of web-mediated relationships. It's necessary to separate the cases of overt dependency on those in which the abuse of internet seems to have a different value, offering the only way to achieve the possible relationship. Internet is mediating a new way of communicating and thinking, this may favor the onset of clinical phenomena intended to surprise.

  3. Defining and Diagnosing Sepsis.

    PubMed

    Scott, Michael C

    2017-02-01

    Sepsis is a heterogeneous clinical syndrome that encompasses infections of many different types and severity. Not surprisingly, it has confounded most attempts to apply a single definition, which has also limited the ability to develop a set of reliable diagnostic criteria. It is perhaps best defined as the different clinical syndromes produced by an immune response to infection that causes harm to the body beyond that of the local effects of the infection.

  4. Deletion of chromosome 21 in a girl with congenital hypothyroidism and mild mental retardation

    SciTech Connect

    Ahlbom, B.E.; Anneren, G.; Sidenvall, R.

    1996-08-23

    We report on a girl with a large interstitial deletion of the long arm of chromosome 21 and with mild mental retardation, congenital hypothyroidism, and hyperopia. The deletion [del(21)(q11.1-q22.1)] extends molecularly from marker D21S215 to D21S213. The distal breakpoint is not clearly defined but is situated between markers D21S213 and IFNAR. This patient has the largest deletion of chromosome 21 known without having severe mental retardation or malformations. The deletion does not involve the {open_quotes}Down syndrome chromosome{close_quotes} region, the region of chromosome 21 which in trisomy causes most of the manifestations of Down syndrome. Apparently, the proximal part of the long arm of chromosome 21 does not include genes that are responsible for severe clinical effects in the event of either deletion or duplication, since several reported patients with either trisomy or deletion of this region have mild phenotypic abnormalities. Congenital hypothyroidism is much more common in Down syndrome than in the average population. Thus, the congenital hypothyroidism of the present patient might indicate that there is one or several genes on the proximal part of chromosome 21, which might be of importance for the thyroid function. 24 refs., 4 figs., 2 tabs.

  5. A stochastic evolution model for residue Insertion-Deletion Independent from Substitution.

    PubMed

    Lèbre, Sophie; Michel, Christian J

    2010-12-01

    We develop here a new class of stochastic models of gene evolution based on residue Insertion-Deletion Independent from Substitution (IDIS). Indeed, in contrast to all existing evolution models, insertions and deletions are modeled here by a concept in population dynamics. Therefore, they are not only independent from each other, but also independent from the substitution process. After a separate stochastic analysis of the substitution and the insertion-deletion processes, we obtain a matrix differential equation combining these two processes defining the IDIS model. By deriving a general solution, we give an analytical expression of the residue occurrence probability at evolution time t as a function of a substitution rate matrix, an insertion rate vector, a deletion rate and an initial residue probability vector. Various mathematical properties of the IDIS model in relation with time t are derived: time scale, time step, time inversion and sequence length. Particular expressions of the nucleotide occurrence probability at time t are given for classical substitution rate matrices in various biological contexts: equal insertion rate, insertion-deletion only and substitution only. All these expressions can be directly used for biological evolutionary applications. The IDIS model shows a strongly different stochastic behavior from the classical substitution only model when compared on a gene dataset. Indeed, by considering three processes of residue insertion, deletion and substitution independently from each other, it allows a more realistic representation of gene evolution and opens new directions and applications in this research field. Copyright © 2010 Elsevier Ltd. All rights reserved.

  6. Chromosome 9p deletions in cutaneous malignant melanoma tumors: the minimal deleted region involves markers outside the p16 (CDKN2) gene.

    PubMed Central

    Puig, S; Ruiz, A; Lázaro, C; Castel, T; Lynch, M; Palou, J; Vilalta, A; Weissenbach, J; Mascaro, J M; Estivill, X

    1995-01-01

    We have analyzed 12 microsatellite markers on chromosome 9p in 54 paired cutaneous malignant melanoma (CMM) tumors and normal tissues. Forty-six percent of the tumors, including two in situ CMMs, showed loss of heterozygosity (LOH) at 9p. Only one tumor was homozygously deleted for 9p markers. The smallest deleted region was defined by five tumors and included markers D9S126 to D9S259. Loss of eight or more markers correlated significantly with worse prognosis (P < .002). Among the primary tumors, 87.5% of those with large deletions have a high risk of metastasis, as compared with only 18% of those without deletions or with loss of fewer than 8 markers (P < .001). It was not possible to demonstrate homozygous deletions of p16 in any of the CMM tumors. In four tumors, the LOH for 9p markers did not involve p16. The reported data suggest the existence of several tumor suppressor genes at 9p that are involved in the predisposition to and/or progression of CMM and exclude p16 from involvement in the early development of some melanoma tumors. Images Figure 3 Figure 4 Figure 5 PMID:7668266

  7. Molecular definition of 22q11 deletions in 151 velo-cardio-facial syndrome patients.

    PubMed Central

    Carlson, C; Sirotkin, H; Pandita, R; Goldberg, R; McKie, J; Wadey, R; Patanjali, S R; Weissman, S M; Anyane-Yeboa, K; Warburton, D; Scambler, P; Shprintzen, R; Kucherlapati, R; Morrow, B E

    1997-01-01

    Velo-cardio-facial syndrome (VCFS) is a relatively common developmental disorder characterized by craniofacial anomalies and conotruncal heart defects. Many VCFS patients have hemizygous deletions for a part of 22q11, suggesting that haploinsufficiency in this region is responsible for its etiology. Because most cases of VCFS are sporadic, portions of 22q11 may be prone to rearrangement. To understand the molecular basis for chromosomal deletions, we defined the extent of the deletion, by genotyping 151 VCFS patients and performing haplotype analysis on 105, using 15 consecutive polymorphic markers in 22q11. We found that 83% had a deletion and >90% of these had a similar approximately 3 Mb deletion, suggesting that sequences flanking the common breakpoints are susceptible to rearrangement. We found no correlation between the presence or size of the deletion and the phenotype. To further define the chromosomal breakpoints among the VCFS patients, we developed somatic hybrid cell lines from a set of VCFS patients. An 11-kb resolution physical map of a 1,080-kb region that includes deletion breakpoints was constructed, incorporating genes and expressed sequence tags (ESTs) isolated by the hybridization selection method. The ordered markers were used to examine the two separated copies of chromosome 22 in the somatic hybrid cell lines. In some cases, we were able to map the chromosome breakpoints within a single cosmid. A 480-kb critical region for VCFS has been delineated, including the genes for GSCL, CTP, CLTD, HIRA, and TMVCF, as well as a number of novel ordered ESTs. PMID:9326327

  8. Molecular analyses of 17p11.2 deletions in 62 Smith-Magenis syndrome patients

    SciTech Connect

    Juyal, R.C.; Figuera, L.E.; Hauge, X.

    1996-05-01

    Smith-Magenis syndrome (SMS) is a clinically recognizable, multiple congenital anomalies/mental retardation syndrome caused by an interstitial deletion involving band p11.2 of chromosome 17. Toward the molecular definition of the interval defining this microdeletion syndrome, 62 unrelated SMS patients in conjunction with 70 available unaffected parents were molecularly analyzed with respect to the presence or absence of 14 loci in the proximal region of the short arm of chromosome 17. A multifaceted approach was used to determine deletion status at the various loci that combined (1) FISH analysis, (2) PCR and Southern analysis of somatic cell hybrids retaining the deleted chromosome 17 from selected patients, and (3) genotype determination of patients for whom a parent(s) was available at four microsatellite marker loci and at four loci with associated RFLPs. The relative order of two novel anonymous markers and a new microsatellite marker was determined in 17p11.2. The results confirmed that the proximal deletion breakpoint in the majority of SMS patients is located between markers D17S58 (EW301) and D17S446 (FG1) within the 17p11.1-17p11.2 region. The common distal breakpoint was mapped between markers cCI17-638, which lies distal to D17S71, and cCI17-498, which lies proximal to the Charcot Marie-Tooth disease type 1A locus. The locus D17S258 was found to be deleted in all 62 patients, and probes from this region can be used for diagnosis of the SMS deletion by FISH. Ten patients demonstrated molecularly distinct deletions; of these, two patients had smaller deletions and will enable the definition of the critical interval for SMS. 49 refs.

  9. De novo 911 Kb interstitial deletion on chromosome 1q43 in a boy with mental retardation and short stature.

    PubMed

    Perrone, M D; Rocca, M S; Bruno, I; Faletra, F; Pecile, V; Gasparini, P

    2012-02-01

    Patients with distal deletions of chromosome 1q have a recognizable syndrome that includes microcephaly, hypoplasia or agenesis of the corpus callosum, and psychomotor retardation. Although these symptoms have been attributed to deletions of 1q42-1q44, the minimal chromosomal region involved has not yet defined. In this report, we describe a 7 years old male with mental retardation, cryptorchid testes, short stature and alopecia carrying only an interstitial de novo deletion of 911 Kb in the 1q43 region (239,597,095-240,508,817) encompassing three genes CHRM3, RPS7P5 and FMN2. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

  10. Severe fetal and neonatal hemolytic anemia due to a 198 kb deletion removing the complete β-globin gene cluster.

    PubMed

    Verhovsek, Madeleine; Shah, Nirmish R; Wilcox, Ibifiri; Koenig, Sara C; Barros, Tiago; Thornburg, Courtney D; Steinberg, Martin H; Luo, Hong-yuan; Chui, David H K

    2012-11-01

    Fetal and neonatal hemolytic anemia can be caused by (γδβ)(0)-thalassemia deletions of the β-globin gene cluster. Many of these deletions have not been well characterized, and diagnostic tests are not readily available, thus hampering carrier detection, family counseling, and antenatal diagnosis. We report and define a 198 kb deletion removing the entire β-globin gene cluster, which was found in members of a multigeneration family of Irish/Scottish descent. The proband had life-threatening fetal and neonatal hemolytic anemia which subsided by 1 year of age. Copyright © 2012 Wiley Periodicals, Inc.

  11. Defining functional dyspepsia.

    PubMed

    Mearin, Fermín; Calleja, José Luis

    2011-12-01

    Dyspepsia and functional dyspepsia represent a highly significant public health issue. A good definition of dyspepsia is key for helping us to better approach symptoms, decision making, and therapy indications.During the last few years many attempts were made at establishing a definition of dyspepsia. Results were little successful on most occasions, and clear discrepancies arose on whether symptoms should be associated with digestion, which types of symptoms were to be included, which anatomic location should symptoms have, etc.The Rome III Committee defined dyspepsia as "a symptom or set of symptoms that most physicians consider to originate from the gastroduodenal area", including the following: postprandial heaviness, early satiety, and epigastric pain or burning. Two new entities were defined: a) food-induced dyspeptic symptoms (postprandial distress syndrome); and b) epigastric pain (epigastric pain syndrome). These and other definitions have shown both strengths and weaknesses. At times they have been much too complex, at times much too simple; furthermore, they have commonly erred on the side of being inaccurate and impractical. On the other hand, some (the most recent ones) are difficult to translate into the Spanish language. In a meeting of gastroenterologists with a special interest in digestive functional disorders, the various aspects of dyspepsia definition were discussed and put to the vote, and the following conclusions were arrived at: dyspepsia is defined as a set of symptoms, either related or unrelated to food ingestion, localized on the upper half of the abdomen. They include: a) epigastric discomfort (as a category of severity) or pain; b) postprandial heaviness; and c) early satiety. Associated complaints include: nausea, belching, bloating, and epigastric burn (heartburn). All these must be scored according to severity and frequency. Furthermore, psychological factors may be involved in the origin of functional dyspepsia. On the other hand

  12. HDR-del: A tool based on Hamming distance for prioritizing pathogenic chromosomal deletions in exome sequencing.

    PubMed

    Imai, Atsuko; Kohda, Masakazu; Kobayashi, Kaori; Hirata, Tomoko; Sakata, Yasushi; Murayama, Kei; Ohtake, Akira; Okazaki, Yasushi; Nakaya, Akihiro; Ott, Jurg

    2017-07-19

    High-density oligonucleotide arrays have been widely used to detect pathogenic chromosomal deletions. In addition to high-density oligonucleotide arrays, programs using whole exome sequencing have become available for estimating copy number variations using depth of coverage. Here we propose a new statistical method, HDR-del, to prioritize pathogenic chromosomal deletions based on Hamming distance in exome sequencing. In vcf (Variant Call Format) files generated from exome sequencing, hemizygous chromosomal deletion regions lack heterozygous variants and lead to apparent long runs of homozygosity (ROH). In our HDR-del approach, we calculate the "difference" in heterozygous status between an affected individual and control individuals using the Hamming Distance Ratio (HDR) over all candidate chromosomal deletion regions defined as ROH longer than 1Mbp. Using a suitable test statistic, which is expected to be large for a true pathogenic deletion region, we prioritize candidate chromosomal deletion regions based on this statistic. In our approach, we were able to considerably narrow down true pathogenic chromosomal deletion regions, which were confirmed by high-density oligonucleotide arrays in four mitochondrial disease patients. Our HDR-del approach represents an easy method for detecting chromosomal deletions. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  13. 19 CFR 142.49 - Deletion of C-4 Code.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... director may temporarily or permanently delete an entry filer's C-4 Code without providing the participant.... Entry filers may delete C-4 Codes from Line Release by notifying the port director in writing on a Deletion Data Loading Sheet. Such notification shall state the C-4 Code which is to be deleted, the port...

  14. 19 CFR 142.49 - Deletion of C-4 Code.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... director may temporarily or permanently delete an entry filer's C-4 Code without providing the participant.... Entry filers may delete C-4 Codes from Line Release by notifying the port director in writing on a Deletion Data Loading Sheet. Such notification shall state the C-4 Code which is to be deleted, the port...

  15. 46 CFR 67.171 - Deletion; requirement and procedure.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 46 Shipping 2 2014-10-01 2014-10-01 false Deletion; requirement and procedure. 67.171 Section 67...; Requirement for Exchange, Replacement, Deletion, Cancellation § 67.171 Deletion; requirement and procedure. (a... provided in § 67.161, and the vessel is subject to deletion from the roll of actively documented vessels...

  16. 46 CFR 67.171 - Deletion; requirement and procedure.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 2 2013-10-01 2013-10-01 false Deletion; requirement and procedure. 67.171 Section 67...; Requirement for Exchange, Replacement, Deletion, Cancellation § 67.171 Deletion; requirement and procedure. (a... provided in § 67.161, and the vessel is subject to deletion from the roll of actively documented vessels...

  17. 46 CFR 67.171 - Deletion; requirement and procedure.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 2 2011-10-01 2011-10-01 false Deletion; requirement and procedure. 67.171 Section 67...; Requirement for Exchange, Replacement, Deletion, Cancellation § 67.171 Deletion; requirement and procedure. (a... provided in § 67.161, and the vessel is subject to deletion from the roll of actively documented vessels...

  18. 46 CFR 67.171 - Deletion; requirement and procedure.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 2 2012-10-01 2012-10-01 false Deletion; requirement and procedure. 67.171 Section 67...; Requirement for Exchange, Replacement, Deletion, Cancellation § 67.171 Deletion; requirement and procedure. (a... provided in § 67.161, and the vessel is subject to deletion from the roll of actively documented vessels...

  19. 46 CFR 67.171 - Deletion; requirement and procedure.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 2 2010-10-01 2010-10-01 false Deletion; requirement and procedure. 67.171 Section 67...; Requirement for Exchange, Replacement, Deletion, Cancellation § 67.171 Deletion; requirement and procedure. (a... provided in § 67.161, and the vessel is subject to deletion from the roll of actively documented vessels...

  20. Defining periodontal health

    PubMed Central

    2015-01-01

    Assessment of the periodontium has relied exclusively on a variety of physical measurements (e.g., attachment level, probing depth, bone loss, mobility, recession, degree of inflammation, etc.) in relation to various case definitions of periodontal disease. Periodontal health was often an afterthought and was simply defined as the absence of the signs and symptoms of a periodontal disease. Accordingly, these strict and sometimes disparate definitions of periodontal disease have resulted in an idealistic requirement of a pristine periodontium for periodontal health, which makes us all diseased in one way or another. Furthermore, the consequence of not having a realistic definition of health has resulted in potentially questionable recommendations. The aim of this manuscript was to assess the biological, environmental, sociological, economic, educational and psychological relationships that are germane to constructing a paradigm that defines periodontal health using a modified wellness model. The paradigm includes four cardinal characteristics, i.e., 1) a functional dentition, 2) the painless function of a dentition, 3) the stability of the periodontal attachment apparatus, and 4) the psychological and social well-being of the individual. Finally, strategies and policies that advocate periodontal health were appraised. I'm not sick but I'm not well, and it's a sin to live so well. Flagpole Sitta, Harvey Danger PMID:26390888

  1. Rapid deletion production in fungi via Agrobacterium mediated transformation of OSCAR deletion contructs.

    USDA-ARS?s Scientific Manuscript database

    Precise deletion of gene(s) of interest, while leaving the rest of the genome unchanged, provides the ideal product to determine that particular gene’s function in the living organism. In this protocol we describe the OSCAR method of precise and rapid deletion plasmid construction. OSCAR relies on t...

  2. Somatic mosaicism for a DMD gene deletion

    SciTech Connect

    Saito, Kayoko; Ikeya, Kiyoko; Kondo, Eri

    1995-03-13

    Mosaicism is a mixed state, with two cell populations of different genetic origins caused by a cell mutation occurring after fertilization. In the present case, DNA analysis of lymphocytes led to a DMD diagnosis before death. Postmortem immunocytochemical and DNA analysis showed somatic mosaicism. At age 18 years, blood lymphocyte DNA analysis showed a DMD gene deletion, upstream from exon 7 to the 5{prime} end containing both muscle and brain promoters. As the patient`s mother and elder sister had no deletions, he was considered to have a new mutation. Immunocytochemical studies of postmortem tissues showed that dystrophin was absent from the tongue, deltoid, intercostal, psoas and rectus femoris muscles, but there was a mix of dystrophin-positive and negative fibers in the rectus abdominis, cardiac, temporalis and sternocleidomastoid muscles. All diaphragm cells were dystrophin positive. Polymerase chain reaction (PCR) amplification from all tissues except the temporalis and sternocleidomastoid muscles, diaphragm and kidney, in which no deletion was found, showed the deletion from at least exon 6 to the 5{prime} end containing both muscle and brain promoters. In this case, a genomic deletion of the DMD gene contributed to the formation of tissues derived from both ectoderm and endoderm, and cells of mesodermal origin showed genotypic and phenotypic heterogeneity. Our results indicate a mutation of the present case may have occurred just before the period of germ layer formation. 34 refs., 7 figs.

  3. Chromosome 7q31.1 deletion in myeloid neoplasms.

    PubMed

    Tripputi, Pasquale; Bianchi, Paola; Fermo, Elisa; Bignotto, Monica; Zanella, Alberto

    2014-02-01

    We studied monosomy and deletions of chromosome 7 in 208 patients with myeloid disorders; we found 39 patients (19%) with monosomy or deletion of chromosome 7: 24 patients with chromosome 7 deletion and 15 with monosomy 7. In the 24 patients with chromosome 7 deletions, studied with copy-number variants, short-tandem repeats, microsatellites, single nucleotide polymorphisms, and deletion polymorphisms, the most common deleted region was 7q31.1 (20 patients). Deletion polymorphism studies performed in these 20 patients showed an interstitial deletion of at least 140 kilobase in 6 patients; the deletion spans between the genes forkhead box P2 and Myo D family inhibitor domain containing. Because both genes do not seem to be involved in leukogenesis, we suggest to look carefully into this deletion for the presence of tumor suppressor genes and microRNAs. © 2014.

  4. Repeats, longevity and the sources of mtDNA deletions: evidence from “deletional spectra”

    PubMed Central

    Guo, Xinhong; Popadin, Konstantin Yu.; Markuzon, Natalya; Orlov, Yuriy L.; Kraytsberg, Yevgenya; Krishnan, Kim. J.; Zsurka, Gabor; Turnbull, Douglas M.; Kunz, Wolfram S.; Khrapko, Konstantin

    2010-01-01

    Perfect direct repeats and, in particular, the prominent 13-bp repeat, are thought to cause mitochondrial DNA (mtDNA) deletions, which have been associated with the aging process. Accordingly, individuals lacking the 13-bp repeat are highly prevalent among centenarians and the number of repeats negatively correlates with mammalian longevity. However, detailed examination of the distribution of mtDNA deletions challenges the role of the 13-bp repeat and other perfect repeats in generating mtDNA deletions. Instead, deletions appear to depend on long and stable, albeit imperfect, duplexes between distant mtDNA segments. Furthermore, significant dissimilarities in breakpoint distributions suggest that multiple mechanisms are involved in creating mtDNA deletions. PMID:20591530

  5. Maternal mosaicism for IDUA deletion clarifies recurrence risk in MPS I

    PubMed Central

    Breen, Catherine; Mercer, Jean; Jones, Simon A; Jahic, Amir; Heptinstall, Lesley; Tylee, Karen; Newman, William G; Beetz, Christian

    2016-01-01

    Mucopolysaccharidosis I (MPS I) is a rare autosomal recessive multisystem lysosomal storage disorder. It is caused by biallelic loss-of-function variants in IDUA, encoding alpha-l iduronidase. Here, we describe an individual affected by MPS I due to a paternally inherited deletion of IDUA exons 1 and 2, c.(?_-88)_(299+1_300-1)del and a whole-gene deletion of IDUA (?_-88?)_(*136?)del secondary to maternal somatic mosaicism. We define a previously unreported mutational mechanism for this disorder. PMID:27766162

  6. Defined contribution health benefits.

    PubMed

    Fronstin, P

    2001-03-01

    This Issue Brief discusses the emerging issue of "defined contribution" (DC) health benefits. The term "defined contribution" is used to describe a wide variety of approaches to the provision of health benefits, all of which have in common a shift in the responsibility for payment and selection of health care services from employers to employees. DC health benefits often are mentioned in the context of enabling employers to control their outlay for health benefits by avoiding increases in health care costs. DC health benefits may also shift responsibility for choosing a health plan and the associated risks of choosing a plan from employers to employees. There are three primary reasons why some employers currently are considering some sort of DC approach. First, they are once again looking for ways to keep their health care cost increases in line with overall inflation. Second, some employers are concerned that the public "backlash" against managed care will result in new legislation, regulations, and litigation that will further increase their health care costs if they do not distance themselves from health care decisions. Third, employers have modified not only most employee benefit plans, but labor market practices in general, by giving workers more choice, control, and flexibility. DC-type health benefits have existed as cafeteria plans since the 1980s. A cafeteria plan gives each employee the opportunity to determine the allocation of his or her total compensation (within employer-defined limits) among various employee benefits (primarily retirement or health). Most types of DC health benefits currently being discussed could be provided within the existing employment-based health insurance system, with or without the use of cafeteria plans. They could also allow employees to purchase health insurance directly from insurers, or they could drive new technologies and new forms of risk pooling through which health care services are provided and financed. DC health

  7. Generating Bona Fide Mammalian Prions with Internal Deletions

    PubMed Central

    Munoz-Montesino, Carola; Sizun, Christina; Moudjou, Mohammed; Herzog, Laetitia; Reine, Fabienne; Chapuis, Jérôme; Ciric, Danica; Igel-Egalon, Angelique; Laude, Hubert; Béringue, Vincent; Rezaei, Human

    2016-01-01

    neurodegenerative disorders. Other aggregation-prone proteins appear to have a prion-like mode of expansion in brains, such as in Alzheimer's or Parkinson's diseases. To date, the resolution of prion structure remains elusive. Thus, to genetically define the landscape of regions critical for prion conversion, we tested the effect of short deletions. We found that, surprisingly, removal of a portion of PrP, the C terminus of alpha-helix H2, did not hamper prion formation but generated infectious agents with an internal deletion that showed characteristics essentially similar to those of original infecting strains. Thus, we demonstrate that completeness of the residues inside prions is not necessary for maintaining infectivity and the main strain-specific information, while reporting one of the few if not the only bona fide prions with an internal deletion. PMID:27226369

  8. Generating Bona Fide Mammalian Prions with Internal Deletions.

    PubMed

    Munoz-Montesino, Carola; Sizun, Christina; Moudjou, Mohammed; Herzog, Laetitia; Reine, Fabienne; Chapuis, Jérôme; Ciric, Danica; Igel-Egalon, Angelique; Laude, Hubert; Béringue, Vincent; Rezaei, Human; Dron, Michel

    2016-08-01

    disorders. Other aggregation-prone proteins appear to have a prion-like mode of expansion in brains, such as in Alzheimer's or Parkinson's diseases. To date, the resolution of prion structure remains elusive. Thus, to genetically define the landscape of regions critical for prion conversion, we tested the effect of short deletions. We found that, surprisingly, removal of a portion of PrP, the C terminus of alpha-helix H2, did not hamper prion formation but generated infectious agents with an internal deletion that showed characteristics essentially similar to those of original infecting strains. Thus, we demonstrate that completeness of the residues inside prions is not necessary for maintaining infectivity and the main strain-specific information, while reporting one of the few if not the only bona fide prions with an internal deletion. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  9. TAPERED DEFINING SLOT

    DOEpatents

    Pressey, F.W.

    1959-09-01

    An improvement is reported in the shape and formation of the slot or opening in the collimating slot member which forms part of an ion source of the type wherein a vapor of the material to be ionized is bombarded by electrons in a magnetic field to strike an arc-producing ionization. The defining slot is formed so as to have a substantial taper away from the cathode, causing the electron bombardment from the cathode to be dispersed over a greater area reducing its temperature and at the same time bringing the principal concentration of heat from the electron bombardment nearer the anode side of the slot, thus reducing deterioration and prolonging the life of the slot member during operation.

  10. Method for introducing unidirectional nested deletions

    DOEpatents

    Dunn, John J.; Quesada, Mark A.; Randesi, Matthew

    2001-01-01

    Disclosed is a method for the introduction of unidirectional deletions in a cloned DNA segment in the context of a cloning vector which contains an f1 endonuclease recognition sequence adjacent to the insertion site of the DNA segment. Also disclosed is a method for producing single-stranded DNA probes utilizing the same cloning vector. An optimal vector, PZIP is described. Methods for introducing unidirectional deletions into a terminal location of a cloned DNA sequence which is inserted into the vector of the present invention are also disclosed. These methods are useful for introducing deletions into either or both ends of a cloned DNA insert, for high throughput sequencing of any DNA of interest.

  11. Deletion 22q13.3 syndrome.

    PubMed

    Phelan, Mary C

    2008-05-27

    The deletion 22q13.3 syndrome (deletion 22q13 syndrome or Phelan-McDermid syndrome) is a chromosome microdeletion syndrome characterized by neonatal hypotonia, global developmental delay, normal to accelerated growth, absent to severely delayed speech, and minor dysmorphic features. The deletion occurs with equal frequency in males and females and has been reported in mosaic and non-mosaic forms. Due to lack of clinical recognition and often insufficient laboratory testing, the syndrome is under-diagnosed and its true incidence remains unknown. Common physical traits include long eye lashes, large or unusual ears, relatively large hands, dysplastic toenails, full brow, dolicocephaly, full cheeks, bulbous nose, and pointed chin. Behavior is autistic-like with decreased perception of pain and habitual chewing or mouthing. The loss of 22q13.3 can result from simple deletion, translocation, ring chromosome formation and less common structural changes affecting the long arm of chromosome 22, specifically the region containing the SHANK3 gene. The diagnosis of deletion 22q13 syndrome should be considered in all cases of hypotonia of unknown etiology and in individuals with absent speech. Although the deletion can sometimes be detected by high resolution chromosome analysis, fluorescence in situ hybridization (FISH) or array comparative genomic hybridization (CGH) is recommended for confirmation. Differential diagnosis includes syndromes associated with hypotonia, developmental delay, speech delay and/or autistic-like affect (Prader-Willi, Angelman, Williams, Smith-Magenis, Fragile X, Sotos, FG, trichorhinophalangeal and velocardiofacial syndromes, autism spectrum disorders, cerebral palsy). Genetic counseling is recommended and parental laboratory studies should be considered to identify cryptic rearrangements and detect parental mosaicism. Prenatal diagnosis should be offered for future pregnancies in those families with inherited rearrangements. Individuals with

  12. Defining the Anthropocene

    NASA Astrophysics Data System (ADS)

    Lewis, Simon; Maslin, Mark

    2016-04-01

    Time is divided by geologists according to marked shifts in Earth's state. Recent global environmental changes suggest that Earth may have entered a new human-dominated geological epoch, the Anthropocene. Should the Anthropocene - the idea that human activity is a force acting upon the Earth system in ways that mean that Earth will be altered for millions of years - be defined as a geological time-unit at the level of an Epoch? Here we appraise the data to assess such claims, first in terms of changes to the Earth system, with particular focus on very long-lived impacts, as Epochs typically last millions of years. Can Earth really be said to be in transition from one state to another? Secondly, we then consider the formal criteria used to define geological time-units and move forward through time examining whether currently available evidence passes typical geological time-unit evidence thresholds. We suggest two time periods likely fit the criteria (1) the aftermath of the interlinking of the Old and New Worlds, which moved species across continents and ocean basins worldwide, a geologically unprecedented and permanent change, which is also the globally synchronous coolest part of the Little Ice Age (in Earth system terms), and the beginning of global trade and a new socio-economic "world system" (in historical terms), marked as a golden spike by a temporary drop in atmospheric CO2, centred on 1610 CE; and (2) the aftermath of the Second World War, when many global environmental changes accelerated and novel long-lived materials were increasingly manufactured, known as the Great Acceleration (in Earth system terms) and the beginning of the Cold War (in historical terms), marked as a golden spike by the peak in radionuclide fallout in 1964. We finish by noting that the Anthropocene debate is politically loaded, thus transparency in the presentation of evidence is essential if a formal definition of the Anthropocene is to avoid becoming a debate about bias. The

  13. Critical region in 2q31.2q32.3 deletion syndrome: Report of two phenotypically distinct patients, one with an additional deletion in Alagille syndrome region

    PubMed Central

    2012-01-01

    Background Standard cytogenetic analysis has revealed to date more than 30 reported cases presenting interstitial deletions involving region 2q31-q32, but with poorly defined breakpoints. After the postulation of 2q31.2q32.3 deletion as a clinically recognizable disorder, more patients were reported with a critical region proposed and candidate genes pointed out. Results We report two female patients with de novo chromosome 2 cytogenetically visible deletions, one of them with an additional de novo deletion in chromosome 20p12.2p12.3. Patient I presents a 16.8 Mb deletion in 2q31.2q32.3 while patient II presents a smaller deletion of 7 Mb in 2q32.1q32.3, entirely contained within patient I deleted region, and a second 4 Mb deletion in Alagille syndrome region. Patient I clearly manifests symptoms associated with the 2q31.2q32.3 deletion syndrome, like the muscular phenotype and behavioral problems, while patient II phenotype is compatible with the 20p12 deletion since she manifests problems at the cardiac level, without significant dysmorphisms and an apparently normal psychomotor development. Conclusions Whereas Alagille syndrome is a well characterized condition mainly caused by haploinsufficiency of JAG1 gene, with manifestations that can range from slight clinical findings to major symptoms in different domains, the 2q31.2q32.3 deletion syndrome is still being delineated. The occurrence of both imbalances in reported patient II would be expected to cause a more severe phenotype compared to the individual phenotype associated with each imbalance, which is not the case, since there are no manifestations due to the 2q32 deletion. This, together with the fact that patient I deleted region overlaps previously reported cases and patient II deletion is outside this common region, reinforces the existence of a critical region in 2q31.3q32.1, between 181 to 185 Mb, responsible for the clinical phenotype. PMID:22550961

  14. TSHZ3 deletion causes an autism syndrome and defects in cortical projection neurons

    PubMed Central

    Andrieux, Joris; Roubertoux, Pierre L.; Metwaly, Mehdi; Jacq, Bernard; Fatmi, Ahmed; Had-Aissouni, Laurence; Kwan, Kenneth Y.; Salin, Pascal; Carlier, Michèle; Liedén, Agne; Rudd, Eva; Shinawi, Marwan; Vincent-Delorme, Catherine; Cuisset, Jean-Marie; Lemaitre, Marie-Pierre; Abderrehamane, Fatimetou; Duban, Bénédicte; Lemaitre, Jean-François; Woolf, Adrian S.; Bockenhauer, Detlef; Severac, Dany; Dubois, Emeric; Zhu, Ying; Sestan, Nenad; Garratt, Alistair N.; Kerkerian-Le Goff, Lydia; Fasano, Laurent

    2016-01-01

    TSHZ3, which encodes a zinc-finger transcription factor, was recently positioned as a hub gene in a module of genes with the highest expression in the developing human neocortex, but its functions remained unknown. Here, we identify TSHZ3 as the critical region for a syndrome associated with heterozygous deletions at 19q12q13.11, which includes autism spectrum disorder (ASD). In Tshz3 null mice, differentially expressed genes include layer-specific markers of cerebral cortical projection neurons (CPNs) and their human orthologues are strongly associated with ASD. Furthermore, mice heterozygous for Tshz3 deletion show functional changes at synapses established by CPNs and exhibit core ASD-like behavioral abnormalities. These findings reveal essential roles for Tshz3 in CPN development and function, whose alterations can account for ASD in the newly-defined TSHZ3 deletion syndrome. PMID:27668656

  15. Specialized Transduction Designed for Precise High-Throughput Unmarked Deletions in Mycobacterium tuberculosis

    PubMed Central

    Jain, Paras; Hsu, Tsungda; Arai, Masayoshi; Biermann, Karolin; Thaler, David S.; Nguyen, Andrew; González, Pablo A.; Tufariello, Joann M.; Kriakov, Jordan; Chen, Bing; Larsen, Michelle H.

    2014-01-01

    ABSTRACT Specialized transduction has proven to be useful for generating deletion mutants in most mycobacteria, including virulent Mycobacterium tuberculosis. We have improved this system by developing (i) a single-step strategy for the construction of allelic exchange substrates (AES), (ii) a temperature-sensitive shuttle phasmid with a greater cloning capacity than phAE87, and (iii) bacteriophage-mediated transient expression of site-specific recombinase to precisely excise antibiotic markers. The methods ameliorate rate-limiting steps in strain construction in these difficult-to-manipulate bacteria. The new methods for strain construction were demonstrated to generalize to all classes of genes and chromosomal loci by generating more than 100 targeted single- or multiple-deletion substitutions. These improved methods pave the way for the generation of a complete ordered library of M. tuberculosis null strains, where each strain is deleted for a single defined open reading frame in M. tuberculosis. PMID:24895308

  16. Defining hypercalciuria in nephrolithiasis

    PubMed Central

    Pak, Charles Y.C.; Sakhaee, Khashayar; Moe, Orson W.; Poindexter, John; Adams-Huet, Beverley

    2014-01-01

    The classic definition of hypercalciuria, an upper normal limit of 200 mg/day, is based on a constant diet restricted in calcium, sodium, and animal protein; however, random diet data challenge this. Here our retrospective study determined the validity of the classic definition of hypercalciuria by comparing data from 39 publications analyzing urinary calcium excretion on a constant restricted diet and testing whether hypercalciuria could be defined when extraneous dietary influences were controlled. These papers encompassed 300 non-stone-forming patients, 208 patients with absorptive hypercalciuria type I (presumed due to high intestinal calcium absorption), and 234 stone formers without absorptive hypercalciuria; all evaluated on a constant restricted diet. In non-stone formers, the mean urinary calcium was well below 200 mg/day, and the mean for all patients was 127±46 mg/day with an upper limit of 219 mg/day. In absorptive hypercalciuria type I, the mean urinary calcium significantly exceeded 200 mg/day in all studies with a combined mean of 259±55 mg/day. Receiver operating characteristic curve analysis showed the optimal cutoff point for urinary calcium excretion was 172 mg/day on a restricted diet, a value that approximates the traditional limit of 200 mg/day. Thus, on a restricted diet, a clear demarcation was seen between urinary calcium excretion of kidney stone formers with absorptive hypercalciuria type I and normal individuals. When dietary variables are controlled, the classic definition of hypercalciuria of nephrolithiasis appears valid. PMID:21775970

  17. Defining equity in health

    PubMed Central

    Braveman, P; Gruskin, S

    2003-01-01

    Study objective: To propose a definition of health equity to guide operationalisation and measurement, and to discuss the practical importance of clarity in defining this concept. Design: Conceptual discussion. Setting, Patients/Participants, and Main results: not applicable. Conclusions: For the purposes of measurement and operationalisation, equity in health is the absence of systematic disparities in health (or in the major social determinants of health) between groups with different levels of underlying social advantage/disadvantage—that is, wealth, power, or prestige. Inequities in health systematically put groups of people who are already socially disadvantaged (for example, by virtue of being poor, female, and/or members of a disenfranchised racial, ethnic, or religious group) at further disadvantage with respect to their health; health is essential to wellbeing and to overcoming other effects of social disadvantage. Equity is an ethical principle; it also is consonant with and closely related to human rights principles. The proposed definition of equity supports operationalisation of the right to the highest attainable standard of health as indicated by the health status of the most socially advantaged group. Assessing health equity requires comparing health and its social determinants between more and less advantaged social groups. These comparisons are essential to assess whether national and international policies are leading toward or away from greater social justice in health. PMID:12646539

  18. Defining Neonatal Sepsis

    PubMed Central

    Wynn, James L.

    2016-01-01

    Purpose of the review Although infection rates have modestly decreased in the neonatal intensive care unit (NICU) as a result of ongoing quality improvement measures, neonatal sepsis remains a frequent and devastating problem among hospitalized preterm neonates. Despite multiple attempts to address this unmet need, there have been minimal advances in clinical management, outcomes, and accuracy of diagnostic testing options over the last three decades. One strong contributor to a lack of medical progress is a variable case definition of disease. The inability to agree on a precise definition greatly reduces the likelihood of aligning findings from epidemiologists, clinicians, and researchers, which, in turn, severely hinders progress towards improving outcomes. Recent findings Pediatric consensus definitions for sepsis are not accurate in term infants and are not appropriate for preterm infants. In contrast to the defined multi-stage criteria for other devastating diseases encountered in the NICU (e.g., bronchopulmonary dysplasia), there is significant variability in the criteria used by investigators to substantiate the diagnosis of neonatal sepsis. Summary The lack of an accepted consensus definition for neonatal sepsis impedes our efforts towards improved diagnostic and prognostic options as well as accurate outcomes information for this vulnerable population. PMID:26766602

  19. Phenotypic variability in Angelman syndrome: comparison among different deletion classes and between deletion and UPD subjects.

    PubMed

    Varela, Monica Castro; Kok, Fernando; Otto, Paulo Alberto; Koiffmann, Celia Priszkulnik

    2004-12-01

    Angelman syndrome (AS) can result from either a 15q11-q13 deletion (del), paternal uniparental disomy (UPD), imprinting, or UBE3A mutations. Here, we describe the phenotypic and behavioral variability detected in 49 patients with different classes of deletions and nine patients with UPD. Diagnosis was made by methylation pattern analysis of exon 1 of the SNRPN-SNURF gene and by microsatellite profiling of loci within and outside the 15q11-q13 region. There were no major phenotypic differences between the two main classes (BP1-BP3; BP2-BP3) of AS deletion patients, except for the absence of vocalization, more prevalent in patients with BP1-BP3 deletions, and for the age of sitting without support, which was lower in patients with BP2-BP3 deletions. Our data suggest that gene deletions (NIPA1, NIPA2, CYF1P1, GCP5) mapped to the region between breakpoints BP1 and BP2 may be involved in the severity of speech impairment, since all BP1-BP3 deletion patients showed complete absence of vocalization, while 38.1% of the BP2-BP3 deletion patients were able to pronounce syllabic sounds, with doubtful meaning. Compared to UPD patients, deletion patients presented a higher incidence of swallowing disorders (73.9% del x 22.2% UPD) and hypotonia (73.3% del x 28.57% UPD). In addition, children with UPD showed better physical growth, fewer or no seizures, a lower incidence of microcephaly, less ataxia and higher cognitive skills. As a consequence of their milder or less typical phenotype, AS may remain undiagnosed, leading to an overall underdiagnosis of the disease.

  20. 22q11.2 Deletions in Patients with Conotruncal Defects: Data from 1610 Consecutive Cases

    PubMed Central

    Peyvandi, Shabnam; Lupo, Philip J; Garbarini, Jennifer; Woyciechowski, Stacy; Edman, Sharon; Emanuel, Beverly S; Mitchell, Laura; Goldmuntz, Elizabeth

    2013-01-01

    Background The 22q11.2 deletion syndrome is characterized by multiple congenital anomalies including conotruncal cardiac defects. Identifying the patient with a 22q11.2 deletion (22q11del) can be challenging because many extracardiac features become apparent later in life. We sought to better define the cardiac phenotype associated with a 22q11del to help direct genetic testing. Methods 1,610 patients with conotruncal defects were sequentially tested for a 22q11del. Counts and frequencies for primary lesions and cardiac features were tabulated for those with and without a 22q11del. Logistic regression models investigated cardiac features that predicted deletion status in tetralogy of Fallot (TOF). Results Deletion frequency varied by primary anatomic phenotype. Regardless of the cardiac diagnosis, a concurrent aortic arch anomaly (AAA) was strongly associated with deletion status (OR 5.07, 95% CI: 3.66–7.04). In the TOF subset, the strongest predictor of deletion status was an AAA (OR 3.14, 95% CI: 1.87–5.27, p <0.001), followed by pulmonary valve atresia (OR 2.03, 95% CI: 1.02–4.02, p= 0.04). Among those with double outlet right ventricle and transposition of the great arteries, only those with an AAA had a 22q11del. However, five percent of patients with an isolated conoventricular ventricular septal defect and normal aortic arch anatomy had a 22q11del, while no one with an IAA-A had a 22q11del. Conclusion A subset of patients with conotruncal defects are at risk for a 22q11del. A concurrent AAA increases the risk regardless of the intracardiac anatomy. These findings help direct genetic screening for the 22q11.2 deletion syndrome in the cardiac patient. PMID:23604262

  1. Two New Cases of 1p21.3 Deletions and an Unbalanced Translocation t(8;12) among Individuals with Syndromic Obesity

    PubMed Central

    D'Angelo, Carla S.; Moller dos Santos, Mauren F.; Alonso, Luis G.; Koiffmann, Celia P.

    2015-01-01

    Obesity is a highly heritable but genetically heterogeneous disorder. Various well-known microdeletion syndromes (e.g. 1p36, 2q37, 6q16, 9q34, 17p11.2) can cause this phenotype along with intellectual disability (ID) and other findings. Chromosomal microarrays have identified ‘new’ microdeletion/duplication syndromes often associated with obesity. We report on 2 unrelated patients with an overlapping region of deletion at 1p21.3p21.2, and a third patient with a de novo recurrent unbalanced translocation der(8)t(8;12)(p23.1;p13.31), detected by 180K array CGH in a prospective cohort of syndromic obesity patients. Deletion of 1p21.3 is a rare condition, and there have been only 11 cases of the same recurrent translocation between chromosomes 8 and 12 [t(8;12)] reported to date. The former has been associated with ID, autistic spectrum disorder (ASD) and mild dysmorphic features, and in 4 patients who were obese or had a tendency to obesity, a minimal overlapping region of 2 genes, DPYD and MIR137, was detected; t(8;12) has recently been recognized to cause a childhood obesity syndrome due to duplication of the GNB3 gene. Thus, our findings add to the existing literature on the clinical description of these new syndromes, providing additional support that these loci are associated with syndromic obesity. We suggest that heterozygous loss of MIR137 may contribute to obesity as well as ID and ASD. PMID:26279650

  2. Two New Cases of 1p21.3 Deletions and an Unbalanced Translocation t(8;12) among Individuals with Syndromic Obesity.

    PubMed

    D'Angelo, Carla S; Moller Dos Santos, Mauren F; Alonso, Luis G; Koiffmann, Celia P

    2015-07-01

    Obesity is a highly heritable but genetically heterogeneous disorder. Various well-known microdeletion syndromes (e.g. 1p36, 2q37, 6q16, 9q34, 17p11.2) can cause this phenotype along with intellectual disability (ID) and other findings. Chromosomal microarrays have identified 'new' microdeletion/duplication syndromes often associated with obesity. We report on 2 unrelated patients with an overlapping region of deletion at 1p21.3p21.2, and a third patient with a de novo recurrent unbalanced translocation der(8)t(8;12)(p23.1;p13.31), detected by 180K array CGH in a prospective cohort of syndromic obesity patients. Deletion of 1p21.3 is a rare condition, and there have been only 11 cases of the same recurrent translocation between chromosomes 8 and 12 [t(8;12)] reported to date. The former has been associated with ID, autistic spectrum disorder (ASD) and mild dysmorphic features, and in 4 patients who were obese or had a tendency to obesity, a minimal overlapping region of 2 genes, DPYD and MIR137, was detected; t(8;12) has recently been recognized to cause a childhood obesity syndrome due to duplication of the GNB3 gene. Thus, our findings add to the existing literature on the clinical description of these new syndromes, providing additional support that these loci are associated with syndromic obesity. We suggest that heterozygous loss of MIR137 may contribute to obesity as well as ID and ASD.

  3. Deletion 5q35.3

    SciTech Connect

    Stratton, R.F.; Tedrowe, N.A.; Tolworthy, J.A.; Patterson, R.M.; Ryan, S.G.; Young, R.S.

    1994-06-01

    The authors report on a 15-month-old boy with a de novo deletion of the terminal band of 5q, macrocephaly, mild retrognathia, anteverted nares with low flat nasal bridge, telecanthus, minor earlobe anomalies, bellshaped chest, diastasis recti, short fingers, and mild developmental delay.

  4. Interstitial deletion (6)q13q15

    SciTech Connect

    Gershoni-Baruch, R.; Mandel, H.; Bar El, H.; Bar-Nizan, N.; Borochowitz, Z.; Dar, Hanna

    1996-04-24

    We report on a 2-year-old child with psychomotor retardation, facial and urogenital anomalies. His chromosome constitution was 46,XY,del(6)(q13q15). This case further contributes to the karyotype-phenotype correlation of proximal deletion 6q syndromes. 18 refs., 3 figs., 1 tab.

  5. 22q11 deletion syndrome: current perspective

    PubMed Central

    Hacıhamdioğlu, Bülent; Hacıhamdioğlu, Duygu; Delil, Kenan

    2015-01-01

    Chromosome 22q11 is characterized by the presence of chromosome-specific low-copy repeats or segmental duplications. This region of the chromosome is very unstable and susceptible to mutations. The misalignment of low-copy repeats during nonallelic homologous recombination leads to the deletion of the 22q11.2 region, which results in 22q11 deletion syndrome (22q11DS). The 22q11.2 deletion is associated with a wide variety of phenotypes. The term 22q11DS is an umbrella term that is used to encompass all 22q11.2 deletion-associated phenotypes. The haploinsufficiency of genes located at 22q11.2 affects the early morphogenesis of the pharyngeal arches, heart, skeleton, and brain. TBX1 is the most important gene for 22q11DS. This syndrome can ultimately affect many organs or systems; therefore, it has a very wide phenotypic spectrum. An increasing amount of information is available related to the pathogenesis, clinical phenotypes, and management of this syndrome in recent years. This review summarizes the current clinical and genetic status related to 22q11DS. PMID:26056486

  6. Nature of frequent deletions in CEBPA.

    PubMed

    Fuchs, Ota; Kostecka, Arnost; Provaznikova, Dana; Krasna, Blazena; Brezinova, Jana; Filkukova, Jitka; Kotlin, Roman; Kouba, Michal; Kobylka, Petr; Neuwirtova, Radana; Jonasova, Anna; Caniga, Miroslav; Schwarz, Jiri; Markova, Jana; Maaloufova, Jacqueline; Sponerova, Dana; Novakova, Ludmila; Cermak, Jaroslav

    2009-01-01

    C/EBPalpha (CCAAT/enhancer binding protein alpha) belongs to the family of leucine zipper transcription factors and is necessary for transcriptional control of granulocyte, adipocyte and hepatocyte differentiation, glucose metabolism and lung development. C/EBPalpha is encoded by an intronless gene. CEBPA mutations cause a myeloid differentiation block and were detected in acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), multiple myeloma and non-Hodgkin's lymphoma (NHL) patients. In this study we identified in 41 individuals from 824 screened individuals (290 AML patients, 382 MDS patients, 56 NHL patients and 96 healthy individuals) a single class of 23 deletions in CEBPA gene which involved a direct repeat of at least 2 bp. These mutations are characterised by the loss of one of two same repeats at the ends of deleted sequence. Three most frequent repeats included in these deletions in CEBPA gene are CGCGAG (493-498_865-870), GCCAAGCAGC (508-517_907-916) and GG (486-487_885-886), all according to GenBank accession no. NM_004364.2. A mechanism for deletion formation between two repetitive sequences can be recombination events in the repair process. Double-stranded cut in DNA can initiate these recombination events of adjacent DNA sequences.

  7. Chromosomal deletions in the myelodysplastic syndrome.

    PubMed

    Mufti, G J

    1992-01-01

    Karyotypic abnormalities in primary myelodysplastic syndrome (P-MDS) are less frequent than in secondary myelodysplasia. A review of the literature involving over 3000 reported cases, shows the incidence of karyotypically abnormal clones at presentation in nearly 48% of cases. Approximately 50% of the abnormalities comprise of deletions of chromosomes 5, 7, 11, 12, 13 and 20. Localisation of a number of haemopoietic growth factors and their receptors to the deleted segments of the chromosomes, has invoked considerable interest in the molecular pathology of the interstitial deletions and their consequent role in the multistep pathogenesis of MDS. Present evidence suggests chromosome abnormalities are a later event in the multistep painogenesis, and it is suggested their occurrence may be restricted to a restricted myeloid progenitor cell, although the initial event(s) occur at the common lymphoid-myeloid progenitor. Much has been gleaned from the dominant modes of leukaemogenesis, such as the occurrence of missense mutations at specific positions of RAS and FMS mutations. It is suggested that a similar enquiry into the mechanisms of chromosomal deletions in P-MDS is required in order to delineate the role of these abnormalities in the clonal evolution of this group of diseases.

  8. Molecular Definition of the 22q11 Deletions in Velo-Cardio-Facial Syndrome

    PubMed Central

    Morrow, Bernice; Goldberg, Rosalie; Carlson, Christine; Gupta, Ruchira Das; Sirotkin, Howard; Collins, John; Dunham, Ian; O'Donnell, Hilary; Scambler, Peter; Shprintzen, Robert; Kucherlapati, Raju

    1995-01-01

    Velo-cardio-facial syndrome (VCFS) is a common genetic disorder among individuals with cleft palate and is associated with hemizygous deletions in human chromosome 22q11. Toward the molecular definition of the deletions, we constructed a physical map of 22q11 in the form of overlapping YACs. The physical map covers >9 cM of genetic distance, estimated to span 5 Mb of DNA, and contains a total of 64 markers. Eleven highly polymorphic short tandem-repeat polymorphic (STRP) markers were placed on the physical map, and 10 of these were unambiguously ordered. The 11 polymorphic markers were used to type the DNA from a total of 61 VCFS patients and 49 unaffected relatives. Comparison of levels of heterozygosity of these markers in VCFS patients and their unaffected relatives revealed that four of these markers are commonly hemizygous among VCFS patients. To confirm these results and to define further the breakpoints in VCFS patients, 15 VCFS individuals and their unaffected parents were genotyped for the 11 STRP markers. Haplotypes generated from this study revealed that 82% of the patients have deletions that can be defined by the STRP markers. The results revealed that all patients who have a deletion share a common proximal breakpoint, while there are two distinct distal breakpoints. Markers D22S941 and D22S944 appear to be consistently hemizygous in patients with deletions. Both of these markers are located on a single nonchimeric YAC that is 400 kb long. The results also show that the parental origin of the deleted chromosome does not have any effect on the phenotypic manifestation ImagesFigure 2Figure 3 PMID:7762562

  9. Expanding the ocular phenotype of 14q terminal deletions: A novel presentation of microphthalmia and coloboma in ring 14 syndrome with associated 14q32.31 deletion and review of the literature.

    PubMed

    Salter, Claire G; Baralle, Diana; Collinson, Morag N; Self, James E

    2016-04-01

    A variety of ocular anomalies have been described in the rare ring 14 and 14q terminal deletion syndromes, yet the character, prevalence, and extent of these anomalies are not well defined. Identification of these ocular anomalies can be central to providing diagnoses and facilitating optimal individual patient management. We report a child with a 14q32.31 terminal deletion and ring chromosome formation, presenting with severe visual impairment secondary to significant bilateral coloboma and microphthalmia. This patient is compared to previously reported patients with similar ocular findings and deletion sizes to further refine a locus for coloboma in the 14q terminal region. Those with ring formation and linear deletions are compared and the possibility of ring formation affecting the proximal 14q region is discussed. This report highlights the severity of ocular anomalies that can be associated with ring 14 and 14q terminal deletion syndromes and reveals the limited documentation of ocular examination in these two related syndromes. This suggests that many children with these genetic changes do not undergo an ophthalmology examination as part of their clinical assessment, yet it is only when this evaluation becomes routine that the true prevalence and extent of ocular involvement can be defined. This report therefore advocates for a thorough ophthalmological exam in children with ring 14 or 14q terminal deletion syndrome.

  10. Interstitial and terminal deletion of chromosome Y in a male individual with cryptozoospermia.

    PubMed

    Duell, T; Mathews, S; Wunderlich, B; Mittermüller, J; Schmetzer, H

    1998-04-01

    A constitutional de-novo deletion of the long arm of the Y chromosome was detected by standard cytogenetic analysis in a 38-year old male who, except for small testes and cryptozoospermia, was phenotypically normal. The deletion was further characterized by fluorescent in-situ hybridization (FISH) and digital image analysis using contigs of overlapping yeast artificial chromosome (YAC) clones, spanning almost the entire Y chromosome. These results showed that the deletion involved a large interstitial segment on the proximal long arm of the Y chromosome (Yq11.1-->Yq11.22) as well as a more distal portion of the Y chromosome, including the entire heterochromatic region (Yq11.23-->qter). The breakpoints as determined by the YAC probes were defined within the published Vergnaud intervals so that region 6B and 6C was mostly retained. However, the AZFc region harbouring the DAZ locus on distal subinterval 6F was lost in the deletion, making the absence of this region the most probable location for the patient's infertility. The data underline the usefulness of FISH as an alternative technique to conventional banding for the refined detection of chromosome Y deletions/rearrangements.

  11. Ip deletions in human pheochromocytomas share a common pericentromeric breakpoint and do not involve imprinting

    SciTech Connect

    Moley, J.F.; Marshall, H.N.

    1994-09-01

    We previously reported that loss of heterozygosity (LOH) of 1p is found in all pheochromocytomas from patients with the Multiple Endocrine Neoplasia type 2 syndromes and in 40% of sporadic pheochromocytomas. We used 24 polymorphic DNA markers to map the deleted region in 27 tumors and found that in all tumors with 1p LOH, the deletion involves the entire short arm. LOH of 1q has not been found. The common breakpoint in these tumors is between D1S514 and D1S442 which defines a 2 centiMorgan interval which includes the centromere. To determine whether genomic imprinting plays a role in 1p deletion in these tumors, parental DNA was obtained for eight individuals with pheochromocytomas and the parental DNA was obtained for eight individuals with pheochromocytomas and the parental origin of allelic loss determined. In four cases the paternal allele was lost and in four cases, the maternal allele was lost. In addition, allelic loss was examined in multifocal or bilateral tumors from five individuals. 1p LOH was demonstrated in all tumors examined, but in two patients, tumors from different sites demonstrated opposite patterns of allelic loss, indicating that either maternal or paternal alleles may be lost in different tumors from the same individual. These data show that deletion of 1p is a significant event in the development of human pheochromocytomas, and involves a common breakpoint in the pericentromeric area. Allelic deletion is not influenced by the parent of origin.

  12. Deletional Protein Engineering Based on Stable Fold

    PubMed Central

    Sokalingam, Sriram; Yun, Hyungdon; Lee, Sun-Gu

    2012-01-01

    Diversification of protein sequence-structure space is a major concern in protein engineering. Deletion mutagenesis can generate a protein sequence-structure space different from substitution mutagenesis mediated space, but it has not been widely used in protein engineering compared to substitution mutagenesis, because it causes a relatively huge range of structural perturbations of target proteins which often inactivates the proteins. In this study, we demonstrate that, using green fluorescent protein (GFP) as a model system, the drawback of the deletional protein engineering can be overcome by employing the protein structure with high stability. The systematic dissection of N-terminal, C-terminal and internal sequences of GFPs with two different stabilities showed that GFP with high stability (s-GFP), was more tolerant to the elimination of amino acids compared to a GFP with normal stability (n-GFP). The deletion studies of s-GFP enabled us to achieve three interesting variants viz. s-DL4, s-N14, and s-C225, which could not been obtained from n-GFP. The deletion of 191–196 loop sequences led to the variant s-DL4 that was expressed predominantly as insoluble form but mostly active. The s-N14 and s-C225 are the variants without the amino acid residues involving secondary structures around N- and C-terminals of GFP fold respectively, exhibiting comparable biophysical properties of the n-GFP. Structural analysis of the variants through computational modeling study gave a few structural insights that can explain the spectral properties of the variants. Our study suggests that the protein sequence-structure space of deletion mutants can be more efficiently explored by employing the protein structure with higher stability. PMID:23240034

  13. 5p14 deletion associated with microcephaly and seizures

    PubMed Central

    Johnson, E.; Marinescu, R; Punnett, H.; Tenenholz, B.; Overhauser, J.

    2000-01-01

    We report on a father and son who have an interstitial deletion of 5p14. The father is clinically and mentally normal while the son has significant clinical involvement including microcephaly, seizures, and global developmental delay. The extent of the 5p14 deletion was determined using fluorescence in situ hybridisation (FISH). The deletion in this present family is smaller than a deletion previously described in a multigenerational family that lacks any clinical phenotype. This report shows that a 5p14 deletion does not always lead to a normal phenotype.


Keywords: interstitial deletion; chromosome 5; fluorescence in situ hybridisation; cri du chat syndrome PMID:10662813

  14. Narp Deletion Blocks Extinction of Morphine Place Preference Conditioning

    PubMed Central

    Crombag, Hans S; Dickson, Mercy; Dinenna, Megan; Johnson, Alexander W; Perin, Mark S; Holland, Peter C; Baraban, Jay M; Reti, Irving M

    2008-01-01

    As drug abuse can be viewed as a maladaptive form of neuronal plasticity, attention has focused on defining the synaptic plasticity mechanisms that mediate the long-term effects of these drugs. As Narp is secreted at synaptic sites and binds to the extracellular surface of AMPA receptors, it has been implicated in mediating enduring forms of synaptic plasticity. Accordingly, to assess its potential role in the long-lasting behavioral effects of drugs of abuse, we have investigated the impact of Narp deletion on sustained behavioral responses elicited by repeated morphine administration. Narp knockout mice display normal locomotor sensitization and conditioned place preference, but are markedly resistant to extinction of place preference. Thus, these findings indicate that Narp plays a selective role in extinction, possibly by its effects on AMPA receptor trafficking. PMID:18536700

  15. Structure and variation of CRISPR and CRISPR-flanking regions in deleted-direct repeat region Mycobacterium tuberculosis complex strains.

    PubMed

    Freidlin, Paul Jeffrey; Nissan, Israel; Luria, Anna; Goldblatt, Drora; Schaffer, Lana; Kaidar-Shwartz, Hasia; Chemtob, Daniel; Dveyrin, Zeev; Head, Steven Robert; Rorman, Efrat

    2017-02-15

    CRISPR and CRISPR-flanking genomic regions are important for molecular epidemiology of Mycobacterium tuberculosis complex (MTBC) strains, and potentially for adaptive immunity to phage and plasmid DNA, and endogenous roles in the bacterium. Genotyping in the Israel National Mycobacterium Reference Center Tel-Aviv of over 1500 MTBC strains from 2008-2013 showed three strains with validated negative 43-spacer spoligotypes, that is, with putatively deleted direct repeat regions (deleted-DR/CRISPR regions). Two isolates of each of three negative spoligotype MTBC (a total of 6 isolates) were subjected to Next Generation Sequencing (NGS). As positive controls, NGS was performed for three intact-DR isolates belonging to T3_Eth, the largest multiple-drug-resistant (MDR)-containing African-origin cluster in Israel. Other controls consisted of NGS reads and complete whole genome sequences from GenBank for 20 intact-DR MTBC and for 1 deleted-DR MTBC strain recognized as CAS by its defining RD deletion. NGS reads from negative spoligotype MTBC mapped to reference H37Rv NC_000962.3 suggested that the DR/CRISPR regions were completely deleted except for retention of the middle IS6110 mobile element. Clonally specific deletion of CRISPR-flanking genes also was observed, including deletion of at least cas2 and cas1 genes. Genomic RD deletions defined lineages corresponding to the major spoligotype families Beijing, EAI, and Haarlem, consistent with 24 loci MIRU-VNTR profiles. Analysis of NGS reads, and analysis of contigs obtained by manual PCR confirmed that all 43 gold standard DR/CRISPR spacers were missing in the deleted-DR genomes. Although many negative spoligotype strains are recorded as spoligotype-international-type (SIT) 2669 in the SITVIT international database, this is the first time to our knowledge that it has been shown that negative spoligotype strains are found in at least 4 different 24 loci MIRU-VNTR and RD deletion families. We report for the first time

  16. Tracking the assembly pathway of human immunodeficiency virus type 1 Gag deletion mutants by immunogold labeling.

    PubMed

    Wang, J J; Sandefur, S; Spearman, P; Chiou, C T; Chiang, P H; Ratner, L

    2001-12-01

    The Pr55gag gene product of human immunodeficiency virus type 1 (HIV-1) is sufficient to direct the formation of retrovirus-like particles (RVLPs). Recent biochemical evidence has indicated the presence of Gag intermediates in the cytoplasm; however, the Gag assembly process into RVLPs remains incompletely defined. The authors present here the subcellular localization of Gag mutant proteins in BSC40 and Jurkat cells by immunoelectron microscopy (IEM). The full Gag/Pol and Gag precursors, a C-terminal deletion mutant lacking a portion of nucleocapsid (NC), and all p6Gag gave rise to similar levels of RVLPs at the cell surface. A C-terminal deletion of all NC and p6Gag abrogated particle formation, whereas p24 was found in patches at the cell surface. Deletion of matrix (MA) sequences from Gag resulted in intracellular particles, and myristylation was not required for particle formation in the context of the MA deletion. Matrix expression was enhanced with Gag/Pol or Env coexpression as determined by semiquantitative IEM. p24 protein was targeted at vacuolar and mitochondrial membranes, but not at Golgi cisternae. In addition, aggregations of Gag intermediates and RVLPs in the cytoplasm, rough endoplasmic reticulum, cisternae, and mitochondria were noted. These results provide defined in situ evidence that HIV-1 particle assembly occurs in the cytosol in addition to budding at most intracellular membranes.

  17. Fine structure mapping and deletion analysis of the murine piebald locus

    SciTech Connect

    Metallinos, D.L.; Tilghman, S.M. ); Oppenheimer, A.J. ); Rinchik, E.M.; Russell, L.B. ); Dietrich, W. )

    1994-01-01

    Piebald (s) is a recessive mutation that affects the development of two cell types of neural crest origin: melanocytes, responsible for pigment synthesis in the skin, and enteric ganglia, which innervate the lower bowel. As a result, mice carrying piebald mutations exhibit white spotting in the coat and aganglionic megacolon. Previously the gene had been localized to the distal half of mouse chromosome 14. To determine its precise location relative to molecular markers, an intersubspecific backcross was generated. Two anchor loci of chromosome 14, slaty and hypogonadal, in addition to simple sequence length repeat markers, were used to localize s to a 2-cM interval defined by the markers D14Mit38 and D14Mit42. The molecular markers were also used to characterize nine induced s alleles. Three of these mutations exhibited no deletions or rearrangements of the flanking markers, whereas the other six had two or more of these markers deleted. The extent of the deletions was found to be consistent with the severity of the homozygous phenotype. The location of deletion breakpoints in the induced alleles, coupled with the recombination breakpoints in the backcross progeny, provide useful molecular landmarks to define the location of the piebald gene.

  18. Deletions and candidate genes in Williams syndrome

    SciTech Connect

    Perez Jurado, L.A.; Peoples, R.; Francke, U.

    1994-09-01

    Hemizygosity at the elastin locus (ELN) on chromosome 7q11.23 has recently been reported in several familial and sporadic cases of the developmental disorder, Williams syndrome (WS). Because the deletion is greater than the span of the ELN gene, a contiguous gene deletion syndrome has been suggested as the probable molecular basis for this condition. Thus far, neither the size of the deletion(s), nor other genes within it are known. We have analyzed samples from 27 sporadic WS patients by genotyping two multiallelic ELN intragenic polymorphisms, detectable by PCR amplification, and by Southern blotting for ELN gene dosage. Twenty four patients were hemizygous at the ELN locus while 3 showed no deletion or detectable rearrangement. Genotype studies on parental DNA were informative in 12 of the deletions. All 12 were due to de novo events, 8 in the maternal and 4 in the paternal chromosome. In an attempt to identify genes involved in WS we are also using a candidate gene approach. Delayed clearance of an exogenous calcium load with normal or slightly increased calcitonin levels in serum has been documented in WS patients suggesting a defective calcitonin action or calcium sensing function. The calcitonin receptor (CTR) gene is, therefore, a good candidate since CTR has a dual role as a hormonal receptor for calcitonin and an extracellular calcium sensor. We have mapped the CTR gene to chromosome 7q21.1 by PCR-SSCA of somatic cell hybrids and FISH analysis. Using two color FISH with probes for ELN and CTR, both loci are located on 7q at a distance of {approximately}10 Mb, CTR being telomeric. Our CTR probe does not detect any genomic abnormality by FISH or Southern blot in the patients` samples analyzed. We have identified a diallelic polymorphism in the CTR cDNA and are currently testing the hypothesis of an impaired CTR expression as responsible for some of the clinical features of WS by analysing the CTR transcripts by RT-PCR.

  19. Delineation of 7q11.2 deletions associated with Williams-Beuren syndrome and mapping of a repetitive sequence to within and to either side of the common deletion

    SciTech Connect

    Robinson, W.P.; Waslynka, J.; Wang, M.; Clark, S. |

    1996-05-15

    The majority of Williams-Beuren syndrome (WBS) patients have been shown to have a microdeletion within 7q11.2 including the elastin gene locus. The extent of these deletions has, however, not been well characterized. Thirty-five deletion patients were tested for all polymorphic markers in the 7q11.2 region bounding ELN to define the extent of deletions associated with WBS. With only one exception, ELN, D7S1870, and one copy of the D7S489 locus (D7S489U) were always included in the deletions. One patient showed lack of maternal inheritance at D7S1870 and not at ELN or D7S489U. A product corresponding to D7S489U was amplified form YAC 743G6 and from the P1 clone RMC07P008, thereby localizing both to within the common deletion. The boundary of the deleted region on the proximal (centromeric) side is D7S653 and on the distal side is D7S675, neither of which were ever included in the deletion. One locus, D7S489L, was variably deleted in patients, indicating a minimum of two common breakpoints on the proximal side. At least one additional repeat amplified by D7S489 (D7S489M) was localized to a YAC contig mapping distal to the mologous to several cDNA clones in the GenBank database and contains an Alu sequence. It is possible that this and/or other repetitive sequences in this region could play a role in the mechanism of deletion. 26 refs., 5 figs., 2 tabs.

  20. Genetics Home Reference: distal 18q deletion syndrome

    MedlinePlus

    ... B, O'Donnell L, Gelfond J, Lancaster J, Fox PT, Hale DE. Consequences of chromsome18q deletions. Am ... Cody JD, Andrews T, Hardies LJ, Hale DE, Fox PT. Myelination in children with partial deletions of ...

  1. 49 CFR 7.6 - Deletion of identifying detail.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... necessary to prevent a clearly unwarranted invasion of personal privacy, identifying details will be deleted... withheld by another Federal statute, such information shall be deleted from any record covered by this...

  2. 49 CFR 7.6 - Deletion of identifying detail.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... necessary to prevent a clearly unwarranted invasion of personal privacy, identifying details will be deleted... withheld by another Federal statute, such information shall be deleted from any record covered by this...

  3. 49 CFR 7.6 - Deletion of identifying detail.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... necessary to prevent a clearly unwarranted invasion of personal privacy, identifying details will be deleted... withheld by another Federal statute, such information shall be deleted from any record covered by this...

  4. Deletion of 3p25.3 in a patient with intellectual disability and dysmorphic features with further definition of a critical region.

    PubMed

    Kellogg, Gregory; Sum, John; Wallerstein, Robert

    2013-06-01

    Several recent reports of interstitial deletions at the terminal end of the short arm of chromosome 3 have helped to define the critical region whose deletion causes 3p deletion syndrome. We report on an 11-year-old girl with intellectual disability, obsessive-compulsive tendencies, hypotonia, and dysmorphic facial features in whom a 684 kb interstitial 3p25.3 deletion was characterized using array-CGH. This deletion overlaps with interstitial 3p25 deletions reported in three recent case reports. These deletions share a 124 kb overlap region including only three RefSeq annotated genes, THUMPD3, SETD5, and LOC440944. The current patient had phenotypic similarities, including intellectual disability, hypotonia, depressed nasal bridge, and long philtrum, with previously reported patients, while she did not have the cardiac defects, seizures ormicrocephaly reported in patients with larger deletions. Therefore, this patient furthers our knowledge of the consequences of 3p deletions, while suggesting genotype-phenotype correlations. Copyright © 2013 Wiley Periodicals, Inc.

  5. Duplication/deletion of chromosome 8p

    SciTech Connect

    Priest, J.H.

    1995-09-11

    The article by Guo et al. provides evidence for deletion of D8S596 loci (assigned to 8p23) in at least some patients with inverted duplications of 8p. Cytogenetic break points forming the inverted duplication are remarkably similar among most of their patients and those reported previously, suggesting a common mechanism for this interesting rearrangement. Why should similar breaks occur in 8p and why is a FISH signal absent in the distal short arm when the ONCOR digoxigenin-labeled probe for loci D8S596 is used? Other studies also indicate that duplication for the region 8p12-p22 is associated with a deletion distal to the duplication itself. 4 refs.

  6. Molecular definition of the chromosome 7 deletion in Williams syndrome and parent-of-origin effects on growth

    SciTech Connect

    Perez Jurado, L.A.; Peoples, R.; Francke, U.

    1996-10-01

    Williams syndrome (WS) is a developmental disorder with variable phenotypic expression associated, in most cases, with a hemizygous deletion of part of chromosomal band 7q11.23 that includes the elastin gene (ELN). We have investigated the frequency and size of the deletions, determined the parental origin, and correlated the molecular results with the clinical findings in 65 WS patients. Hemizygosity at the ELN locus was established by typing of two intragenic polymorphisms, quantitative Southern analysis, and/or FISH. Polymorphic markers covering the deletion and flanking regions were ordered by a combination of genetic and physical mapping. Genotyping of WS patients and available parents for 13 polymorphisms revealed that of 65 clinically defined WS patients, 61 (94%) had a deletion of the ELN locus and were also hemizygous (or non-informative) at loci D7S489B, D7S2476, D7S613, D7S2472, and D7S1870. None of the four patients without ELN deletion was hemizygous at any of the polymorphic loci studied. All patients were heterozygous (or noninformative) for centromeric (D7S1816, D7S1483, and D7S653) and telomeric (D7S489A, D7S675, and D7S669) flanking loci. The genetic distance between the most-centromeric deleted locus, D7S489B, and the most-telomeric one, D7S1870, is 2 cM. The breakpoints cluster at {approximately}1 cM to either side of ELN. In 39 families informative for parental origin, all deletions were de novo, and 18 were paternally and 21 maternally derived. Comparison of clinical data, collected in a standardized quantifiable format, revealed significantly more severe growth retardation and microcephaly in the maternal deletion group. An imprinted locus, silent on the paternal chromosome and contributing to statural growth, may be affected by the deletion. 53 refs., 5 figs., 2 tabs.

  7. Molecular definition of the chromosome 7 deletion in Williams syndrome and parent-of-origin effects on growth.

    PubMed Central

    Pérez Jurado, L. A.; Peoples, R.; Kaplan, P.; Hamel, B. C.; Francke, U.

    1996-01-01

    Williams syndrome (WS) is a developmental disorder with variable phenotypic expression associated, in most cases, with a hemizygous deletion of part of chromosomal band 7q11.23 that includes the elastin gene (ELN). We have investigated the frequency and size of the deletions, determined the parental origin, and correlated the molecular results with the clinical findings in 65 WS patients. Hemizygosity at the ELN locus was established by typing of two intragenic polymorphisms, quantitative Southern analysis, and/or FISH. Polymorphic markers covering the deletion and flanking regions were ordered by a combination of genetic and physical mapping. Genotyping of WS patients and available parents for 13 polymorphisms revealed that of 65 clinically defined WS patients, 61 (94%) had a deletion of the ELN locus and were also hemizygous (or noninformative) at loci D7S489B, D7S2476, D7S613, D7S2472, and D7S1870. None of the four patients without ELN deletion was hemizygous at any of the polymorphic loci studied. All patients were heterozygous (or noninformative) for centromeric (D7S1816, D7S1483, and D7S653) and telomeric (D7S489A, D7S675, and D7S669) flanking loci. The genetic distance between the most-centromeric deleted locus, D7S489B, and the most-telomeric one, D7S1870, is 2 cM. The breakpoints cluster at approximately 1 cM to either side of ELN. In 39 families informative for parental origin, all deletions were de novo, and 18 were paternally and 21 maternally derived. Comparison of clinical data, collected in a standardized quantifiable format, revealed significantly more severe growth retardation and microcephaly in the maternal deletion group. An imprinted locus, silent on the paternal chromosome and contributing to statural growth, may be affected by the deletion. Images Figure 1 Figure 4 PMID:8808592

  8. 19 CFR 142.49 - Deletion of C-4 Code.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 19 Customs Duties 2 2013-04-01 2013-04-01 false Deletion of C-4 Code. 142.49 Section 142.49... TREASURY (CONTINUED) ENTRY PROCESS Line Release § 142.49 Deletion of C-4 Code. (a) By Customs. A port director may temporarily or permanently delete an entry filer's C-4 Code without providing the participant...

  9. Creating, Searching, and Deleting KD Trees Using C++

    DTIC Science & Technology

    2014-09-01

    Creating, Searching, and Deleting KD Trees Using C++ by Robert J Yager ARL-TN-0629 September 2014...Deleting KD Trees Using C++ by Robert J Yager Weapons and Materials Research Directorate, ARL...Searching, and Deleting KD Trees Using C++ 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Robert J Yager

  10. Investigation of NRXN1 deletions: clinical and molecular characterization.

    PubMed

    Dabell, Mindy Preston; Rosenfeld, Jill A; Bader, Patricia; Escobar, Luis F; El-Khechen, Dima; Vallee, Stephanie E; Dinulos, Mary Beth Palko; Curry, Cynthia; Fisher, Jamie; Tervo, Raymond; Hannibal, Mark C; Siefkas, Kiana; Wyatt, Philip R; Hughes, Lauren; Smith, Rosemarie; Ellingwood, Sara; Lacassie, Yves; Stroud, Tracy; Farrell, Sandra A; Sanchez-Lara, Pedro A; Randolph, Linda M; Niyazov, Dmitriy; Stevens, Cathy A; Schoonveld, Cheri; Skidmore, David; MacKay, Sara; Miles, Judith H; Moodley, Manikum; Huillet, Adam; Neill, Nicholas J; Ellison, Jay W; Ballif, Blake C; Shaffer, Lisa G

    2013-04-01

    Deletions at 2p16.3 involving exons of NRXN1 are associated with susceptibility for autism and schizophrenia, and similar deletions have been identified in individuals with developmental delay and dysmorphic features. We have identified 34 probands with exonic NRXN1 deletions following referral for clinical microarray-based comparative genomic hybridization. To more firmly establish the full phenotypic spectrum associated with exonic NRXN1 deletions, we report the clinical features of 27 individuals with NRXN1 deletions, who represent 23 of these 34 families. The frequency of exonic NRXN1 deletions among our postnatally diagnosed patients (0.11%) is significantly higher than the frequency among reported controls (0.02%; P = 6.08 × 10(-7) ), supporting a role for these deletions in the development of abnormal phenotypes. Generally, most individuals with NRXN1 exonic deletions have developmental delay (particularly speech), abnormal behaviors, and mild dysmorphic features. In our cohort, autism spectrum disorders were diagnosed in 43% (10/23), and 16% (4/25) had epilepsy. The presence of NRXN1 deletions in normal parents and siblings suggests reduced penetrance and/or variable expressivity, which may be influenced by genetic, environmental, and/or stochastic factors. The pathogenicity of these deletions may also be affected by the location of the deletion within the gene. Counseling should appropriately represent this spectrum of possibilities when discussing recurrence risks or expectations for a child found to have a deletion in NRXN1. Copyright © 2013 Wiley Periodicals, Inc.

  11. Characterizing Deletion Transformations across Dialects using a Sophisticated Tying Mechanism

    DTIC Science & Technology

    2011-03-30

    suggest nrle candidates for further linguistic studies. Potential appli- cations include forensic phonetics, accent training, and dialect recognition...03-2011 Technical Paper MAR 2011 - APR 2011 Characterizing Deletion Transformations across Dialects using a Sophisticated Tying Mechanism FA8720-05...modeling deletion transformations between dialects . We empirically show that the proposed tying mechanism reduces deletion errors by 33% when compared to a

  12. Characterization of five partial deletions of the factor VIII gene

    SciTech Connect

    Youssoufian, H.; Antonarakis, S.E.; Aronis, S.; Tsiftis, G.; Phillips, D.G.; Kazazian, H.H. Jr.

    1987-06-01

    Hemophilia A is an X-linked disorder of coagulation caused by a deficiency of factor VIII. By using cloned DNA probes, the authors have characterized the following five different partial deletions of the factor VIII gene from a panel of 83 patients with hemophilia A: (i) a 7-kilobase (kb) deletion that eliminates exon 6; (ii) a 2.5-kb deletion that eliminates 5' sequences of exon 14; (iii) a deletion of at least 7 kb that eliminates exons 24 and 25; (iv) a deletion of at least 16 kb that eliminates exons 23-25; and (v) a 5.5-kb deletion that eliminates exon 22. The first four deletions are associated with severe hemophilia A. By contrast, the last deletion is associated with moderate disease, possibly because of in-frame splicing from adjacent exons. None of those patients with partial gene deletions had circulating inhibitors to factor VIII. One deletion occurred de novo in a germ cell of the maternal grandmother, while a second deletion occurred in a germ cell of the maternal grandfather. These observations demonstrate that de novo deletions of X-linked genes can occur in either male or female gametes.

  13. Chromosome 11q13 deletion syndrome

    PubMed Central

    Kim, Yu-Seon; Kim, Gun-Ha; Byeon, Jung Hye; Eun, So-Hee

    2016-01-01

    Chromosome 11q13 deletion syndrome has been previously reported as either otodental syndrome or oculo-oto-dental syndrome. The otodental syndrome is characterized by dental abnormalities and high-frequency sensorineural hearing loss, and by ocular coloboma in some cases. The underlying genetic defect causing otodental syndrome is a hemizygous microdeletion involving the FGF3 gene on chromosome 11q13.3. Recently, a new form of severe deafness, microtia (small ear) and small teeth, without the appearance of eye abnormalities, was also reported. In this report, we describe a 1-year-old girl presenting with ptosis of the left upper eyelid, right auricular deformity, high-arched palate, delayed dentition, simian line on the right hand, microcephaly, and developmental delay. In this patient, we identified a deletion in the chromosome 11q13.2-q13.3 (2.75 Mb) region by using an array-comparative genomic hybridization analysis. The deletion in chromosome 11q13 results in a syndrome characterized by variable clinical manifestations. Some of these manifestations involve craniofacial dysmorphology and require a functional workup for hearing, ophthalmic examinations, and long-term dental care. PMID:28018436

  14. Deletion Diagnostics for Alternating Logistic Regressions

    PubMed Central

    Preisser, John S.; By, Kunthel; Perin, Jamie; Qaqish, Bahjat F.

    2013-01-01

    Deletion diagnostics are introduced for the regression analysis of clustered binary outcomes estimated with alternating logistic regressions, an implementation of generalized estimating equations (GEE) that estimates regression coefficients in a marginal mean model and in a model for the intracluster association given by the log odds ratio. The diagnostics are developed within an estimating equations framework that recasts the estimating functions for association parameters based upon conditional residuals into equivalent functions based upon marginal residuals. Extensions of earlier work on GEE diagnostics follow directly, including computational formulae for one-step deletion diagnostics that measure the influence of a cluster of observations on the estimated regression parameters and on the overall marginal mean or association model fit. The diagnostic formulae are evaluated with simulations studies and with an application concerning an assessment of factors associated with health maintenance visits in primary care medical practices. The application and the simulations demonstrate that the proposed cluster-deletion diagnostics for alternating logistic regressions are good approximations of their exact fully iterated counterparts. PMID:22777960

  15. Immune function in patients with chromosome deletions.

    PubMed Central

    Nurmi, T; Uhari, M; Linna, S L; Silvennoinen-Kassinen, S; Koskela, M; Kiuttu, J; Tiilikainen, A

    1982-01-01

    Non-specific, cell-mediated and humoral immunity were evaluated in six patients with different autosomal deletions, and in two patients with X-chromosome deletions. Six had an increased number of bacterial, viral, and mycotic infections. Mild disturbances were found in the immunological functions of almost every patient. Granulocyte phagocytosis and killing of bacteria were normal in all patients. The chemotactic response was increased in two, and normal in the others. The responses to phytohaemagglutinin and pokeweed mitogen were normal in all patients and the response to concanavalin A was decreased in one patient. The lymphocyte response to purified protein derivative was decreased in the patients as a group when compared to the controls (P less than 0 . 005), but normal to oidiomycin. The number of acid-alpha-naphthyl acetate esterase positive cells was low in four patients. One had a high titre of antinuclear and antithyroid antibodies. One had a low concentration of serum IgA, C3 and C4. One had a high concentration of IgM. Two had elevated levels of C3 and C4. Our results show that several different chromosomal deletions are associated with immunological abnormality. PMID:6979446

  16. U-insertion/deletion Edited Sequence Database.

    PubMed

    Simpson, L; Wang, S H; Thiemann, O H; Alfonzo, J D; Maslov, D A; Avila, H A

    1998-01-01

    Uridine insertion/deletion RNA editing is a post-transcriptional RNA modification occurring in the mitochondria of kinetoplastid protozoa. The U-insertion/deletion Edited Sequence Database is a compilation of mitochondrial genes and edited mRNAs from five kinetoplastid species. It contains separate files with the DNA, mRNA (both unedited and edited) and predicted protein sequences, as well as alignments of the Leishmania tarentolae and Trypanosoma brucei protein sequences from edited and unedited genes. The sequence files are in GCG format. A 'map' sequence file showing the location of U-deletions, U-insertions and the translated amino acid sequences is also provided for each gene. Genomic maps for each species are also provided with clickable genes, including maxicircle-encoded gRNAs. Sets of aligned nuclear rRNA sequences from kinetoplastid protozoa are also provided, which were used for phylogenetic reconstructions in an analysis of the origin of RNA editing. The database is available through the World Wide Web as an HTML document at the URLhttp://www.lifesci.ucla.edu/RNA/trypanosome/ database.html

  17. Cardiac Med1 deletion promotes early lethality, cardiac remodeling, and transcriptional reprogramming.

    PubMed

    Spitler, Kathryn M; Ponce, Jessica M; Oudit, Gavin Y; Hall, Duane D; Grueter, Chad E

    2017-04-01

    The mediator complex, a multisubunit nuclear complex, plays an integral role in regulating gene expression by acting as a bridge between transcription factors and RNA polymerase II. Genetic deletion of mediator subunit 1 (Med1) results in embryonic lethality, due in large part to impaired cardiac development. We first established that Med1 is dynamically expressed in cardiac development and disease, with marked upregulation of Med1 in both human and murine failing hearts. To determine if Med1 deficiency protects against cardiac stress, we generated two cardiac-specific Med1 knockout mouse models in which Med1 is conditionally deleted (Med1cKO mice) or inducibly deleted in adult mice (Med1cKO-MCM mice). In both models, cardiac deletion of Med1 resulted in early lethality accompanied by pronounced changes in cardiac function, including left ventricular dilation, decreased ejection fraction, and pathological structural remodeling. We next defined how Med1 deficiency alters the cardiac transcriptional profile using RNA-sequencing analysis. Med1cKO mice demonstrated significant dysregulation of genes related to cardiac metabolism, in particular genes that are coordinated by the transcription factors Pgc1α, Pparα, and Errα. Consistent with the roles of these transcription factors in regulation of mitochondrial genes, we observed significant alterations in mitochondrial size, mitochondrial gene expression, complex activity, and electron transport chain expression under Med1 deficiency. Taken together, these data identify Med1 as an important regulator of vital cardiac gene expression and maintenance of normal heart function.NEW & NOTEWORTHY Disruption of transcriptional gene expression is a hallmark of dilated cardiomyopathy; however, its etiology is not well understood. Cardiac-specific deletion of the transcriptional coactivator mediator subunit 1 (Med1) results in dilated cardiomyopathy, decreased cardiac function, and lethality. Med1 deletion disrupted cardiac

  18. DELETION MAPPING OF CRITICAL REGION FOR HYPOSPADIAS, PENOSCROTAL TRANSPOSITION AND IMPERFORATE ANUS ON HUMAN CHROMOSOME 13

    PubMed Central

    Garcia, Nilda M.; Allgood, Jocelyn; Santos, Lane J.; Lonergan, D.; Batanian, J.R.; Henkemeyer, Mark; Bartsch, Oliver; Schultz, Roger A.; Zinn, Andrew R.; Baker, Linda A.

    2007-01-01

    Background The 13q-deletion syndrome causes human congenital birth defects due to the loss of regions of one long arm of human chromosome 13. A distal critical region for severe genitourinary and anorectal birth defects in the region of 13q32.2-34 has been suggested; we sought to narrow this critical region. Methods From patients with karyotypes revealing haploinsufficiency for distal chromosome 13q and their parents, peripheral blood was obtained and lymphocytes were immortalized for DNA isolation. Genetic and molecular cytogenetic methods were used to map deletions. Patient and parental samples were genotyped with a panel of 20 microsatellite markers spanning 13q31.3 qter and deletions identified by loss of heterozygosity. Deletions were also mapped using a panel of 35 BAC clones from the same region as probes for fluorescence in-situ hybridization on patient lymphoblastoid metaphase preparations. The data were synthesized and a deletion map defining the critical region was generated. Results Eight patients with known deletions around 13q32qter and their parents were analyzed, and categorized into three groups: three patients with anorectal and genitourinary anomalies (hypospadias, penoscrotal transposition), four male patients without anorectal and genitourinary anomalies, and one XY patient with ambiguous genitalia without anorectal anomalies. We mapped the critical region for anorectal and genitourinary anomalies to a ∼9.5-Mb interval of 13q33.3-q34 delineated by markers D13S280-D13S285; this spans ∼8% of the chromosome and contains 20 annotated genes Conclusion The critical region of chromosome 13q mediating genitourinary/anorectal anomalies has been mapped, and will be narrowed by additional patients and further mapping. Identification of the gene(s) mediating these syndromic genitourinary defects should further our knowledge of molecular mediators of non-syndromic hypospadias, penoscrotal transposition and anorectal malformations. PMID:17476316

  19. Deletion of pyruvate decarboxylase by a new method for efficient markerless gene deletions in Gluconobacter oxydans.

    PubMed

    Peters, Björn; Junker, Anja; Brauer, Katharina; Mühlthaler, Bernadette; Kostner, David; Mientus, Markus; Liebl, Wolfgang; Ehrenreich, Armin

    2013-03-01

    Gluconobacter oxydans, a biotechnologically relevant species which incompletely oxidizes a large variety of carbohydrates, alcohols, and related compounds, contains a gene for pyruvate decarboxylase (PDC). This enzyme is found only in very few species of bacteria where it is normally involved in anaerobic ethanol formation via acetaldehyde. In order to clarify the role of PDC in the strictly oxidative metabolism of acetic acid bacteria, we developed a markerless in-frame deletion system for strain G. oxydans 621H which uses 5-fluorouracil together with a plasmid-encoded uracil phosphoribosyltransferase as counter selection method and used this technique to delete the PDC gene (GOX1081) of G. oxydans 621H. The PDC deletion mutant accumulated large amounts of pyruvate but almost no acetate during growth on D-mannitol, D-fructose or in the presence of L-lactate. This suggested that in G. oxydans acetate formation occurs by decarboxylation of pyruvate and subsequent oxidation of acetaldehyde to acetate. This observation and the efficiency of the markerless deletion system were confirmed by constructing deletion mutants of two acetaldehyde dehydrogenases (GOX1122 and GOX2018) and of the acetyl-CoA-synthetase (GOX0412). Acetate formation during growth of these mutants on mannitol did not differ significantly from the wild-type strain.

  20. Interstitial deletion of proximal 8q including part of the centromere from unbalanced segregation of a paternal deletion/marker karyotype with neocentromere formation at 8p22.

    PubMed

    Burnside, R D; Ibrahim, J; Flora, C; Schwartz, S; Tepperberg, J H; Papenhausen, P R; Warburton, P E

    2011-01-01

    The 'McClintock mechanism' of chromosome breakage and centromere misdivision, in which a deleted chromosome with its concomitant excised marker or ring chromosome is formed, has been described in approximately one dozen reports. We report a case of a girl with short stature, developmental delay, and dysmorphic features. Analysis was performed on the proband and father using cytogenetic chromosome analysis and the Affymetrix 6.0 SNP microarray. Fluorescence in situ hybridization (FISH) using a chromosome 8 alpha-satellite probe and immunofluorescence with antibodies to CENP-C were used to examine the centromere positions in these chromosomes. An abnormal chromosome 8 with a cytogenetically visible deletion was further defined by SNP array as a 10.6-Mb deletion from 8q11.1→q12.1. FISH with a chromosome 8 alpha-satellite probe demonstrated that the deletion removed a significant portion of the pericentromeric alpha-satellite repeat sequences and proximal q arm. The deleted chromosome 8 appeared to have a constriction at 8p22, suggesting the formation of a neocentromere, even though alpha-satellite sequences still appeared at the normal location. Chromosome analysis of the phenotypically normal father revealed the same deleted chromosome 8, as well as an apparently balancing mosaic marker chromosome 8. FISH studies revealed that the majority of the chromosome 8 alpha-satellite DNA resided in the marker chromosome. Immunofluorescence studies with antibodies to CENP-C, a kinetochore protein, proved the presence of a neocentromere at 8p22. The excision of the marker from the deleted chromosome 8 likely necessitated the formation of a new kinetochore at the 8p22 neocentromere to stabilize the chromosome during mitosis. This case clearly illustrates the utilization of classic cytogenetics, FISH, and array technologies to better characterize chromosomal abnormalities and provide information on recurrence risks. It also represents a rare case where a neocentromere can form

  1. Memory in Intellectually Matched Groups of Young Participants with 22q11.2 Deletion Syndrome and Those with Schizophrenia

    ERIC Educational Resources Information Center

    Kravariti, Eugenia; Jacobson, Clare; Morris, Robin; Frangou, Sophia; Murray, Robin M.; Tsakanikos, Elias; Habel, Alex; Shearer, Jo

    2010-01-01

    The 22q11.2 deletion syndrome (22qDS) and schizophrenia have genetic and neuropsychological similarities, but are likely to differ in memory profile. Confirming differences in memory function between the two disorders, and identifying their genetic determinants, can help to define genetic subtypes in both syndromes, identify genetic risk factors…

  2. Memory in Intellectually Matched Groups of Young Participants with 22q11.2 Deletion Syndrome and Those with Schizophrenia

    ERIC Educational Resources Information Center

    Kravariti, Eugenia; Jacobson, Clare; Morris, Robin; Frangou, Sophia; Murray, Robin M.; Tsakanikos, Elias; Habel, Alex; Shearer, Jo

    2010-01-01

    The 22q11.2 deletion syndrome (22qDS) and schizophrenia have genetic and neuropsychological similarities, but are likely to differ in memory profile. Confirming differences in memory function between the two disorders, and identifying their genetic determinants, can help to define genetic subtypes in both syndromes, identify genetic risk factors…

  3. Targeted gene deletion in Zygosaccharomyces bailii.

    PubMed

    Mollapour, M; Piper, P

    2001-01-30

    Yeasts of the genus Zygosaccharomyces are notable agents of large-scale food spoilage. Despite the economic importance of these organisms, little is known about the stress adaptations whereby they adapt to many of the more severe conditions of food preservation. In this study it was shown that genes of Z. bailii, a yeast notable for its high resistances to food preservatives and ethanol, can be isolated by complementation of the corresponding mutant strains of Saccharomyces cerevisiae. It was also discovered that the acquisition by S. cerevisiae of a single small Z. bailii gene (ZbYME2) was sufficient for the former yeast to acquire the ability to degrade two major food preservatives, benzoic acid and sorbic acid. Using DNA cassettes containing dominant selectable markers and methods originally developed for performing gene deletions in S. cerevisiae, the two copies of ZbYME2 in the Z. bailii genome were sequentially deleted. The resulting Zbyme2/Zbyme2 homozygous deletant strain had lost any ability to utilize benzoate as sole carbon source and was more sensitive to weak acid preservatives during growth on glucose. Thus, ZbYME2, probably the nuclear gene for a mitochondrial mono-oxygenase function, is essential for Z. bailii to degrade food preservatives. This ability to catabolize weak acid preservatives is a significant factor contributing to the preservative resistance of Z. bailii under aerobic conditions. This study is the first to demonstrate that it is possible to delete in Z. bailii genes that are suspected as being important for growth of this organism in preserved foods and beverages. With the construction of further mutant of Z. bailii strains, a clearer picture should emerge of how this yeast adapts to the conditions of food preservation. This information will, in turn, allow the design of new preservation strategies. GenBank Accession Nos: ZbURA3 (AF279259), ZbTIM9 (AF279260), ZbYME2 (AF279261), ZbTRP1 (AF279262), ZbHHT1(AF296170).

  4. Writing and deleting single magnetic skyrmions.

    PubMed

    Romming, Niklas; Hanneken, Christian; Menzel, Matthias; Bickel, Jessica E; Wolter, Boris; von Bergmann, Kirsten; Kubetzka, André; Wiesendanger, Roland

    2013-08-09

    Topologically nontrivial spin textures have recently been investigated for spintronic applications. Here, we report on an ultrathin magnetic film in which individual skyrmions can be written and deleted in a controlled fashion with local spin-polarized currents from a scanning tunneling microscope. An external magnetic field is used to tune the energy landscape, and the temperature is adjusted to prevent thermally activated switching between topologically distinct states. Switching rate and direction can then be controlled by the parameters used for current injection. The creation and annihilation of individual magnetic skyrmions demonstrates the potential for topological charge in future information-storage concepts.

  5. Molecular definition of the shortest region of deletion overlap in the Langer-Giedion syndrome

    PubMed Central

    Lüdecke, Hermann-Josef; Johnson, Carey; Wagner, Michael J.; Wells, Dan E.; Turleau, Catherine; Tommerup, Niels; Latos-Bielenska, Anna; Sandig, Klaus-Rainer; Meinecke, Peter; Zabel, Bernhard; Horsthemke, Bernhard

    1991-01-01

    The Langer-Giedion syndrome (LGS), which is characterized by craniofacial dysmorphism and skeletal abnormalities, is caused by a genetic defect in 8q24.1. We have used 13 anonymous DNA markers from an 8q24.1-specific microdissection library, as well as c-myc and thyroglobulin gene probes, to map the deletion breakpoints in 16 patients with LGS. Twelve patients had a cytogenetically visible deletion, two patients had an apparently balanced translocation, and two patients had an apparently normal karyotype. In all cases except one translocation patient, loss of genetic material was detected. The DNA markers fall into 10 deletion intervals. Clone L48 (D8S51) defines the shortest region of deletion overlap (SRO), which is estimated to be less than 2 Mbp. Three clones–pl7-2.3EE (D8S43), L24 (D8S45), and L40 (D8S49)–which flank the SRO recognize evolutionarily conserved sequences. ImagesFigure 1Figure 3Figure 4 PMID:1836105

  6. Deletion of neuropilin 2 enhances detrusor contractility following bladder outlet obstruction

    PubMed Central

    Vasquez, Evalynn; Cristofaro, Vivian; Lukianov, Stefan; Burkhard, Fiona C.; Monastyrskaya, Katia; Bielenberg, Diane R.; Sullivan, Maryrose P.; Adam, Rosalyn M.

    2017-01-01

    Chronic urethral obstruction and the ensuing bladder wall remodeling can lead to diminished bladder smooth muscle (BSM) contractility and debilitating lower urinary tract symptoms. No effective pharmacotherapy exists to restore BSM contractile function. Neuropilin 2 (Nrp2) is a transmembrane protein that is highly expressed in BSM. Nrp2 deletion in mice leads to increased BSM contraction. We determined whether genetic ablation of Nrp2 could restore BSM contractility following obstruction. Partial bladder outlet obstruction (pBOO) was created by urethral occlusion in mice with either constitutive and ubiquitous, or inducible smooth muscle–specific deletion of Nrp2, and Nrp2-intact littermates. Mice without obstruction served as additional controls. Contractility was measured by isometric tension testing. Nrp2 deletion prior to pBOO increased force generation in BSM 4 weeks following surgery. Deletion of Nrp2 in mice already subjected to pBOO for 4 weeks showed increased contractility of tissues tested 6 weeks after surgery compared with nondeleted controls. Assessment of tissues from patients with urodynamically defined bladder outlet obstruction revealed reduced NRP2 levels in obstructed bladders with compensated compared with decompensated function, relative to asymptomatic controls. We conclude that downregulation of Nrp2 promotes BSM force generation. Neuropilin 2 may represent a novel target to restore contractility following obstruction. PMID:28194441

  7. Genotype–Phenotype Association Studies of Chromosome 8p Inverted Duplication Deletion Syndrome

    PubMed Central

    Davis, Ryan; Youngblom, Janey; Gregg, Jeff

    2015-01-01

    Individuals diagnosed with chromosome 8p inverted duplication deletion (invdupdel(8p)) manifest a wide range of clinical features and cognitive impairment. The purpose of this study is to employ array CGH technology to define more precisely the cytogenetic breakpoints and regions of copy number variation found in several individuals with invdupdel(8p), and compare these results with their neuropsychological characteristics. We examined the cognitive-behavioral features of two male and two female children, ages 3–15 years, with invdupdel(8p). We noted cognitive deficits that ranged from mild to severe, and adaptive behavior composites that ranged from significantly to substantially lower than adequate levels. CARS scores, a measure of autistic behavior, identified three children with autism or autistic-like features. Three of the four children exhibited attention deficits and hyperactivity consistent with a DSM-IV-TR diagnosis of ADHD. One child showed extreme emotional lability. Interestingly, intellectual disability was not correlated with deletion size, nor was the deletion location associated with the autistic phenotype. On the other hand, the duplication length in 8p21.1/8p22 was associated with cognitive deficit. In addition, a small locus of over-expression in 8p21.3 was common for all three participants diagnosed as autistic. A limitation of the study is its small sample size. Further analyses of the deleted and over-expressed regions are needed to ascertain the genes involved in cognitive function and, possibly, autism. PMID:21259039

  8. Deletion of neuropilin 2 enhances detrusor contractility following bladder outlet obstruction.

    PubMed

    Vasquez, Evalynn; Cristofaro, Vivian; Lukianov, Stefan; Burkhard, Fiona C; Gheinani, Ali Hashemi; Monastyrskaya, Katia; Bielenberg, Diane R; Sullivan, Maryrose P; Adam, Rosalyn M

    2017-02-09

    Chronic urethral obstruction and the ensuing bladder wall remodeling can lead to diminished bladder smooth muscle (BSM) contractility and debilitating lower urinary tract symptoms. No effective pharmacotherapy exists to restore BSM contractile function. Neuropilin 2 (Nrp2) is a transmembrane protein that is highly expressed in BSM. Nrp2 deletion in mice leads to increased BSM contraction. We determined whether genetic ablation of Nrp2 could restore BSM contractility following obstruction. Partial bladder outlet obstruction (pBOO) was created by urethral occlusion in mice with either constitutive and ubiquitous, or inducible smooth muscle-specific deletion of Nrp2, and Nrp2-intact littermates. Mice without obstruction served as additional controls. Contractility was measured by isometric tension testing. Nrp2 deletion prior to pBOO increased force generation in BSM 4 weeks following surgery. Deletion of Nrp2 in mice already subjected to pBOO for 4 weeks showed increased contractility of tissues tested 6 weeks after surgery compared with nondeleted controls. Assessment of tissues from patients with urodynamically defined bladder outlet obstruction revealed reduced NRP2 levels in obstructed bladders with compensated compared with decompensated function, relative to asymptomatic controls. We conclude that downregulation of Nrp2 promotes BSM force generation. Neuropilin 2 may represent a novel target to restore contractility following obstruction.

  9. Deleting 'irrational' responses from discrete choice experiments: a case of investigating or imposing preferences?

    PubMed

    Lancsar, Emily; Louviere, Jordan

    2006-08-01

    Investigation of the 'rationality' of responses to discrete choice experiments (DCEs) has been a theme of research in health economics. Responses have been deleted from DCEs where they have been deemed by researchers to (a) be 'irrational', defined by such studies as failing tests for non-satiation, or (b) represent lexicographic preferences. This paper outlines a number of reasons why deleting responses from DCEs may be inappropriate after first reviewing the theory underpinning rationality, highlighting that the importance placed on rationality depends on the approach to consumer theory to which one ascribes. The aim of this paper is not to suggest that all preferences elicited via DCEs are rational. Instead, it is to suggest a number of reasons why it may not be the case that all preferences labelled as 'irrational' are indeed so. Hence, deleting responses may result in the removal of valid preferences; induce sample selection bias; and reduce the statistical efficiency and power of the estimated choice models. Further, evidence suggests random utility theory may be able to cope with such preferences. Finally, we discuss a number of implications for the design, implementation and interpretation of DCEs and recommend caution regarding the deletion of preferences from stated preference experiments. Copyright 2006 John Wiley & Sons, Ltd.

  10. Use of Cre-adenovirus and CAR transgenic mice for efficient deletion of genes in post-thymic T cells

    PubMed Central

    Zha, Yuanyuan; Shah, Ramila; Locke, Frederick; Wong, Austin; Gajewski, Thomas F.

    2012-01-01

    Conditional gene deletion using lineage-specific transgenic expression of Cre has been useful for defining the role of specific gene products in mice in vivo. However, this technology has had limitations for studies of peripheral T cell biology, since the T-lineage promoters commonly used are active early in thymic development. As such, T cell development can be altered by the resulting genetic alterations, thus limiting the interpretation of the data in post-thymic T cell studies. Thus, new strategies are needed to delete targeted genes directly in peripheral T lymphocytes. The availability of transgenic mice expressing the CAR in the T cell compartment enabled testing of Cre-mediated recombination using an adenoviral vector in naïve peripheral T cells in vitro, even without cellular activation. Using Rosa26R reporter×CAR transgenic mice, we describe conditions by which Cre-mediated deletion of targeted genes can be achieved with primary T cells in vitro. These cells can also be adoptively transferred into defined recipient mice for study in vivo. We use conditional PTEN-deficient mice as proof of concept to confirm the value of this technique for deleting a negative regulator of T cell activation. This technology should be broadly applicable for studies of T cell specific gene deletion to gain understanding of function in the post-thymic T cell compartment. PMID:18177887

  11. Chassis organism from Corynebacterium glutamicum – a top-down approach to identify and delete irrelevant gene clusters

    PubMed Central

    Unthan, Simon; Baumgart, Meike; Radek, Andreas; Herbst, Marius; Siebert, Daniel; Brühl, Natalie; Bartsch, Anna; Bott, Michael; Wiechert, Wolfgang; Marin, Kay; Hans, Stephan; Krämer, Reinhard; Seibold, Gerd; Frunzke, Julia; Kalinowski, Jörn; Rückert, Christian; Wendisch, Volker F; Noack, Stephan

    2015-01-01

    For synthetic biology applications, a robust structural basis is required, which can be constructed either from scratch or in a top-down approach starting from any existing organism. In this study, we initiated the top-down construction of a chassis organism from Corynebacterium glutamicum ATCC 13032, aiming for the relevant gene set to maintain its fast growth on defined medium. We evaluated each native gene for its essentiality considering expression levels, phylogenetic conservation, and knockout data. Based on this classification, we determined 41 gene clusters ranging from 3.7 to 49.7 kbp as target sites for deletion. 36 deletions were successful and 10 genome-reduced strains showed impaired growth rates, indicating that genes were hit, which are relevant to maintain biological fitness at wild-type level. In contrast, 26 deleted clusters were found to include exclusively irrelevant genes for growth on defined medium. A combinatory deletion of all irrelevant gene clusters would, in a prophage-free strain, decrease the size of the native genome by about 722 kbp (22%) to 2561 kbp. Finally, five combinatory deletions of irrelevant gene clusters were investigated. The study introduces the novel concept of relevant genes and demonstrates general strategies to construct a chassis suitable for biotechnological application. PMID:25139579

  12. A coalescence of two syndromes in a girl with terminal deletion and inverted duplication of chromosome 5.

    PubMed

    Krgovic, Danijela; Blatnik, Ana; Burmas, Ante; Zagorac, Andreja; Kokalj Vokac, Nadja

    2014-02-11

    Rearrangements involving chromosome 5p often result in two syndromes, Cri-du-chat (CdC) and Trisomy 5p, caused by a deletion and duplication, respectively. The 5p15.2 has been defined as a critical region for CdC syndrome; however, genotype-phenotype studies allowed isolation of particular characteristics such as speech delay, cat-like cry and mental retardation, caused by distinct deletions of 5p. A varied clinical outcome was also observed in patients with Trisomy 5p. Duplications of 5p10-5p13.1 manifest themselves in a more severe phenotype, while trisomy of regions distal to 5p13 mainly causes mild and indistinct features. Combinations of a terminal deletion and inverted duplication of 5p are infrequent in literature. Consequences of these chromosomal rearrangements differ, depending on size of deletion and duplication in particular cases, although authors mainly describe the deletion as the cause of the observed clinical picture. Here we present a 5-month-old Slovenian girl, with de novo terminal deletion and inverted duplication of chromosome 5p. Our patient presents features of both CdC and Trisomy 5. The most prominent features observed in our patient are a cat-like cry and severe malformations of the right ear. The cat-like cry, characteristic of CdC syndrome, is noted in our patient despite the fact that the deletion is not fully consistent with previously defined cat-like cry critical region in this syndrome. Features like dolichocephaly, macrocephaly and ear malformations, associated with duplication of the critical region of Trisomy 5p, are also present, although this region has not been rearranged in our case. Therefore, the true meaning of the described chromosomal rearrangements is discussed.

  13. A coalescence of two syndromes in a girl with terminal deletion and inverted duplication of chromosome 5

    PubMed Central

    2014-01-01

    Background Rearrangements involving chromosome 5p often result in two syndromes, Cri-du-chat (CdC) and Trisomy 5p, caused by a deletion and duplication, respectively. The 5p15.2 has been defined as a critical region for CdC syndrome; however, genotype-phenotype studies allowed isolation of particular characteristics such as speech delay, cat-like cry and mental retardation, caused by distinct deletions of 5p. A varied clinical outcome was also observed in patients with Trisomy 5p. Duplications of 5p10-5p13.1 manifest themselves in a more severe phenotype, while trisomy of regions distal to 5p13 mainly causes mild and indistinct features. Combinations of a terminal deletion and inverted duplication of 5p are infrequent in literature. Consequences of these chromosomal rearrangements differ, depending on size of deletion and duplication in particular cases, although authors mainly describe the deletion as the cause of the observed clinical picture. Case presentation Here we present a 5-month-old Slovenian girl, with de novo terminal deletion and inverted duplication of chromosome 5p. Our patient presents features of both CdC and Trisomy 5. The most prominent features observed in our patient are a cat-like cry and severe malformations of the right ear. Conclusion The cat-like cry, characteristic of CdC syndrome, is noted in our patient despite the fact that the deletion is not fully consistent with previously defined cat-like cry critical region in this syndrome. Features like dolichocephaly, macrocephaly and ear malformations, associated with duplication of the critical region of Trisomy 5p, are also present, although this region has not been rearranged in our case. Therefore, the true meaning of the described chromosomal rearrangements is discussed. PMID:24517234

  14. Analysis of chromosome 22 deletions in neurofibromatosis type 2-related tumors

    SciTech Connect

    Wolff, R.K.; Frazer, K.A.; Jackler, R.K.; Lanser, M.J.; Pitts, L.H.; Cox, D.R. )

    1992-09-01

    The neurofibromatosis type 2 (NF2) gene has been hypothesized to be a recessive tumor suppressor, with mutations at the same locus on chromosome 22 that lead to NF2 also leading to sporadic tumors of the types seen in NF2. Flanking markers for this gene have previously been defined as D22S1 centromeric and D22S28 telomeric. Identification of subregions of this interval that are consistently rearranged in the NF2-related tumors would aid in better defining the disease locus. To this end, the authors have compared tumor and constitutional DNAs, isolated from 39 unrelated patients with sporadic and NF2-associated acoustic neuromas, meningiomas, schwannomas, and ependymomas, at eight polymorphic loci on chromosome 22. Two of the tumors studied revealed loss-of-heterozygosity patterns, which is consistent with the presence of chromosome 22 terminal deletions. By using additional polymorphic markers, the terminal deletion breakpoint found in one of the tumors, an acoustic neuroma from an NF2 patient, was mapped within the previously defined NF2 region. The breakpoint occurred between the haplotyped markers D22S41/D22S46 and D22S56. This finding redefines the proximal flanking marker and localizes the NF2 gene between markers D22S41/D22S46 and D22S28. In addition, the authors identified a sporadic acoustic neuroma that reveals a loss-of-heterozygosity pattern consistent with mitotic recombination or deletion and reduplication, which are mechanisms not previously seen in studies of these tumors. This finding, while inconsistent with models of tumorigenesis that invoke single deletions and their gene-dosage effects, lends further support to the recessive tumor-suppressor model. 33 refs., 2 figs., 1 tab.

  15. Microarray based comparative genomic hybridization testing in deletion bearing patients with Angelman syndrome: genotype-phenotype correlations.

    PubMed

    Sahoo, T; Peters, S U; Madduri, N S; Glaze, D G; German, J R; Bird, L M; Barbieri-Welge, R; Bichell, T J; Beaudet, A L; Bacino, C A

    2006-06-01

    Angelman syndrome (AS) is a neurodevelopmental disorder characterised by severe mental retardation, dysmorphic features, ataxia, seizures, and typical behavioural characteristics, including a happy sociable disposition. AS is caused by maternal deficiency of UBE3A (E6 associated protein ubiquitin protein ligase 3A gene), located in an imprinted region on chromosome 15q11-q13. Although there are four different molecular types of AS, deletions of the 15q11-q13 region account for approximately 70% of the AS patients. These deletions are usually detected by fluorescence in situ hybridisation studies. The deletions can also be subclassified based on their size into class I and class II, with the former being larger and encompassing the latter. We studied 22 patients with AS due to microdeletions using a microarray based comparative genomic hybridisation (array CGH) assay to define the deletions and analysed their phenotypic severity, especially expression of the autism phenotype, in order to establish clinical correlations. Overall, children with larger, class I deletions were significantly more likely to meet criteria for autism, had lower cognitive scores, and lower expressive language scores compared with children with smaller, class II deletions. Children with class I deletions also required more medications to control their seizures than did those in the class II group. There are four known genes (NIPA1, NIPA2, CYFIP1, & GCP5) that are affected by class I but not class II deletions, thus raising the possibility of a role for these genes in autism as well as the development of expressive language skills.

  16. The cognitive and behavioral phenotype of the 16p11.2 deletion in a clinically ascertained population.

    PubMed

    Hanson, Ellen; Bernier, Raphael; Porche, Ken; Jackson, Frank I; Goin-Kochel, Robin P; Snyder, LeeAnne Green; Snow, Anne V; Wallace, Arianne Stevens; Campe, Katherine L; Zhang, Yuan; Chen, Qixuan; D'Angelo, Debra; Moreno-De-Luca, Andres; Orr, Patrick T; Boomer, K B; Evans, David W; Kanne, Stephen; Berry, Leandra; Miller, Fiona K; Olson, Jennifer; Sherr, Elliot; Martin, Christa L; Ledbetter, David H; Spiro, John E; Chung, Wendy K

    2015-05-01

    Deletion of the recurrent ~600 kb BP4-BP5 chromosomal region 16p11.2 has been associated with a wide range of neurodevelopmental outcomes. To clarify the phenotype of 16p11.2 deletion, we examined the psychiatric and developmental presentation of predominantly clinically referred individuals, with a particular emphasis on broader autism phenotype characteristics in individuals with recurrent ~600 kb chromosome 16p11.2 deletions. Using an extensive standardized assessment battery across three clinical sites, 85 individuals with the 16p11.2 deletion and 153 familial control subjects were evaluated for symptom presentation and clinical diagnosis. Individuals with the 16p11.2 deletion presented with a high frequency of psychiatric and developmental disorders (>90%). The most commonly diagnosed conditions were developmental coordination disorder, phonologic processing disorder, expressive and receptive language disorders (71% of individuals >3 years old with a speech and language-related disorder), and autism spectrum disorder. Individuals with the 16p11.2 deletion not meeting diagnostic criteria for autism spectrum disorder had a significantly higher prevalence of autism-related characteristics compared with the familial noncarrier control group. Individuals with the 16p11.2 deletion had a range of intellectual ability, but IQ scores were 26 points lower than noncarrier family members on average. Clinically referred individuals with the 16p11.2 deletion have high rates of psychiatric and developmental disorders and provide a genetically well-defined group to study the emergence of developmental difficulties, particularly associated with the broader autism phenotype. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  17. Presence of Large Deletions in Kindreds with Autism

    PubMed Central

    Yu, Chang-En; Dawson, Geraldine; Munson, Jeffrey; D’Souza, Ian; Osterling, Julie; Estes, Annette; Leutenegger, Anne-Louise; Flodman, Pamela; Smith, Moyra; Raskind, Wendy H.; Spence, M. Anne; McMahon, William; Wijsman, Ellen M.; Schellenberg, Gerard D.

    2002-01-01

    Autism is caused, in part, by inheritance of multiple interacting susceptibility alleles. To identify these inherited factors, linkage analysis of multiplex families is being performed on a sample of 105 families with two or more affected sibs. Segregation patterns of short tandem repeat polymorphic markers from four chromosomes revealed null alleles at four marker sites in 12 families that were the result of deletions ranging in size from 5 to >260 kb. In one family, a deletion at marker D7S630 was complex, with two segments deleted (37 kb and 18 kb) and two retained (2,836 bp and 38 bp). Three families had deletions at D7S517, with each family having a different deletion (96 kb, 183 kb, and >69 kb). Another three families had deletions at D8S264, again with each family having a different deletion, ranging in size from <5.9 kb to >260 kb. At a fourth marker, D8S272, a 192-kb deletion was found in five families. Unrelated subjects and additional families without autism were screened for deletions at these four sites. Families screened included 40 families from Centre d'Etude du Polymorphisme Humaine and 28 families affected with learning disabilities. Unrelated samples were 299 elderly control subjects, 121 younger control subjects, and 248 subjects with Alzheimer disease. The deletion allele at D8S272 was found in all populations screened. For the other three sites, no additional deletions were identified in any of the groups without autism. Thus, these deletions appear to be specific to autism kindreds and are potential autism-susceptibility alleles. An alternative hypothesis is that autism-susceptibility alleles elsewhere cause the deletions detected here, possibly by inducing errors during meiosis. PMID:12058345

  18. AZF deletions in infertile men from the Republic of Macedonia.

    PubMed

    Plaseski, Toso; Novevski, Predrag; Kocevska, Borka; Dimitrovski, Cedomir; Efremov, Georgi D; Plaseska-Karanfilska, Dijana

    2006-07-01

    Y chromosome deletions in the three azoospermia factor (AZF) regions constitute the most common genetic cause of spermatogenic failure. The aim of this study was to estimate the length and boundaries of the AZF deletions and to correlate the AZF deletions with the sperm concentrations, testicular histology, Y haplogroups and the ethnic origin of the men with deletions. PCR analysis of STS loci in the three AZF regions was used to characterize the deletions. Y haplogroup was predicted from a set of 17 Y short tandem repeats (STR) marker values. A total of nine men out of 218 infertile/subfertile men showed the presence of Y microdeletions. In eight patients the results were consistent with the presence of AZFc deletions, while in one patient a larger deletion involving both AZFb and AZFc regions was detected. In two patients, the deletion, initially diagnosed as AZFc, involved part of the distal part of the AZFb region and in one of them the deletion also extended into the region distal to the AZFc. The 3.5 Mb AZFc deletion, due to homologous recombination between b2 and b4 amplicons, was detected in six men (66.7% of all Y deletions), thus being the most common type of AZF deletion among infertile men from the Republic of Macedonia. Patients with the 3.5 Mb AZFc deletion had azoospermia or severe oligozoospermia and variable histological results [Sertoly cell only syndrome (SCOS), maturity arrest (MA) and hypospermatogenesis (HSG)]. They were of different ethnic origin (Macedonian, Albanian and Romany) and belonged to different Y haplogroups (I1b, J2, E3b and G).

  19. A genome-wide study of de novo deletions identifies a candidate locus for non-syndromic isolated cleft lip/palate risk

    PubMed Central

    2014-01-01

    Background Copy number variants (CNVs) may play an important part in the development of common birth defects such as oral clefts, and individual patients with multiple birth defects (including clefts) have been shown to carry small and large chromosomal deletions. In this paper we investigate de novo deletions defined as DNA segments missing in an oral cleft proband but present in both unaffected parents. We compare de novo deletion frequencies in children of European ancestry with an isolated, non-syndromic oral cleft to frequencies in children of European ancestry from randomly sampled trios. Results We identified a genome-wide significant 62 kilo base (kb) non-coding region on chromosome 7p14.1 where de novo deletions occur more frequently among oral cleft cases than controls. We also observed wider de novo deletions among cleft lip and palate (CLP) cases than seen among cleft palate (CP) and cleft lip (CL) cases. Conclusions This study presents a region where de novo deletions appear to be involved in the etiology of oral clefts, although the underlying biological mechanisms are still unknown. Larger de novo deletions are more likely to interfere with normal craniofacial development and may result in more severe clefts. Study protocol and sample DNA source can severely affect estimates of de novo deletion frequencies. Follow-up studies are needed to further validate these findings and to potentially identify additional structural variants underlying oral clefts. PMID:24528994

  20. Deletion of ultraconserved elements yields viable mice

    SciTech Connect

    Ahituv, Nadav; Zhu, Yiwen; Visel, Axel; Holt, Amy; Afzal, Veena; Pennacchio, Len A.; Rubin, Edward M.

    2007-07-15

    Ultraconserved elements have been suggested to retainextended perfect sequence identity between the human, mouse, and ratgenomes due to essential functional properties. To investigate thenecessities of these elements in vivo, we removed four non-codingultraconserved elements (ranging in length from 222 to 731 base pairs)from the mouse genome. To maximize the likelihood of observing aphenotype, we chose to delete elements that function as enhancers in amouse transgenic assay and that are near genes that exhibit markedphenotypes both when completely inactivated in the mouse as well as whentheir expression is altered due to other genomic modifications.Remarkably, all four resulting lines of mice lacking these ultraconservedelements were viable and fertile, and failed to reveal any criticalabnormalities when assayed for a variety of phenotypes including growth,longevity, pathology and metabolism. In addition more targeted screens,informed by the abnormalities observed in mice where genes in proximityto the investigated elements had been altered, also failed to revealnotable abnormalities. These results, while not inclusive of all thepossible phenotypic impact of the deleted sequences, indicate thatextreme sequence constraint does not necessarily reflect crucialfunctions required for viability.

  1. Method for introducing unidirectional nested deletions

    DOEpatents

    Dunn, John J.; Quesada, Mark A.; Randesi, Matthew

    1999-07-27

    Disclosed is a method for the introduction of unidirectional deletions in a cloned DNA segment. More specifically, the method comprises providing a recombinant DNA construct comprising a DNA segment of interest inserted in a cloning vector, the cloning vector having an f1 endonuclease recognition sequence adjacent to the insertion site of the DNA segment of interest. The recombinant DNA construct is then contacted with the protein pII encoded by gene II of phage f1 thereby generating a single-stranded nick. The nicked DNA is then contacted with E. coli Exonuclease III thereby expanding the single-stranded nick into a single-stranded gap. The single-stranded gapped DNA is then contacted with a single-strand-specific endonuclease thereby producing a linearized DNA molecule containing a double-stranded deletion corresponding in size to the single-stranded gap. The DNA treated in this manner is then incubated with DNA ligase under conditions appropriate for ligation. Also disclosed is a method for producing single-stranded DNA probes. In this embodiment, single-stranded gapped DNA, produced as described above, is contacted with a DNA polymerase in the presence of labeled nucleotides to fill in the gap. This DNA is then linearized by digestion with a restriction enzyme which cuts outside the DNA segment of interest. The product of this digestion is then denatured to produce a labeled single-stranded nucleic acid probe.

  2. Method for introducing unidirectional nested deletions

    DOEpatents

    Dunn, J.J.; Quesada, M.A.; Randesi, M.

    1999-07-27

    Disclosed is a method for the introduction of unidirectional deletions in a cloned DNA segment. More specifically, the method comprises providing a recombinant DNA construct comprising a DNA segment of interest inserted in a cloning vector. The cloning vector has an f1 endonuclease recognition sequence adjacent to the insertion site of the DNA segment of interest. The recombinant DNA construct is then contacted with the protein pII encoded by gene II of phage f1 thereby generating a single-stranded nick. The nicked DNA is then contacted with E. coli Exonuclease III thereby expanding the single-stranded nick into a single-stranded gap. The single-stranded gapped DNA is then contacted with a single-strand-specific endonuclease thereby producing a linearized DNA molecule containing a double-stranded deletion corresponding in size to the single-stranded gap. The DNA treated in this manner is then incubated with DNA ligase under conditions appropriate for ligation. Also disclosed is a method for producing single-stranded DNA probes. In this embodiment, single-stranded gapped DNA, produced as described above, is contacted with a DNA polymerase in the presence of labeled nucleotides to fill in the gap. This DNA is then linearized by digestion with a restriction enzyme which cuts outside the DNA segment of interest. The product of this digestion is then denatured to produce a labeled single-stranded nucleic acid probe. 1 fig.

  3. Clarifying and Defining Library Services.

    ERIC Educational Resources Information Center

    Shubert, Joseph F., Ed.; Josey, E. J., Ed.

    1991-01-01

    This issue presents articles which, in some way, help to clarify and define library services. It is hoped that this clarification in library service will serve to secure the resources libraries need to serve the people of New York. The following articles are presented: (1) Introduction: "Clarifying and Defining Library Services" (Joseph…

  4. Whole genome HBV deletion profiles and the accumulation of preS deletion mutant during antiviral treatment

    PubMed Central

    2012-01-01

    Background Hepatitis B virus (HBV), because of its error-prone viral polymerase, has a high mutation rate leading to widespread substitutions, deletions, and insertions in the HBV genome. Deletions may significantly change viral biological features complicating the progression of liver diseases. However, the clinical conditions correlating to the accumulation of deleted mutants remain unclear. In this study, we explored HBV deletion patterns and their association with disease status and antiviral treatment by performing whole genome sequencing on samples from 51 hepatitis B patients and by monitoring changes in deletion variants during treatment. Clone sequencing was used to analyze preS regions in another cohort of 52 patients. Results Among the core, preS, and basic core promoter (BCP) deletion hotspots, we identified preS to have the highest frequency and the most complex deletion pattern using whole genome sequencing. Further clone sequencing analysis on preS identified 70 deletions which were classified into 4 types, the most common being preS2. Also, in contrast to the core and BCP regions, most preS deletions were in-frame. Most deletions interrupted viral surface epitopes, and are possibly involved in evading immuno-surveillance. Among various clinical factors examined, logistic regression showed that antiviral medication affected the accumulation of deletion mutants (OR = 6.81, 95% CI = 1.296 ~ 35.817, P = 0.023). In chronic carriers of the virus, and individuals with chronic hepatitis, the deletion rate was significantly higher in the antiviral treatment group (Fisher exact test, P = 0.007). Particularly, preS2 deletions were associated with the usage of nucleos(t)ide analog therapy (Fisher exact test, P = 0.023). Dynamic increases in preS1 or preS2 deletions were also observed in quasispecies from samples taken from patients before and after three months of ADV therapy. In vitro experiments demonstrated that preS2 deletions alone

  5. Are there ethnic differences in deletions in the dystrophin gene?

    SciTech Connect

    Banerjee, M.; Verma, I.C.

    1997-01-20

    We studied 160 cases of Duchenne muscular dystrophy (DMD) drawn from all parts of India, using multiplex PCR of 27 exons. Of these, 103 (64.4%) showed intragenic deletions. Most (69.7%) of the deletions involved exons 45-51. The phenotype of cases with deletion of single exons did not differ significantly from those with deletion of multiple exons. The distribution of deletions in studies from different countries was variable, but this was accounted for either by the small number of cases studied, or by fewer exons analyzed. It is concluded that there is likely to be no ethnic difference with respect to deletions in the DMD gene. 38 refs., 2 figs., 3 tabs.

  6. Genomic deletions suggest a phylogeny for the Mycobacterium tuberculosis complex.

    PubMed

    Mostowy, Serge; Cousins, Debby; Brinkman, Jacqui; Aranaz, Alicia; Behr, Marcel A

    2002-07-01

    To better understand the evolution of the Mycobacterium tuberculosis complex, subspecies were tested for large sequence polymorphisms. Samples with greater numbers of deletions, without exception, were missing all the same regions that were deleted from samples with lesser numbers of deletions. Principal genetic groups based on single-nucleotide polymorphisms were restricted to one of the deletion-based groups, and isolates that shared genotypes based on molecular epidemiological markers were assigned almost exclusively to the same deletion type. The data provide compelling evidence that human tuberculosis did not originate from the present-day bovine form. Genomic deletions present themselves as an attractive modality to study the evolution of the M. tuberculosis complex.

  7. Assessing Trace Evidence Left by Secure Deletion Programs

    NASA Astrophysics Data System (ADS)

    Burke, Paul; Craiger, Philip

    Secure deletion programs purport to permanently erase files from digital media. These programs are used by businesses and individuals to remove sensitive information from media, and by criminals to remove evidence of the tools or fruits of illegal activities. This paper focuses on the trace evidence left by secure deletion programs. In particular, five Windows-based secure deletion programs are tested to determine if they leave identifiable signatures after deleting a file. The results show that the majority of the programs leave identifiable signatures. Moreover, some of the programs do not completely erase file metadata, which enables forensic investigators to extract the name, size, creation date and deletion date of the "deleted" files.

  8. Deletions of the elastin gene in Williams Syndrome

    SciTech Connect

    Greenberg, F.; Nickerson, E.; McCaskill, C.

    1994-09-01

    To investigate deletions in the elastin gene in patients with Williams Syndrome (WS), we screened 37 patients and their parents for deletions in the elastin gene by both fluorescence in situ hybridization (FISH) using cosmid cELN272 containing the 5{prime} end of the elastin gene and by polymerase chain reaction (PCR) using a primer pair which amplifies intron 17 in the elastin gene, producing a polymorphic amplification product. Thirty-two patients have been investigated by both the FISH and PCR techniques, one patient was studied only by PCR, and 4 patients were studied only by FISH. Overall, 34 of 37 patients (92%) were deleted for the elastin gene. Using the PCR marker, 14 patients were informative and 12 were shown to be deleted [maternal (n=5) and paternal (n=7)]. Using cosmid cELN272, 33 of 36 patients demonstrated a deletion of chromosome 7q11.23. In one family, both the mother and daughter were deleted due to an apparently de novo deletion arising in the mother. Three patients were not deleted using the elastin cosmid; 2 of these patients have classic WS. Another non-deleted patient has the typical facial features and hypercalcemia but normal intelligence. These three patients will be important in delineating the critical region(s) responsible for the facial features, hypercalcemia, mental retardation and supravalvular aortic stenosis (SVAS). There was not an absolute correlation between deletions in elastin and SVAS, although these individuals may be at risk for other cardiovascular complications such as hypertention. Since the majority of WS patients are deleted for a portion of the elastin gene, most likely this marker will be an important diagnostic tool, although more patients will need to be studied. Those patients who are not deleted but clinically have WS will be missed using only this one marker. Expansion of the critical region to other loci and identification of additional markers will be essential for identifying all patients with WS.

  9. NPL deletion policy for RCRA-regulated TSD facilities finalized

    SciTech Connect

    1995-05-01

    Under a new policy published by EPA on March 20, 1995, certain sites may be deleted from the National Priorities List (NPL) and deferred to RCRA corrective action. To be deleted from the NPL, a site must (1) be regulated under RCRA as a treatment, storage, or disposal (TSD) facility and (2) meet the four criteria specified by EPA. The new NPL deletion policy, which does not pertain to federal TSD facilities, became effective on April 19, 1995. 1 tab.

  10. Analysis of partial AZFc deletions in Malaysian infertile male subjects.

    PubMed

    Almeamar, Hussein Ali; Ramachandran, Vasudevan; Ismail, Patimah; Nadkarni, Prashan; Fawzi, Nora

    2013-04-01

    Complete deletions in the AZF (a, b, and c) sub-regions of the Y-chromosome have been shown to contribute to unexplained male infertility. However, the role of partial AZFc deletions in male infertility remains to be verified. Three types of partial AZFc deletions have been identified. They are gr/gr, b1/b3, and b2/b3 deletions. A recent meta-analysis showed that ethnic and geographical factors might contribute to the association of partial AZFc deletions with male infertility. This study analyzed the association of partial AZFc deletions in Malaysian infertile males. Fifty two oligozoospermic infertile males and 63 fertile controls were recruited to this study. Screening for partial AZFc deletions was done using the two sequence-tagged sites approach (SY1291 and SY1191) which were analyzed using both the conventional PCR gel-electrophoresis and the high resolution melt, HRM method. Gr/gr deletions were found in 11.53% of the cases and 9.52% of the controls (p = 0.725). A B2/b3 deletion was found in one of the cases (p = 0.269). No B1/b3 deletions were identified in this study. The results of HRM analysis were consistent with those obtained using the conventional PCR gel-electrophoresis method. The HRM analysis was highly repeatable (95% limit of agreement was -0.0879 to 0.0871 for SY1191 melting temperature readings). In conclusion, our study showed that partial AZFc deletions were not associated with male infertility in Malaysian subjects. HRM analysis was a reliable, repeatable, fast, cost-effective, and semi-automated method which can be used for screening of partial AZFc deletions.

  11. Otologic and audiologic findings in 22q11.2 deletion syndrome.

    PubMed

    Verheij, E; Kist, A L; Mink van der Molen, A B; Stegeman, I; van Zanten, G A; Grolman, W; Thomeer, H G X M

    2017-02-01

    Hearing loss is frequently present in the 22q11.2 deletion syndrome. Our aim was to describe the audiologic and otologic features of patients with 22q11.2 deletion syndrome. We conducted a retrospective cohort study in a single tertiary referral center. We reviewed medical files of all patients with 22q11.2 deletion syndrome who visited an otolaryngologist, plastic surgeon or speech therapist, for audiologic or otologic features. Hearing loss was defined as a pure tone average (of 0.5, 1, 2, and 4 kHz) of >20 decibel hearing level. Audiograms were available for 102 of 199 included patients, out of which 163 ears were measured in the required frquencies (0.5-4 kHz). Median age at time of most recent audiogram was 7 years (range 3-29 years). In 62 out of 163 ears (38%), hearing loss was present. Most ears had conductive hearing loss (n = 58) and 4 ears had mixed hearing loss. The severity of hearing loss was most frequently mild (pure tone average of ≤40 decibel hearing level). In 22.5% of ears, otitis media with effusion was observed at time of most recent audiogram. Age was not related to mean air conduction hearing thresholds or to otitis media with effusion (p = 0.43 and p = 0.11, respectively). In conclusion, hearing loss and otitis media are frequently present in patients with 22q11.2 deletion syndrome. Moreover, our results suggest that children with 22q11.2 deletion syndrome remain susceptible for otitis media as they age.

  12. Counterselection employing mutated pheS for markerless genetic deletion in Bacteroides species.

    PubMed

    Kino, Yasuhiro; Nakayama-Imaohji, Haruyuki; Fujita, Masashi; Tada, Ayano; Yoneda, Saori; Murakami, Kazuya; Hashimoto, Masahito; Hayashi, Tetsuya; Okazaki, Katsuichiro; Kuwahara, Tomomi

    2016-12-01

    Markerless gene deletion is necessary for multiple gene disruptions due to the limited number of antibiotic resistant markers for some bacteria. However, even in transformable strains, obtaining the expected mutation without a marker requires laborious screening of a large number of colonies. Previous studies had success in various bacteria with a counter-selection system where a conditional lethal gene was incorporated into the vector. We examined the efficacy of the mutated pheS gene (pheS*) as a counter-selective marker for gene deletion in Bacteroides. This mutation produces an amino acid substitution (A303G) in the alpha subunit of Bacteroides phenylalanyl tRNA synthetase, which in E. coli alters the specificity of the tRNA synthetase resulting in a conditional lethal mutation due to the incorporation of p-chloro-phenylalanine (p-Cl-Phe) into protein. B. fragilis YCH46 and B. thetaiotaomicron VPI-5482 transformed with a pheS*-harboring shuttle vector were clearly growth-inhibited in the presence of >5 mM p-Cl-Phe in liquid defined minimal media (DMM) and on DMM agar plates. A targeting plasmid was constructed to delete the genetic region for capsular polysaccharide PS2 in B. fragilis or PS1 in B. thetaiotaomicron. After counterselection, p-Cl-Phe-resistant colonies were generated at a frequency of 8.1 × 10(-3) for B. fragilis and 1.7 × 10(-3) for B. thetaiotaomicron. Of the p-Cl-Phe-resistant colonies, 4.2% and 72% harbored the correct genetic deletion for B. fragilis and B. thetaiotaomicron, respectively. These results indicate that mutated pheS is a useful counter-selective gene to construct markerless genetic deletions in Bacteroides. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Recurrent X chromosome-linked deletions: discovery of new genetic factors in male infertility.

    PubMed

    Lo Giacco, D; Chianese, C; Ars, E; Ruiz-Castañé, E; Forti, G; Krausz, C

    2014-05-01

    The role of X-linked genes and copy-number variations (CNVs) in male infertility remains poorly explored. Our previous array-CGH analyses showed three recurrent deletions in Xq exclusively (CNV67) and prevalently (CNV64, CNV69) found in patients. Molecular and clinical characterisation of these CNVs was performed in this study. 627 idiopathic infertile patients and 628 controls were tested for each deletion with PCR+/-. We used PCR+/- to map deletion junctions and long-range PCR and direct sequencing to define breakpoints. CNV64 was found in 5.7% of patients and in 3.1% of controls (p=0.013; OR=1.89; 95% CI 1.1 to 3.3) and CNV69 was found in 3.5% of patients and 1.6% of controls (p=0.023; OR=2.204; 95% CI 1.05 to 4.62). For CNV69 we identified two breakpoints, types A and B, with the latter being significantly more frequent in patients than controls (p=0.011; OR=9.19; 95% CI 1.16 to 72.8). CNV67 was detected exclusively in patients (1.1%) and was maternally transmitted. The semen phenotype of one carrier (11-041) versus his normozoospermic non-carrier brother strongly indicates a pathogenic effect of the deletion on spermatogenesis. MAGEA9, an ampliconic gene reported as independently acquired on the human X chromosome with exclusive physiological expression in the testis, is likely to be involved in CNV67. We provide the first evidence for X chromosome-linked recurrent deletions associated with spermatogenic impairment. CNV67, specific to spermatogenic anomaly and with a frequency of 1.1% in oligo/azoospermic men, resembles the AZF regions on the Y chromosome with potential clinical implications.

  14. Hereditary hemorrhagic telangiectasia: two distinct ENG deletions in one family.

    PubMed

    Wooderchak, W; Gedge, F; McDonald, M; Krautscheid, P; Wang, X; Malkiewicz, J; Bukjiok, C J; Lewis, T; Bayrak-Toydemir, P

    2010-11-01

    Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by aberrant vascular development. Mutations in endoglin (ENG) or activin A receptor type II-like 1 (ACVRL1) account for around 90% of HHT patients, 10% of those are large deletions or duplications. We report here the first observation of two distinct, large ENG deletions segregating in one pedigree. An ENG exon 4-7 deletion was observed in a patient with HHT. This deletion was identified in several affected family members. However, some affected family members had an ENG exon 3 deletion instead. These deletions were detected by multiplex ligation-dependent probe amplification and confirmed by mRNA sequencing and an oligo-CGH array. Linkage analysis revealed that one individual with the exon 3 deletion inherited the same chromosome from his mother who has the exon 4-7 deletion. This finding has important clinical implications because it shows that targeted family-specific mutation analysis for exon deletions could have led to the misdiagnosis of some affected family members. © 2010 John Wiley & Sons A/S.

  15. The Problem of Defining Intelligence.

    ERIC Educational Resources Information Center

    Lubar, David

    1981-01-01

    The major philosophical issues surrounding the concept of intelligence are reviewed with respect to the problems surrounding the process of defining and developing artificial intelligence (AI) in computers. Various current definitions and problems with these definitions are presented. (MP)

  16. Directed construction and analysis of a Sinorhizobium meliloti pSymA deletion mutant library.

    PubMed

    Yurgel, Svetlana N; Mortimer, Michael W; Rice, Jennifer T; Humann, Jodi L; Kahn, Michael L

    2013-03-01

    Resources from the Sinorhizobium meliloti Rm1021 open reading frame (ORF) plasmid libraries were used in a medium-throughput method to construct a set of 50 overlapping deletion mutants covering all of the Rm1021 pSymA megaplasmid except the replicon region. Each resulting pSymA derivative carried a defined deletion of approximately 25 ORFs. Various phenotypes, including cytochrome c respiration activity, the ability of the mutants to grow on various carbon and nitrogen sources, and the symbiotic effectiveness of the mutants with alfalfa, were analyzed. This approach allowed us to systematically evaluate the potential impact of regions of Rm1021 pSymA for their free-living and symbiotic phenotypes.

  17. Homozygous deletion in MICU1 presenting with fatigue and lethargy in childhood

    PubMed Central

    Lewis-Smith, David; Kamer, Kimberli J.; Griffin, Helen; Childs, Anne-Marie; Pysden, Karen; Titov, Denis; Duff, Jennifer; Pyle, Angela; Taylor, Robert W.; Yu-Wai-Man, Patrick; Ramesh, Venkateswaran; Horvath, Rita; Mootha, Vamsi K.

    2016-01-01

    Objective: To define the mechanism responsible for fatigue, lethargy, and weakness in 2 cousins who had a normal muscle biopsy. Methods: Exome sequencing, long-range PCR, and Sanger sequencing to identify the pathogenic mutation. Functional analysis in the patient fibroblasts included oxygen consumption measurements, extracellular acidification studies, Western blotting, and calcium imaging, followed by overexpression of the wild-type protein. Results: Analysis of the exome sequencing depth revealed a homozygous deletion of exon 1 of MICU1 within a 2,755-base pair deletion. No MICU1 protein was detected in patient fibroblasts, which had impaired mitochondrial calcium uptake that was rescued through the overexpression of the wild-type allele. Conclusions: MICU1 mutations cause fatigue and lethargy in patients with normal mitochondrial enzyme activities in muscle. The fluctuating clinical course is likely mediated through the mitochondrial calcium uniporter, which is regulated by MICU1. PMID:27123478

  18. Crack-Defined Electronic Nanogaps.

    PubMed

    Dubois, Valentin; Niklaus, Frank; Stemme, Göran

    2016-03-16

    Achieving near-atomic-scale electronic nanogaps in a reliable and scalable manner will facilitate fundamental advances in molecular detection, plasmonics, and nanoelectronics. Here, a method is shown for realizing crack-defined nanogaps separating TiN electrodes, allowing parallel and scalable fabrication of arrays of sub-10 nm electronic nanogaps featuring individually defined gap widths. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  19. Conditional Deletion of Prnp Rescues Behavioral and Synaptic Deficits after Disease Onset in Transgenic Alzheimer's Disease.

    PubMed

    Salazar, Santiago V; Gallardo, Christopher; Kaufman, Adam C; Herber, Charlotte S; Haas, Laura T; Robinson, Sophie; Manson, Jean C; Lee, Michael K; Strittmatter, Stephen M

    2017-09-20

    Biochemical and genetic evidence implicate soluble oligomeric amyloid-β (Aβo) in triggering Alzheimer's disease (AD) pathophysiology. Moreover, constitutive deletion of the Aβo-binding cellular prion protein (PrP(C)) prevents development of memory deficits in APPswe/PS1ΔE9 mice, a model of familial AD. Here, we define the role of PrP(C) to rescue or halt established AD endophenotypes in a therapeutic disease-modifying time window after symptom onset. Deletion of Prnp at either 12 or 16 months of age fully reverses hippocampal synapse loss and completely rescues preexisting behavioral deficits by 17 months. In contrast, but consistent with a neuronal function for Aβo/PrP(C) signaling, plaque density, microgliosis, and astrocytosis are not altered. Degeneration of catecholaminergic neurons remains unchanged by PrP(C) reduction after disease onset. These results define the potential of targeting PrP(C) as a disease-modifying therapy for certain AD-related phenotypes after disease onset.SIGNIFICANCE STATEMENT The study presented here further elucidates our understanding of the soluble oligomeric amyloid-β-Aβo-binding cellular prion protein (PrP(C)) signaling pathway in a familial form of Alzheimer's disease (AD) by implicating PrP(C) as a potential therapeutic target for AD. In particular, genetic deletion of Prnp rescued several familial AD (FAD)-associated phenotypes after disease onset in a mouse model of FAD. This study underscores the therapeutic potential of PrP(C) deletion given that patients already present symptoms at the time of diagnosis. Copyright © 2017 the authors 0270-6474/17/379207-15$15.00/0.

  20. Deletion mapping of genetic regions associated with apomixis in Hieracium.

    PubMed

    Catanach, Andrew S; Erasmuson, Sylvia K; Podivinsky, Ellen; Jordan, Brian R; Bicknell, Ross

    2006-12-05

    Although apomixis has been quoted as a technology with the potential to deliver benefits similar in scale to those achieved with the Green Revolution, very little is currently known of the genetic mechanisms that control this trait in plants. To address this issue, we developed Hieracium, a genus of daisies native to Eurasia and North America, as a genetic model to study apomixis. In a molecular mapping study, we defined the number of genetic loci involved in apomixis, and we explored dominance and linkage relationships between these loci. To avoid difficulties often encountered with inheritance studies of apomicts, we based our mapping effort on the use of deletion mutagenesis, coupled with amplified fragment length polymorphism (AFLP) as a genomic fingerprinting tool. The results indicate that apomixis in Hieracium caespitosum is controlled at two principal loci, one of which regulates events associated with the avoidance of meiosis (apomeiosis) and the other, an unlinked locus that controls events associated with the avoidance of fertilization (parthenogenesis). AFLP bands identified as central to both loci were isolated, sequenced, and used to develop sequence-characterized amplified region (SCAR) markers. The validity of the AFLP markers was verified by using a segregating population generated by hybridization. The validity of the SCAR markers was verified by their pattern of presence/absence in specific mutants. The mutants, markers, and genetic data derived from this work are now being used to isolate genes controlling apomixis in this system.

  1. Atypical deletion of 22q11.2: detection using the FISH TBX1 probe and molecular characterization with high-density SNP arrays.

    PubMed

    Beaujard, Marie-Paule; Chantot, Sandra; Dubois, Michèle; Keren, Boris; Carpentier, Wassila; Mabboux, Philippe; Whalen, Sandra; Vodovar, Michel; Siffroi, Jean-Pierre; Portnoï, Marie-France

    2009-01-01

    Despite the heterogeneous clinical presentations, the majority of patients with 22q11.2 deletion syndrome (22q11.2 DS) have either a common recurrent 3 Mb deletion or a less common, 1.5 Mb nested deletion, with breakpoint sites in flanking low-copy repeats (LCR) sequences. Only a small number of atypical deletions have been reported and precisely defined. Haploinsufficiency of the TBX1 gene was determined to be the likely cause of 22q11.2 DS. The diagnostic procedure usually used is FISH using commercially probes (N25 or TUPLE1). However, this test does not contain TBX1, and fails to detect deletions that are either proximal or distal to the FISH probes. Here, we report on two patients with clinical features suggestive of 22q11.2 DS, a male infant with facial dysmorphia, pulmonary atresia, ventricular septal defect, neonatal hypocalcemia, and his affected mother, with facial dysmorphia, learning disabilities, and hypernasal speech. They were tested negative for 22q11.2 DS using N25 or TUPLE1 probes, but were shown deleted for a probe containing TBX1. Delineation of the deletion was performed using high-density SNP arrays (Illumina, 370K). This atypical deletion was spanning 1.89 Mb. The distal breakpoint resided in LCR-D, sharing the same distal breakpoint with the 3 Mb common deletion. The proximal breakpoint was located 105 kb telomeric to TUPLE1, representing a new breakpoint variant that does not correspond to known LCRs of 22q11.2. We conclude that FISH with the TBX1 probe is an accurate diagnostic tool for 22q11.2 DS, with a higher sensitivity than FISH using standard probes, detecting all but the rarest deletions, greatly reducing the false negative rate.

  2. Deletion of 6q16-q21 in human lymphoid malignancies: a mapping and deletion analysis.

    PubMed

    Jackson, A; Carrara, P; Duke, V; Sinclair, P; Papaioannou, M; Harrison, C J; Foroni, L

    2000-06-01

    Two distinct regions of minimal deletion (RMD) have been identified at 6q25-q27 in non-Hodgkin's lymphoma (RMD-1), and at 6q21-q23 in acute lymphoblastic leukemia (ALL; RMD-2) by loss of heterozygosity and fluorescence in situ hybridization studies. In this study, 30 overlapping yeast artificial chromosomes (YACs), 1 expressed sequence tag, and 11 novel YAC ends were identified using bidirectional YAC walks between markers D6S447 (proximal) and D6S246 (distal) in RMD-2. The genes AF6q21, human homologue of the Drosophila tailless (HTLX), CD24 antigen, the Kruppel-like zinc finger BLIMP1, and cyclin C (CCNC), previously mapped to 6q21, were accurately positioned in a telomere-to-centromere orientation. Approximately 3.5 Mb were found to separate the BLIMP1 (adjacent to D6S447) and AF6q21 genes (telomeric to D6S246). Deletions of 6q were investigated in 21 cases of ALL using the newly characterized YAC clones in dual-color fluorescence in situ hybridization studies. A region centromeric to D6S447 (containing marker D6S283) and a region telomeric to marker CHLC.GGAT16CO2 (and containing marker D6S268) were identified as distinct and nonoverlapping regions of deletion in ALL.

  3. Using Topic Modeling and Text Embeddings to Predict Deleted Tweets

    SciTech Connect

    Potash, Peter J.; Bell, Eric B.; Harrison, Joshua J.

    2016-02-29

    Predictive models for tweet deletion have been a relatively unexplored area of Twitter-related computational research. We first approach the deletion of tweets as a spam detection problem, applying a small set of handcrafted features to improve upon the current state-of-the- art in predicting deleted tweets. Next, we apply our approach to a dataset of deleted tweets that better reflects the current deletion rate. Since tweets are deleted for reasons beyond just the presence of spam, we apply topic modeling and text embeddings in order to capture the semantic content of tweets that can lead to tweet deletion. Our goal is to create an effective model that has a low-dimensional feature space and is also language-independent. A lean model would be computationally advantageous processing high-volumes of Twitter data, which can reach 9,885 tweets per second. Our results show that a small set of spam-related features combined with word topics and character-level text embeddings provide the best f1 when trained with a random forest model. The highest precision of the deleted tweet class is achieved by a modification of paragraph2vec to capture author identity.

  4. 29 CFR 1610.20 - Deletion of exempted matters.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 4 2010-07-01 2010-07-01 false Deletion of exempted matters. 1610.20 Section 1610.20 Labor... Production or Disclosure Under 5 U.S.C. 552 § 1610.20 Deletion of exempted matters. Where requested records contain matters which are exempted under 5 U.S.C. 552(b) but which matters are reasonably segregable...

  5. 29 CFR 1610.20 - Deletion of exempted matters.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 29 Labor 4 2011-07-01 2011-07-01 false Deletion of exempted matters. 1610.20 Section 1610.20 Labor... Production or Disclosure Under 5 U.S.C. 552 § 1610.20 Deletion of exempted matters. Where requested records contain matters which are exempted under 5 U.S.C. 552(b) but which matters are reasonably segregable...

  6. Linguistic and Psychomotor Development in Children with Chromosome 14 Deletions

    ERIC Educational Resources Information Center

    Zampini, Laura; D'Odorico, Laura; Zanchi, Paola; Zollino, Marcella; Neri, Giovanni

    2012-01-01

    The present study focussed on a specific type of rare genetic condition: chromosome 14 deletions. Children with this genetic condition often show developmental delays and brain and neurological problems, although the type and severity of symptoms varies depending on the size and location of the deleted genetic material. The specific aim of the…

  7. Multivariate Variable Deletion Methods: Don't Do Stepwise

    ERIC Educational Resources Information Center

    Kadhi, TauGamba

    2003-01-01

    This paper explains the theory and methodology behind the use of variable deletion in canonical correlational analysis (CCA). Both the Capraro and Capraro (2002) and the Cantrell (1997) data tables are evaluated and explained in order to clarify strategies utilized. Understanding of variable deletion strategies and their proper usages in a CCA…

  8. Towards earlier diagnosis of 22q11 deletions

    PubMed Central

    Tobias, E; Morrison, N; Whiteford, M; Tolmie, J

    1999-01-01

    Over a 7 year period, 551 patients were investigated for the presence of a chromosome 22q11 deletion by fluorescence in situ hybridisation. Analysis of the presenting features of the 67 individuals with this chromosome deletion permitted us to devise guidelines to facilitate early diagnosis.

 PMID:10569971

  9. A Note On Deletion Rules in Fast Speech.

    ERIC Educational Resources Information Center

    Hewlett, Nigel

    In fast speech, certain segments pronounced in careful speech may be deleted. Rules of a generative phonology have been used to account for fast speech forms. An alternative approach is suggested which views fast speech deletions as merely limiting cases of segment reduction, under conditions of increased tempo and/or casualness. To complement…

  10. 75 FR 60739 - Procurement List; Additions and Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-10-01

    ... FROM PEOPLE WHO ARE BLIND OR SEVERELY DISABLED Procurement List; Additions and Deletions AGENCY: Committee for Purchase From People Who Are Blind or Severely Disabled. ACTION: Additions to and Deletions... will be furnished by nonprofit agencies employing persons who are blind or have other...

  11. 19 CFR 142.49 - Deletion of C-4 Code.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... with any justification and without prior notification in cases of willfulness or when public health... 19 Customs Duties 2 2011-04-01 2011-04-01 false Deletion of C-4 Code. 142.49 Section 142.49... TREASURY (CONTINUED) ENTRY PROCESS Line Release § 142.49 Deletion of C-4 Code. (a) By Customs. A...

  12. 19 CFR 142.49 - Deletion of C-4 Code.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... with any justification and without prior notification in cases of willfulness or when public health... 19 Customs Duties 2 2012-04-01 2012-04-01 false Deletion of C-4 Code. 142.49 Section 142.49... TREASURY (CONTINUED) ENTRY PROCESS Line Release § 142.49 Deletion of C-4 Code. (a) By Customs. A...

  13. 37 CFR 2.35 - Adding, deleting, or substituting bases.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 37 Patents, Trademarks, and Copyrights 1 2013-07-01 2013-07-01 false Adding, deleting, or... OFFICE, DEPARTMENT OF COMMERCE RULES OF PRACTICE IN TRADEMARK CASES The Written Application § 2.35 Adding... add, substitute or delete a basis, unless the applicant meets the requirements for...

  14. 37 CFR 2.35 - Adding, deleting, or substituting bases.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 37 Patents, Trademarks, and Copyrights 1 2011-07-01 2011-07-01 false Adding, deleting, or... OFFICE, DEPARTMENT OF COMMERCE RULES OF PRACTICE IN TRADEMARK CASES The Written Application § 2.35 Adding... add, substitute or delete a basis, unless the applicant meets the requirements for...

  15. 37 CFR 2.35 - Adding, deleting, or substituting bases.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 37 Patents, Trademarks, and Copyrights 1 2014-07-01 2014-07-01 false Adding, deleting, or... OFFICE, DEPARTMENT OF COMMERCE RULES OF PRACTICE IN TRADEMARK CASES The Written Application § 2.35 Adding... add, substitute or delete a basis, unless the applicant meets the requirements for...

  16. 78 FR 53733 - Procurement List Additions and Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-08-30

    ... PEOPLE WHO ARE BLIND OR SEVERELY DISABLED Procurement List Additions and Deletions AGENCY: Committee for Purchase from People Who are Blind or Severely Disabled. ACTION: Additions to and Deletions from the...: September 30, 2013. ADDRESSES: Committee for Purchase From People Who Are Blind or Severely Disabled, 1401...

  17. 76 FR 29209 - Procurement List Additions and Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-20

    ... PEOPLE WHO ARE BLIND OR SEVERELY DISABLED Procurement List Additions and Deletions AGENCY: Committee for Purchase From People Who Are Blind or Severely Disabled. ACTION: Additions to and deletions from the.... ADDRESSES: Committee for Purchase From People Who Are Blind or Severely Disabled, Jefferson Plaza 2,...

  18. Coexistence of 9p Deletion Syndrome and Autism Spectrum Disorder

    ERIC Educational Resources Information Center

    Günes, Serkan; Ekinci, Özalp; Ekinci, Nuran; Toros, Fevziye

    2017-01-01

    Deletion or duplication of the short arm of chromosome 9 may lead to a variety of clinical conditions including craniofacial and limb abnormalities, skeletal malformations, mental retardation, and autism spectrum disorder. Here, we present a case report of 5-year-old boy with 9p deletion syndrome and autism spectrum disorder.

  19. Linguistic and Psychomotor Development in Children with Chromosome 14 Deletions

    ERIC Educational Resources Information Center

    Zampini, Laura; D'Odorico, Laura; Zanchi, Paola; Zollino, Marcella; Neri, Giovanni

    2012-01-01

    The present study focussed on a specific type of rare genetic condition: chromosome 14 deletions. Children with this genetic condition often show developmental delays and brain and neurological problems, although the type and severity of symptoms varies depending on the size and location of the deleted genetic material. The specific aim of the…

  20. Computed structures of point deletion mutants and their enzymatic activities

    PubMed Central

    Berrondo, Monica; Gray, Jeffrey J.

    2011-01-01

    Point deletions in enzymes can vary in effect from negligible to complete loss of activity, however, these effects are not generally predictable. Deletions are widely observed in nature and often result in diseases such as cancer, cystic fibrosis, or osteogenesis imperfecta. Here, we have developed an algorithm to model the perturbed structures of deletion mutants with the ultimate goal of predicting their activities. The algorithm works by deleting the specified residue from the wild-type structure, creating a gap that is closed using a combination of local and global moves that change the backbone torsion angles of the protein structure. On a set of five proteins for which both wild-type and deletion mutant x-ray crystal structures are available, the algorithm produces deep, narrow energy funnels within 1.5 Å of the crystal structure for the deletion mutants. To assess the ability of our algorithm to predict activity from the predicted structures, we tested the correlation of experimental activity with several measures of the predicted structure ensemble using a set of 45 point deletions from ricin. Estimates incorporating likely prevalence of active and inactive deletion sites suggest that activity can be predicted correctly over 60% of the time from the active site rmsd of the lowest energy predicted structures. The predictions are stronger than simple sequence organization measures, but more fundamental work is required in structure prediction and enzyme activity determination to allow consistent prediction of activity. PMID:21905110

  1. Exon deletions of the phenylalanine hydroxylase gene in Italian hyperphenylalaninemics

    PubMed Central

    Calì, Francesco; Ruggeri, Giuseppa; Vinci, Mirella; Meli, Concetta; Carducci, Carla; Leuzzi, Vincenzo; Pozzessere, Simone; Schinocca, Pietro; Ragalmuto, Alda; Chiavetta, Valeria; Miccichè, Salvatore

    2010-01-01

    A consistent finding of many studies describing the spectrum of mutant phenylalanine hydroxylase (PAH) alleles underlying hyperphenylalaninemia is the impossibility of achieving a 100% mutation ascertainment rate using conventional gene-scanning methods. These methods include denaturing gradient gel electrophoresis (DGGE), denaturing high performance liquid chromatography (DHPLC), and direct sequencing. In recent years, it has been shown that a significant proportion of undetermined alleles consist of large deletions overlapping one or more exons. These deletions have been difficult to detect in compound heterozygotes using gene-scanning methods due to a masking effect of the non-deleted allele. To date, no systematic search has been carried out for such exon deletions in Italian patients with phenylketonuria or mild hyperphenylalaninemia. We used multiplex ligation- dependent probe amplification (MLPA), comparative multiplex dosage analysis (CMDA), and real-time PCR to search for both large deletions and duplications of the phenylalanine hydroxylase gene in Italian hyperphenylalaninemia patients. Four deletions removing different phenylalanine hydroxylase (PAH) gene exons were identified in 12 patients. Two of these deletions involving exons 4-5-6-7-8 (systematic name c.353-?_912 + ?del) and exon 6 (systematic name c.510-?_706 + ?del) have not been reported previously. In this study, we show that exon deletion of the PAH gene accounts for 1.7% of all mutant PAH alleles in Italian hyperphenylalaninemics. PMID:19946181

  2. 77 FR 12816 - Procurement List Proposed Addition and Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-03-02

    ... PEOPLE WHO ARE BLIND OR SEVERELY DISABLED Procurement List Proposed Addition and Deletions AGENCY: Committee for Purchase From People Who Are Blind or Severely Disabled. ACTION: Proposed addition to and... disabilities and delete products previously furnished by such agencies. Comments Must Be Received On or...

  3. Coexistence of 9p Deletion Syndrome and Autism Spectrum Disorder

    ERIC Educational Resources Information Center

    Günes, Serkan; Ekinci, Özalp; Ekinci, Nuran; Toros, Fevziye

    2017-01-01

    Deletion or duplication of the short arm of chromosome 9 may lead to a variety of clinical conditions including craniofacial and limb abnormalities, skeletal malformations, mental retardation, and autism spectrum disorder. Here, we present a case report of 5-year-old boy with 9p deletion syndrome and autism spectrum disorder.

  4. 75 FR 49481 - Procurement List; Additions and Deletion

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-08-13

    ... PEOPLE WHO ARE BLIND OR SEVERELY DISABLED Procurement List; Additions and Deletion AGENCY: Committee for Purchase From People Who Are Blind or Severely Disabled. ACTION: Additions to and deletion from the.... ADDRESSES: Committee for Purchase From People Who Are Blind or Severely Disabled, Jefferson Plaza 2, Suite...

  5. 75 FR 56995 - Procurement List Proposed Additions and Deletion

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-17

    ... PEOPLE WHO ARE BLIND OR SEVERELY DISABLED Procurement List Proposed Additions and Deletion AGENCY... Deletion From the Procurement List. SUMMARY: The Committee is proposing to add products to the Procurement...-0655, or e-mail: CMTEFedReg@AbilityOne.gov . SUPPLEMENTARY INFORMATION: This notice is published...

  6. 44 CFR 5.27 - Deletion of identifying details.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 44 Emergency Management and Assistance 1 2010-10-01 2010-10-01 false Deletion of identifying details. 5.27 Section 5.27 Emergency Management and Assistance FEDERAL EMERGENCY MANAGEMENT AGENCY... Availability of General Agency Information, Rules, Orders, Policies, and Similar Material § 5.27 Deletion of...

  7. Defining the states of consciousness.

    PubMed

    Tassi, P; Muzet, A

    2001-03-01

    Consciousness remains an elusive concept due to the difficulty to define what has been regarded for many years as a subjective experience, therefore irrelevant for scientific study. Recent development in this field of research has allowed to provide some new insight to a possible way to define consciousness. Going through the extensive literature in this domain, several perspectives are proposed to define this concept. (1) Consciousness and Attention may not reflect the same process. (2) Consciousness during wake and sleep may not involve the same mechanisms. (3) Besides physiological states of consciousness, human beings can experience modified states of consciousness either by self-training (transcendental meditation, hypnosis, etc.) or by drug intake (hallucinogens, anaesthetics, etc.). Altogether, we address the question of a more precise terminology, given the theoretical weight words can convey. To this respect, we propose different definitions for concepts like consciousness, vigilance, arousal and alertness as candidates to separate functional entities.

  8. Low copy repeats mediate distal chromosome 22q11.2 deletions: sequence analysis predicts breakpoint mechanisms.

    PubMed

    Shaikh, Tamim H; O'Connor, Ronald J; Pierpont, Mary Ella; McGrath, James; Hacker, April M; Nimmakayalu, Manjunath; Geiger, Elizabeth; Emanuel, Beverly S; Saitta, Sulagna C

    2007-04-01

    Genomic disorders contribute significantly to genetic disease and, as detection methods improve, greater numbers are being defined. Paralogous low copy repeats (LCRs) mediate many of the chromosomal rearrangements that underlie these disorders, predisposing chromosomes to recombination errors. Deletions of proximal 22q11.2 comprise the most frequently occurring microdeletion syndrome, DiGeorge/Velocardiofacial syndrome (DGS/VCFS), in which most breakpoints have been localized to a 3 Mb region containing four large LCRs. Immediately distal to this region, there are another four related but smaller LCRs that have not been characterized extensively. We used paralog-specific primers and long-range PCR to clone, sequence, and examine the distal deletion breakpoints from two patients with de novo deletions mapping to these distal LCRs. Our results present definitive evidence of the direct involvement of LCRs in 22q11 deletions and map both breakpoints to the BCRL module, common to most 22q11 LCRs, suggesting a potential region for LCR-mediated rearrangement both in the distal LCRs and in the DGS interval. These are the first reported cases of distal 22q11 deletions in which breakpoints have been characterized at the nucleotide level within LCRs, confirming that distal 22q11 LCRs can and do mediate rearrangements leading to genomic disorders.

  9. Chromosome 7 monosomy and deletions in myeloproliferative diseases.

    PubMed

    Tripputi, P; Cassani, B; Alfano, R; Graziani, D; Cigognini, D; Doi, P; Bignotto, M; Corneo, G; Coggi, G

    2001-09-01

    We studied deletion and monosomy of chromosome 7 in 150 patients with myeloproliferative diseases. We found 8/150 patients with monosomy 7 by cytogenetics and 4/150 with deletions of the long arm of chromosome 7 by restriction fragment length polymorphism (RFLP) analysis performed with Southern and polymerase chain reaction. To overcome limitation of RFLP analysis, we restricted loss of heterozygosity study with microsatellites to 45 patients, observing deletion 7q31.1 in 7/45 patients. In all patients with molecular alterations the deletion was observed only in myeloid cells, while the monosomy was detected in both myeloid precursor and lymphocytes. This finding suggests a CD34-totipotent stem cell origin for the monosomy and a colony forming unit - granulocyte, erythrocyte, monocyte, megakaryocytes (CFU-GEMM) stem cell origin for the deletions.

  10. Delineation of 14q32.3 deletion syndrome.

    PubMed

    Ortigas, A P; Stein, C K; Thomson, L L; Hoo, J J

    1997-06-01

    A patient with a 14q32.3 terminal band deletion and cat cry is reported. Review of four other 14q32.3 deletion cases suggests the possible presence of a recognisable 14q32.3 terminal deletion syndrome, which is characterised by (1) apparently postnatal onset of small head size in comparison to body size, (2) high forehead with lateral hypertrichosis, (3) epicanthic folds, (4) broad nasal bridge, (5) high arched palate, (6) single palmar crease, and (7) mild to moderate developmental delay. Although none of the above seven features in unique to this syndrome, and indeed are quite common in other chromosomal disorders or genetic syndromes, patients with a terminal 14q32.3 deletion do show a recognisable facial gestalt. Interestingly, unlike ring chromosome 14, the 14q32.3 terminal deletion has rarely been reported, possibly because it is harder to detect, and an optimal chromosome preparation is required for its identification.

  11. Attenuation of monkeypox virus by deletion of genomic regions

    USGS Publications Warehouse

    Lopera, Juan G.; Falendysz, Elizabeth A.; Rocke, Tonie E.; Osorio, Jorge E.

    2015-01-01

    Monkeypox virus (MPXV) is an emerging pathogen from Africa that causes disease similar to smallpox. Two clades with different geographic distributions and virulence have been described. Here, we utilized bioinformatic tools to identify genomic regions in MPXV containing multiple virulence genes and explored their roles in pathogenicity; two selected regions were then deleted singularly or in combination. In vitro and in vivostudies indicated that these regions play a significant role in MPXV replication, tissue spread, and mortality in mice. Interestingly, while deletion of either region led to decreased virulence in mice, one region had no effect on in vitro replication. Deletion of both regions simultaneously also reduced cell culture replication and significantly increased the attenuation in vivo over either single deletion. Attenuated MPXV with genomic deletions present a safe and efficacious tool in the study of MPX pathogenesis and in the identification of genetic factors associated with virulence.

  12. Breakpoint Associated with a novel 2.3 Mb deletion in the VCFS region of 22q11 and the role of Alu (SINE) in recurring microdeletions

    PubMed Central

    Uddin, Raihan K; Zhang, Yang; Siu, Victoria Mok; Fan, Yao-Shan; O'Reilly, Richard L; Rao, Jay; Singh, Shiva M

    2006-01-01

    Background Chromosome 22q11.2 region is highly susceptible to rearrangement, specifically deletions that give rise to a variety of genomic disorders including velocardiofacial or DiGeorge syndrome. Individuals with this 22q11 microdeletion syndrome are at a greatly increased risk to develop schizophrenia. Methods Genotype analysis was carried out on the DNA from a patient with the 22q11 microdeletion using genetic markers and custom primer sets to define the deletion. Bioinformatic analysis was performed for molecular characterization of the deletion breakpoint sequences in this patient. Results This 22q11 deletion patient was established to have a novel 2.3 Mb deletion with a proximal breakpoint located between genetic markers RH48663 and RH48348 and a distal breakpoint between markers D22S1138 and SHGC-145314. Molecular characterization of the sequences at the breakpoints revealed a 270 bp shared sequence of the breakpoint regions (SSBR) common to both ends that share >90% sequence similarity to each other and also to short interspersed nuclear elements/Alu elements. Conclusion This Alu sequence like SSBR is commonly in the proximity of all known deletion breakpoints of 22q11 region and also in the low copy repeat regions (LCRs). This sequence may represent a preferred sequence in the breakpoint regions or LCRs for intra-chromosomal homologous recombination mechanisms resulting in common 22q11 deletion. PMID:16512914

  13. gr/gr-DAZ2-DAZ4-CDY1b deletion is a high-risk factor for male infertility in Tunisian population.

    PubMed

    Ghorbel, Myriam; Baklouti-Gargouri, Siwar; Keskes, Rim; Chakroun, Nozha; Sellami, Afifa; Fakhfakh, Faiza; Ammar-Keskes, Leila

    2016-10-30

    The azoospermia factor c (AZFc) region harbors multi-copy genes that are expressed in the testis. Deletions of this region lead to reduced copy numbers of these genes. In this present study we aimed to determine the frequency of AZFc subdeletion in infertile and fertile men from Tunisia and to identify whether deletions of DAZ and CDY1 gene copies are deleterious on spermatogenesis and on semen quality. We studied a group of 241 infertile men and 115 fertile healthy males using a sequence tagged site (STS)±method. To gain insight into the molecular basis of the heterogeneous phenotype observed in men with the deletion we defined the type of DAZ and CDY1 genes deleted. We reported in the present study and for the first time a new type of AZFc deletion (gr/gr-DAZ2-DAZ4-CDY1b) and hypothesis that this new deletion is the result of two successive events. We also demonstrated that this deletion constitutes a relative high-risk factor for male infertility in Tunisian population.

  14. Pre- and Postnatal Analysis of Chromosome 15q26.1 and 8p23.1 Deletions in Congenital Diaphragmatic Hernia

    PubMed Central

    Shetty, Mitesh; Kadandale, Jayarama; Hegde, Sridevi

    2016-01-01

    Congenital diaphragmatic hernia (CDH) is defined as a protrusion of abdominal content into the thoracic cavity through an abnormal opening in the diaphragm present at birth. It is a common birth defect with high mortality and morbidity. Submicroscopic deletions of 15q26.1 and 8p23.1 have been reported in several cases of CDH. We studied a total of 17 cases with CDH in pre- and postnatal samples using FISH probes. Deletion 15q26.1 was seen in 1/17 prenatal samples. There was no deletion for 8p23.1 in all the samples analyzed. CDH has a genetic etiology, and deletion 15q26.1 increases the risk of CDH. Deletion 15q26.1 in a fetus with CDH is a predictor of poor prognosis. This deletion is also seen in a phenotype similar to Fryns syndrome. CDH identified pre- or postnatally should be investigated further to exclude a 15q26.1 deletion and enable appropriate parental counseling. PMID:26997946

  15. Specific mitochondrial DNA deletions in idiopathic dilated cardiomyopathy.

    PubMed

    Marin-Garcia, J; Goldenthal, M J; Ananthakrishnan, R; Pierpont, M E; Fricker, F J; Lipshultz, S E; Perez-Atayde, A

    1996-02-01

    Structural changes in human mitochondrial DNA (mtDNA) have been implicated in a number of clinical conditions with dysfunctions in oxidative phosphorylation called OX-PHOS diseases, some of which have cardiac involvement. The objective of this study was to assess the frequency and extent of specific mitochondrial DNA deletions in idiopathic dilated cardiomyopathy. DNA extracted from tissue derived from the left ventricle of 41 patients with idiopathic dilated cardiomyopathy and 17 controls was amplified by polymerase chain reaction using specific primers to assess the incidence and proportion of 5-kb and 7.4-kb deletions in mitochondrial DNA. In reactions using primers to detect the 5-kb deletion, an amplified product of 593 bp was found in low abundance relative to undeleted mitochondrial DNA but with high frequency in a number of controls and patients. A second deletion of 7.4 kb in size was also frequently present in controls and patients. In contrast to previous reports, these deletions were found to be present in both controls and in cardiomyopathic patients, 18 years and younger, including several infants. The 7.4-kb deletion was prominently increased in both frequency and in its proportion relative to undeleted mitochondrial DNA in patients 40 years and older with idiopathic dilated cardiomyopathy. At variance with current literature our study reports a significant presence of both 5 and 7.4-kb deletions in the young and a higher frequency and quantity of the 7.4-kb deletion in the older cardiomyopathic patients in comparison with controls. The increased accumulation of the 7.4-kb deletion as both a function of aging and cardiomyopathy is suggestive that this specific mitochondrial DNA deletion arises more likely as an effect of heart dysfunction rather than as a primary cause of cardiomyopathy.

  16. Defining "Folklore" in the Classroom.

    ERIC Educational Resources Information Center

    Falke, Anne

    Folklore, a body of traditional beliefs of a people conveyed orally or by means of custom, is very much alive, involves all people, and is not the study of popular culture. In studying folklore, the principal tasks of the folklorist have been defined as determining definition, classification, source (the folk), origin (who composed folklore),…

  17. Defining and Measuring Psychomotor Performance

    ERIC Educational Resources Information Center

    Autio, Ossi

    2007-01-01

    Psychomotor performance is fundamental to human existence. It is important in many real world activities and nowadays psychomotor tests are used in several fields of industry, army, and medical sciences in employee selection. This article tries to define psychomotor activity by introducing some psychomotor theories. Furthermore the…

  18. Defined by Word and Space

    ERIC Educational Resources Information Center

    Brisco, Nicole D.

    2010-01-01

    In the author's art class, she found that many of her students in an intro art class have some technical skill, but lack the ability to think conceptually. Her goal was to create an innovative project that combined design, painting, and sculpture into a compact unit that asked students how they define themselves. In the process of answering this…

  19. Defined by Word and Space

    ERIC Educational Resources Information Center

    Brisco, Nicole D.

    2010-01-01

    In the author's art class, she found that many of her students in an intro art class have some technical skill, but lack the ability to think conceptually. Her goal was to create an innovative project that combined design, painting, and sculpture into a compact unit that asked students how they define themselves. In the process of answering this…

  20. Defining and Differentiating the Makerspace

    ERIC Educational Resources Information Center

    Dousay, Tonia A.

    2017-01-01

    Many resources now punctuate the maker movement landscape. However, some schools and communities still struggle to understand this burgeoning movement. How do we define these spaces and differentiate them from previous labs and shops? Through a multidimensional framework, stakeholders should consider how the structure, access, staffing, and tools…

  1. "Oops, I deleted it"--a solution for recovering deleted or reformatted digital images from memory cards.

    PubMed

    Revankar, Ameet V; Gandedkar, Narayan H; Ganeshkar, Sanjay V

    2009-06-01

    Capturing patient photographs on digital flash cards rather than film has several advantages, but also a few disadvantages. Among the latter, the primary disadvantage is the possibility of accidentally deleting or corruping the files before they are downloaded from the memory card. In this article, we describe utilities that enable image recovery from deleted, reformatted, or physically damaged flash memory cards.

  2. 'Deletion rescue' by mitotic 11q uniparental disomy in a family with recurrence of 11q deletion Jacobsen syndrome.

    PubMed

    Johnson, J P; Haag, M; Beischel, L; McCann, C; Phillips, S; Tunby, M; Hansen, J; Schwanke, C; Reynolds, J F

    2014-04-01

    We describe a family with recurrent 11q23-qter deletion Jacobsen syndrome in two affected brothers, with unique mosaic deletion 'rescue' through development of uniparental disomy (UPD) in the mother and one of the brothers. Inheritance studies show that the deleted chromosome is of maternal origin in both boys, and microarray shows a break near the ASAM gene. Parental lymphocyte chromosomes were normal. However, the mother is homozygous in lymphocytes for all loci within the deleted region in her sons, and presumably has UPD for this region. In addition, she is mosaic for the 11q deletion seen in her sons at a level of 20-30% in skin fibroblasts. We hypothesize that one of her #11 chromosomes shows fragility, that breakage at 11q23 occurred with telomeric loss in some cells, but 'rescue' from the deletion occurred in most cells by the development of mitotic UPD. She apparently carries the 11q deletion in her germ line resulting in recurrence of the syndrome. The older son is mosaic for the 11q cell line (70-88%, remainder 46,XY), and segmental UPD11 'rescue' apparently also occurred in his cytogenetically normal cells. This is a novel phenomenon restoring disomy to an individual with a chromosomal deletion.

  3. ACE insert/delete polymorphism and atherosclerosis.

    PubMed

    Scheer, W Douglas; Boudreau, Donald A; Hixson, James E; McGill, Henry C; Newman, William P; Tracy, Richard E; Zieske, Arthur W; Strong, Jack P

    2005-02-01

    We report on the results of a large autopsy study focusing upon the hypothesis that deletion of the Alu insert in the angiotensin converting enzyme (ACE) gene is associated with: (a) greater prevalence or extent of atherosclerosis in the aorta and coronary arteries; and (b) microscopic qualities of established atherosclerotic plaques in the coronary arteries. This study was conducted in young US black (n=290) and white (n=379) males using available materials and data from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study, a multi-center cooperative autopsy study organized in 1985 to explore the relationships of known cardiovascular risk factors to atherosclerosis in victims of accidents, homicides, or suicides in the age range of 15-34 years. The results provide strong evidence that ACE genotype may not be a predictor of either the prevalence or the extent of the lesions of atherosclerosis in the right coronary artery or the aorta of young adults, an observation that confirms previous studies that estimated the prevalence and extent of atherosclerosis using coronary angiography. In addition, the results suggest that ACE genotype does not contribute to the formation of atherosclerotic lesions that have the characteristics of vulnerable plaques in the left anterior descending coronary artery of young adults.

  4. Tau deletion promotes brain insulin resistance

    PubMed Central

    Marciniak, Elodie; Leboucher, Antoine; Caron, Emilie; Ahmed, Tariq; Tailleux, Anne; Dumont, Julie; Issad, Tarik; Gerhardt, Ellen; Pagesy, Patrick; Vileno, Margaux; Hamdane, Malika; Bantubungi, Kadiombo; Lancel, Steve; Demeyer, Dominique; Eddarkaoui, Sabiha; Vallez, Emmanuelle; Vieau, Didier; Humez, Sandrine; Faivre, Emilie; Grenier-Boley, Benjamin; Outeiro, Tiago F.; Amouyel, Philippe; Balschun, Detlef

    2017-01-01

    The molecular pathways underlying tau pathology–induced synaptic/cognitive deficits and neurodegeneration are poorly understood. One prevalent hypothesis is that hyperphosphorylation, misfolding, and fibrillization of tau impair synaptic plasticity and cause degeneration. However, tau pathology may also result in the loss of specific physiological tau functions, which are largely unknown but could contribute to neuronal dysfunction. In the present study, we uncovered a novel function of tau in its ability to regulate brain insulin signaling. We found that tau deletion leads to an impaired hippocampal response to insulin, caused by altered IRS-1 and PTEN (phosphatase and tensin homologue on chromosome 10) activities. Our data also demonstrate that tau knockout mice exhibit an impaired hypothalamic anorexigenic effect of insulin that is associated with energy metabolism alterations. Consistently, we found that tau haplotypes are associated with glycemic traits in humans. The present data have far-reaching clinical implications and raise the hypothesis that pathophysiological tau loss-of-function favors brain insulin resistance, which is instrumental for cognitive and metabolic impairments in Alzheimer’s disease patients. PMID:28652303

  5. 8.5 Mb deletion at distal 5p in a male ascertained for azoospermia.

    PubMed

    Rossi, Elena; de Gregori, Manuela; Grazia Patricelli, Maria; Pramparo, Tiziano; Argentiero, Luisa; Giglio, Sabrina; Sosta, Katiuscia; Foresti, Giovanni; Zuffardi, Orsetta

    2005-03-01

    We report on a 5p- azoospermic male not showing the clinical features diagnostic for the cri-du-chat syndrome but for a breathy, raspy voice. The 5p deletion breakpoint, determined by fluorescent in situ hybridization (FISH) analysis with BAC clones, maps 8.5 Mb far from the short arm telomere in 5p15.31. Genotype/phenotype correlations in this subject, including his neuropsychological assessment, led us to define that the gene for the cat-like cry and one gene responsible for mild mental retardation with speech delay map both in the distal 8.5 Mb of chromosome 5 short arm.

  6. Biologically active mutants with deletions in the v-mos oncogene assayed with retroviral vectors.

    PubMed Central

    Bold, R J; Donoghue, D J

    1985-01-01

    We have constructed retroviral expression vectors by manipulation of the Moloney murine leukemia virus genome such that an exogenous DNA sequence may be inserted and subsequently expressed when introduced into mammalian cells. A series of N-terminal deletions of the v-mos oncogene was constructed and assayed for biological activity with these retroviral expression vectors. The results of the deletion analysis demonstrate that the region of p37mos coding region upstream of the third methionine codon is dispensable with respect to transformation. However, deletion mutants of v-mos which allow initiation of translation at the fourth methionine codon have lost the biological activity of the parental v-mos gene. Furthermore, experiments were also carried out to define the C-terminal limit of the active region of p37mos by the construction of premature termination mutants by the insertion of a termination oligonucleotide. Insertion of the oligonucleotide just 69 base pairs upstream from the wild-type termination site abolished the focus-forming ability of v-mos. Thus, we have shown the N-terminal limit of the active region of p37mos to be between the third and fourth methionines, while the C-terminal limit is within the last 23 amino acids of the protein. PMID:3018503

  7. New traits in crops produced by genome editing techniques based on deletions.

    PubMed

    van de Wiel, C C M; Schaart, J G; Lotz, L A P; Smulders, M J M

    2017-01-01

    One of the most promising New Plant Breeding Techniques is genome editing (also called gene editing) with the help of a programmable site-directed nuclease (SDN). In this review, we focus on SDN-1, which is the generation of small deletions or insertions (indels) at a precisely defined location in the genome with zinc finger nucleases (ZFN), TALENs, or CRISPR-Cas9. The programmable nuclease is used to induce a double-strand break in the DNA, while the repair is left to the plant cell itself, and mistakes are introduced, while the cell is repairing the double-strand break using the relatively error-prone NHEJ pathway. From a biological point of view, it could be considered as a form of targeted mutagenesis. We first discuss improvements and new technical variants for SDN-1, in particular employing CRISPR-Cas, and subsequently explore the effectiveness of targeted deletions that eliminate the function of a gene, as an approach to generate novel traits useful for improving agricultural sustainability, including disease resistances. We compare them with examples of deletions that resulted in novel functionality as known from crop domestication and classical mutation breeding (both using radiation and chemical mutagens). Finally, we touch upon regulatory and access and benefit sharing issues regarding the plants produced.

  8. Commonly deleted region on the long arm of chromosome 7 in differentiated adenocarcinoma of the stomach.

    PubMed

    Nishizuka, S; Tamura, G; Terashima, M; Satodate, R

    1997-01-01

    Loss of heterozygosity (LOH) at several chromosomal loci is a common event in human malignancies. Frequent LOH on the long arm of chromosome 7 has been reported in various human malignancies, and investigators have identified the most common site of LOH as 7q31.1. We have identified ten chromosomal loci, including chromosome 7q, that have been shown by previous allelotype study to be sites of frequent LOH in differentiated adenocarcinoma of the stomach. In the present study, we performed a polymerase chain reaction (PCR) microsatellite analysis to define the common deleted region on 7q, using 14 polymorphic microsatellite markers in matched tumour and non-tumour DNAs from 53 patients with primary gastric carcinoma of the differentiated type. LOH at any locus on 7q occurred in 34% (18 out of 53) of the tumours. Although many tumours exhibited total or large interstitial deletions, we determined the smallest common deleted region to be at D7S480 (7q31.1). This is identical to the region identified for other human malignancies. These observations indicate that a putative tumour suppressor gene at 7q31.1 may be involved in the pathogenesis of differentiated adenocarcinoma of the stomach.

  9. Commonly deleted region on the long arm of chromosome 7 in differentiated adenocarcinoma of the stomach.

    PubMed Central

    Nishizuka, S.; Tamura, G.; Terashima, M.; Satodate, R.

    1997-01-01

    Loss of heterozygosity (LOH) at several chromosomal loci is a common event in human malignancies. Frequent LOH on the long arm of chromosome 7 has been reported in various human malignancies, and investigators have identified the most common site of LOH as 7q31.1. We have identified ten chromosomal loci, including chromosome 7q, that have been shown by previous allelotype study to be sites of frequent LOH in differentiated adenocarcinoma of the stomach. In the present study, we performed a polymerase chain reaction (PCR) microsatellite analysis to define the common deleted region on 7q, using 14 polymorphic microsatellite markers in matched tumour and non-tumour DNAs from 53 patients with primary gastric carcinoma of the differentiated type. LOH at any locus on 7q occurred in 34% (18 out of 53) of the tumours. Although many tumours exhibited total or large interstitial deletions, we determined the smallest common deleted region to be at D7S480 (7q31.1). This is identical to the region identified for other human malignancies. These observations indicate that a putative tumour suppressor gene at 7q31.1 may be involved in the pathogenesis of differentiated adenocarcinoma of the stomach. Images Figure 1 PMID:9413943

  10. Mitochondrial DNA deletion of proximal tubules is the result of itai-itai disease.

    PubMed

    Takebayashi, Shigeo; Jimi, Shiro; Segawa, Masaru; Takaki, Aya

    2003-03-01

    The pathogenesis of itai-itai disease continues to be controversial, although cadmium (Cd) poisoning which arises via polluted water and rice in Japan is likely involved. Until recently, however, a well-defined animal model for Cd intoxication was not available. An animal model for itai-itai disease was produced in rats by low-dose Cd treatment, intraperitoneally for a period of 70-80 weeks. Osteomalacia followed the renal damage. A gene deletion in the mitochondrial DNA was found in the mitochondria of the proximal tubule cells of rats with chronic Cd intoxication, as was shown by the increased smaller PCR product seen by gel electrophoresis in one DNA region, where ATPase and cytochrome oxidase genes are located. However, the PCR product was different from that seen with a gene deletion associated with aging: del4834bp. Renal damage from Cd intoxication initially caused mitochondrial dysfunction indicated by the disturbance in reabsorption in the proximal tubules and decreased amounts of ATP, ATPase, and cytochrome oxidase with gradually progressing tubular proteinuria, and, finally, chronic renal failure with tubulointerstitial damage throughout the renal cortex. These gave rise to osteomalacia, subsequently. We concluded that in Cd poisoning, a mitochondrial gene deletion in the mitochondria of the proximal tubule cells was the primary event for the pathogenesis of osteomalacia in itai-itai disease.

  11. Deletion at ITPR1 Underlies Ataxia in Mice and Spinocerebellar Ataxia 15 in Humans

    PubMed Central

    Knight, Melanie A; Holtzclaw, Lynne A; Scholz, Sonja; Cookson, Mark R; Houlden, Henry; Gwinn-Hardy, Katrina; Fung, Hon-Chung; Lin, Xian; Hernandez, Dena; Simon-Sanchez, Javier; Wood, Nick W; Giunti, Paola; Rafferty, Ian; Hardy, John; Storey, Elsdon; Gardner, R. J. McKinlay; Forrest, Susan M; Fisher, Elizabeth M. C; Russell, James T; Cai, Huaibin; Singleton, Andrew B

    2007-01-01

    We observed a severe autosomal recessive movement disorder in mice used within our laboratory. We pursued a series of experiments to define the genetic lesion underlying this disorder and to identify a cognate disease in humans with mutation at the same locus. Through linkage and sequence analysis we show here that this disorder is caused by a homozygous in-frame 18-bp deletion in Itpr1 (Itpr1Δ18/Δ18), encoding inositol 1,4,5-triphosphate receptor 1. A previously reported spontaneous Itpr1 mutation in mice causes a phenotype identical to that observed here. In both models in-frame deletion within Itpr1 leads to a decrease in the normally high level of Itpr1 expression in cerebellar Purkinje cells. Spinocerebellar ataxia 15 (SCA15), a human autosomal dominant disorder, maps to the genomic region containing ITPR1; however, to date no causal mutations had been identified. Because ataxia is a prominent feature in Itpr1 mutant mice, we performed a series of experiments to test the hypothesis that mutation at ITPR1 may be the cause of SCA15. We show here that heterozygous deletion of the 5′ part of the ITPR1 gene, encompassing exons 1–10, 1–40, and 1–44 in three studied families, underlies SCA15 in humans. PMID:17590087

  12. Expression of I-CreI Endonuclease Generates Deletions Within the rDNA of Drosophila

    PubMed Central

    Paredes, Silvana; Maggert, Keith A.

    2009-01-01

    The rDNA arrays in Drosophila contain the cis-acting nucleolus organizer regions responsible for forming the nucleolus and the genes for the 28S, 18S, and 5.8S/2S RNA components of the ribosomes and so serve a central role in protein synthesis. Mutations or alterations that affect the nucleolus organizer region have pleiotropic effects on genome regulation and development and may play a role in genomewide phenomena such as aging and cancer. We demonstrate a method to create an allelic series of graded deletions in the Drosophila Y-linked rDNA of otherwise isogenic chromosomes, quantify the size of the deletions using real-time PCR, and monitor magnification of the rDNA arrays as their functions are restored. We use this series to define the thresholds of Y-linked rDNA required for sufficient protein translation, as well as establish the rate of Y-linked rDNA magnification in Drosophila. Finally, we show that I-CreI expression can revert rDNA deletion phenotypes, suggesting that double-strand breaks are sufficient to induce rDNA magnification. PMID:19171942

  13. A Human Minor Histocompatibility Antigen Resulting from Differential Expression due to a Gene Deletion

    PubMed Central

    Murata, Makoto; Warren, Edus H.; Riddell, Stanley R.

    2003-01-01

    Minor histocompatibility antigens (minor H antigens) are targets of graft-versus-host disease and graft-versus-leukemia responses after allogeneic human leukocyte antigen identical hematopoietic stem cell transplantation. Only a few human minor H antigens have been molecularly characterized and in all cases, amino acid differences between homologous donor and recipient proteins due to nucleotide polymorphisms in the respective genes were responsible for immunogenicity. Here, we have used cDNA expression cloning to identify a novel human minor H antigen encoded by UGT2B17, an autosomal gene in the multigene UDP-glycosyltransferase 2 family that is selectively expressed in liver, intestine, and antigen-presenting cells. In contrast to previously defined human minor H antigens, UGT2B17 is immunogenic because of differential expression of the protein in donor and recipient cells as a consequence of a homozygous gene deletion in the donor. Deletion of individual members of large gene families is a common form of genetic variation in the population and our results provide the first evidence that differential protein expression as a consequence of gene deletion is a mechanism for generating minor H antigens in humans. PMID:12743171

  14. Delineation of a minimal region of deletion at 6q16.3 in follicular lymphoma and construction of a bacterial artificial chromosome contig spanning a 6-megabase region of 6q16-q21.

    PubMed

    Henderson, Laura-Jane; Okamoto, Ichiro; Lestou, Valia S; Ludkovski, Olga; Robichaud, Marc; Chhanabhai, Mukesh; Gascoyne, Randy D; Klasa, Richard J; Connors, Joseph M; Marra, Marco A; Horsman, Douglas E; Lam, Wan L

    2004-05-01

    Regional deletions of 6q are frequent karyotypic alterations in malignant lymphoma and are associated with an adverse clinical outcome. One such region of recurrent deletion is 6q16-q21; however, the specific genes affected have not been identified. Our objective in this study was to identify cases with deletion of 6q16-q21 in follicular lymphoma and to define a minimal region of deletion. A physical map of 6q16.2-q21 was constructed using map information from both sequence-based and bacterial artificial chromosome (BAC) fingerprint-based maps. Forty-three BAC clones spanning a 6-Mb region of 6q16.2-q21 were identified and obtained from the RP-11 library. Selected BACs were fluorescence-labeled and hybridized to a series of 34 follicular lymphomas with a regional 6q deletion detected by G banding. Twenty-four cases with deletion of the 6q16.3 region were detected. A minimal deletion of 2.3 Mb was defined. Our study has identified a limited region of deletion of 6q16.3 that may implicate four known genes in follicular lymphoma and possibly in other cancers. A BAC contig spanning a 6-Mb region has been anchored to the 6q16.2-q21 region. This map represents a useful resource for gene identification in this region, not only in lymphoma but also in other neoplasms with 6q alterations.

  15. Distinct germline progenitor subsets defined through Tsc2–mTORC1 signaling

    PubMed Central

    Hobbs, Robin M; La, Hue M; Mäkelä, Juho-Antti; Kobayashi, Toshiyuki; Noda, Tetsuo; Pandolfi, Pier Paolo

    2015-01-01

    Adult tissue maintenance is often dependent on resident stem cells; however, the phenotypic and functional heterogeneity existing within this self-renewing population is poorly understood. Here, we define distinct subsets of undifferentiated spermatogonia (spermatogonial progenitor cells; SPCs) by differential response to hyperactivation of mTORC1, a key growth-promoting pathway. We find that conditional deletion of the mTORC1 inhibitor Tsc2 throughout the SPC pool using Vasa-Cre promotes differentiation at the expense of self-renewal and leads to germline degeneration. Surprisingly, Tsc2 ablation within a subset of SPCs using Stra8-Cre did not compromise SPC function. SPC activity also appeared unaffected by Amh-Cre-mediated Tsc2 deletion within somatic cells of the niche. Importantly, we find that differentiation-prone SPCs have elevated mTORC1 activity when compared to SPCs with high self-renewal potential. Moreover, SPCs insensitive to Tsc2 deletion are preferentially associated with mTORC1-active committed progenitor fractions. We therefore delineate SPC subsets based on differential mTORC1 activity and correlated sensitivity to Tsc2 deletion. We propose that mTORC1 is a key regulator of SPC fate and defines phenotypically distinct SPC subpopulations with varying propensities for self-renewal and differentiation. PMID:25700280

  16. The HLA-G 14-base pair deletion allele and the deletion/deletion genotype are associated with persistent HBe antigenemia in chronic hepatis B infection.

    PubMed

    Ferreira, Sandro da Costa; Chachá, Silvana Gama Florêncio; Souza, Fernanda Fernandes; Teixeira, Andreza Corrêa; Santana, Rodrigo de Carvalho; Deghaide, Neifi Hassan Saloun; Rodrigues, Sandra; Marano, Leonardo A; Mendes-Junior, Celso Teixeira; Ramalho, Leandra Naira Zambelli; Zucoloto, Sérgio; Donadi, Eduardo Antônio; Martinelli, Ana de Lourdes Candolo

    2017-02-01

    HLA-G has well-recognized immunomodulatory properties, and this molecule is frequently expressed in the livers of hepatitis B virus (HBV)-infected patients. Because the HLA-G 14 bp-insertion/deletion polymorphism (rs371194629) has been associated with the magnitude of HLA-G expression, we evaluated this polymorphism in the recognized evolutionary forms of chronic HBV infection. We studied 196 chronic HBV-infected patients (118 HBeAg-negative chronic hepatitis, 53 HBeAg-positive chronic hepatitis and 25 inactive carriers exhibiting low levels of serum HBVDNA and persistently normal ALT levels), and 202 healthy individuals. Chronic hepatitis HLA-G typing was performed using PCR-amplified DNA hybridized with specific primers. The frequencies of the insertion/deletion alleles and genotypes were very similar in patients and controls. After patient stratification according to the evolutionary form of the chronic HBV infection, the frequencies of the deletion allele (P=0.0460; OR=1.26; 95%CI=1.01-1.45) and of the deletion/deletion genotype (P=0.0356; OR=2.08; 95%CI=1.05-4.09) were overrepresented in HBeAg-positive patients when compared to HBeAg-negative patients. No differences were observed when HBV inactive carriers were compared to HBeAg-negative chronic hepatitis patients. Because the 14-bp deletion allele has been associated with increased HLA-G production and because HLA-G may down regulate the cytotoxic activity of TCD8 and NK cells, patients exhibiting the 14-bp deletion allele at single or double doses are at increased risk for developing chronic forms of HBV associated with persistent viremia and worse prognoses. Copyright © 2017 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

  17. Molecular characterization of patients with 18q23 deletions.

    PubMed Central

    Strathdee, G; Sutherland, R; Jonsson, J J; Sataloff, R; Kohonen-Corish, M; Grady, D; Overhauser, J

    1997-01-01

    The 18q- syndrome is a deletion syndrome that is characterized by mental retardation, hearing loss, midfacial hypoplasia, growth deficiency, and limb anomalies. Most patients with this syndrome have deletions from 18q21-qter. We report on three patients with deletions of 18q23. A mother and daughter with identical deletions of 18q23 have many of the typical features of the 18q- syndrome, including midfacial hypoplasia and hearing loss. In contrast, the third patient has few of the symptoms of the 18q- syndrome. A contig of the 18q23 region was generated to aid in the mapping of the breakpoints. FISH was used to map both breakpoints to the same YAC clone. Furthermore, somatic-cell hybrids from the daughter and the third patient were isolated. The mapping results of sequence-tagged sites relative to the two breakpoints were identical, suggesting that the two deletion breakpoints map very close to one another. The analyses of these patients demonstrate that the critical region for the 18q- syndrome maps to 18q23 but that a deletion of 18q23 does not always lead to the clinical features associated with the syndrome. These patients demonstrate the wide phenotypic variability associated with deletions of 18q. Images Figure 2 Figure 3 PMID:9106532

  18. Recurrent deletions of IKZF1 in pediatric acute myeloid leukemia

    PubMed Central

    de Rooij, Jasmijn D.E.; Beuling, Eva; van den Heuvel-Eibrink, Marry M.; Obulkasim, Askar; Baruchel, André; Trka, Jan; Reinhardt, Dirk; Sonneveld, Edwin; Gibson, Brenda E.S.; Pieters, Rob; Zimmermann, Martin; Zwaan, C. Michel; Fornerod, Maarten

    2015-01-01

    IKAROS family zinc finger 1/IKZF1 is a transcription factor important in lymphoid differentiation, and a known tumor suppressor in acute lymphoid leukemia. Recent studies suggest that IKZF1 is also involved in myeloid differentiation. To investigate whether IKZF1 deletions also play a role in pediatric acute myeloid leukemia, we screened a panel of pediatric acute myeloid leukemia samples for deletions of the IKZF1 locus using multiplex ligation-dependent probe amplification and for mutations using direct sequencing. Three patients were identified with a single amino acid variant without change of IKZF1 length. No frame-shift mutations were found. Out of 11 patients with an IKZF1 deletion, 8 samples revealed a complete loss of chromosome 7, and 3 cases a focal deletion of 0.1–0.9Mb. These deletions included the complete IKZF1 gene (n=2) or exons 1–4 (n=1), all leading to a loss of IKZF1 function. Interestingly, differentially expressed genes in monosomy 7 cases (n=8) when compared to non-deleted samples (n=247) significantly correlated with gene expression changes in focal IKZF1-deleted cases (n=3). Genes with increased expression included genes involved in myeloid cell self-renewal and cell cycle, and a significant portion of GATA target genes and GATA factors. Together, these results suggest that loss of IKZF1 is recurrent in pediatric acute myeloid leukemia and might be a determinant of oncogenesis in acute myeloid leukemia with monosomy 7 PMID:26069293

  19. Do listeners recover "deleted" final /t/ in German?

    PubMed

    Zimmerer, Frank; Reetz, Henning

    2014-01-01

    Reduction and deletion processes occur regularly in conversational speech. A segment that is affected by such reduction and deletion processes in many Germanic languages (e.g., Dutch, English, German) is /t/. There are similarities concerning the factors that influence the likelihood of final /t/ to get deleted, such as segmental context. However, speakers of different languages differ with respect to the acoustic cues they leave in the speech signal when they delete final /t/. German speakers usually lengthen a preceding /s/ when they delete final /t/. This article investigates to what extent German listeners are able to reconstruct /t/ when they are presented with fragments of words where final /t/ has been deleted. It aims also at investigating whether the strategies that are used by German depend on the length of /s/, and therefore whether listeners are using language-specific cues. Results of a forced-choice segment detection task suggest that listeners are able to reconstruct deleted final /t/ in about 45% of the times. The length of /s/ plays some role in the reconstruction, however, it does not explain the behavior of German listeners completely.

  20. Death receptor 3 (DR3) gene duplication in a chromosome region 1p36.3: gene duplication is more prevalent in rheumatoid arthritis.

    PubMed

    Osawa, K; Takami, N; Shiozawa, K; Hashiramoto, A; Shiozawa, S

    2004-09-01

    The death receptor 3 (DR3) gene is a member of the apoptosis-inducing Fas gene family. In the current study, fluorescence in situ hybridization (FISH) and Fiber-FISH revealed the existence of a second DR3 gene approximately 200 kb upstream of the original DR3 gene. The existence of the duplicated DR3 gene was confirmed by sequencing the corresponding human artificial chromosome clones as well as with quantitative PCR that measured the ratio of the DR3 gene mutation (Rm), intrinsic to rheumatoid arthritis (RA) patients, by simultaneous amplification of the normal and mutated DR3 sequences. The DR3 gene duplication measured by FISH was found to be more frequent in patients with RA as compared to healthy individuals. We therefore surmise that the human DR3 gene can be duplicated and that this gene duplication is more prevalent in patients with RA.

  1. GENOME-WIDE SCAN FOR SERUM GHRELIN DETECTS LINKAGE ON CHROMOSOME 1P36 IN HISPANIC CHILDREN: RESULTS FROM THE VIVA LA FAMILIA STUDY

    USDA-ARS?s Scientific Manuscript database

    This study was conducted to investigate genetic influence on serum ghrelin and its relationship with adiposity-related phenotypes in Hispanic children (n = 1030) from the Viva La Familia study (VFS). Anthropometric measurements and levels of serum ghrelin were estimated and genetic analyses conducte...

  2. Defining Our National Cyberspace Boundaries

    DTIC Science & Technology

    2010-02-17

    invention of the World Wide Web in 19 1989, the Internet Corporation for Assigned Names and Numbers ( ICANN ) (the international organization that...anonymity in cyberspace could be accomplished through the issuing of IP addresses as the Internet transitions from IPv4 to IPv6. ICANN should issue...agreement (MOA) between the U.S. Department of Commerce and ICANN . This new MOA should define which blocks of IP addresses will be used for entities

  3. Defining the Smallest Common Region of Chromosome l7p that is Deleted in Sporadic Breast Tumors.

    DTIC Science & Technology

    1995-10-01

    techniques on glass coverslips and stained by trypsin Giemsa banding. Microdissection was performed with glass microneedles controlled by a micromanipulator...mounted on an inverted microscope. Approximately 20 copies of 17pter were scraped and the -• chromosome fragments adhering to the glass microneedles

  4. How to define green adjuvants.

    PubMed

    Beck, Bert; Steurbaut, Walter; Spanoghe, Pieter

    2012-08-01

    The concept 'green adjuvants' is difficult to define. This paper formulates an answer based on two approaches. Starting from the Organisation for Economic Cooperation and Development (OECD) definition for green chemistry, production-based and environmental-impact-based definitions for green adjuvants are proposed. According to the production-based approach, adjuvants are defined as green if they are manufactured using renewable raw materials as much as possible while making efficient use of energy, preferably renewable energy. According to the environmental impact approach, adjuvants are defined as green (1) if they have a low human and environmental impact, (2) if they do not increase active ingredient environmental mobility and/or toxicity to humans and non-target organisms, (3) if they do not increase the exposure to these active substances and (4) if they lower the impact of formulated pesticides by enhancing the performance of active ingredients, thus potentially lowering the required dosage of active ingredients. Based on both approaches, a tentative definition for 'green adjuvants' is given, and future research and legislation directions are set out.

  5. How do people define moderation?

    PubMed

    vanDellen, Michelle R; Isherwood, Jennifer C; Delose, Julie E

    2016-06-01

    Eating in moderation is considered to be sound and practical advice for weight maintenance or prevention of weight gain. However, the concept of moderation is ambiguous, and the effect of moderation messages on consumption has yet to be empirically examined. The present manuscript examines how people define moderate consumption. We expected that people would define moderate consumption in ways that justified their current or desired consumption rather than view moderation as an objective standard. In Studies 1 and 2, moderate consumption was perceived to involve greater quantities of an unhealthy food (chocolate chip cookies, gummy candies) than perceptions of how much one should consume. In Study 3, participants generally perceived themselves to eat in moderation and defined moderate consumption as greater than their personal consumption. Furthermore, definitions of moderate consumption were related to personal consumption behaviors. Results suggest that the endorsement of moderation messages allows for a wide range of interpretations of moderate consumption. Thus, we conclude that moderation messages are unlikely to be effective messages for helping people maintain or lose weight. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. What Defines the "Kingdom" Fungi?

    PubMed

    Richards, Thomas A; Leonard, Guy; Wideman, Jeremy G

    2017-06-01

    The application of environmental DNA techniques and increased genome sequencing of microbial diversity, combined with detailed study of cellular characters, has consistently led to the reexamination of our understanding of the tree of life. This has challenged many of the definitions of taxonomic groups, especially higher taxonomic ranks such as eukaryotic kingdoms. The Fungi is an example of a kingdom which, together with the features that define it and the taxa that are grouped within it, has been in a continual state of flux. In this article we aim to summarize multiple lines of data pertinent to understanding the early evolution and definition of the Fungi. These include ongoing cellular and genomic comparisons that, we will argue, have generally undermined all attempts to identify a synapomorphic trait that defines the Fungi. This article will also summarize ongoing work focusing on taxon discovery, combined with phylogenomic analysis, which has identified novel groups that lie proximate/adjacent to the fungal clade-wherever the boundary that defines the Fungi may be. Our hope is that, by summarizing these data in the form of a discussion, we can illustrate the ongoing efforts to understand what drove the evolutionary diversification of fungi.

  7. Impact of partial DAZ1/2 deletion and partial DAZ3/4 deletion on male infertility.

    PubMed

    Zhang, Yuening; Li, Muyan; Xiao, Feifan; Teng, Ruobing; Zhang, Chengdong; Lan, Aihua; Gu, Kailong; Li, Jiatong; Wang, Di; Li, Hongtao; Jiang, Li; Zeng, Siping; He, Min; Huang, Yi; Guo, Peifen; Zhang, Xinhua; Yang, Xiaoli

    2015-10-15

    This study aims to investigate the effect of the partial DAZ1/2 deletion and partial DAZ3/4 deletion on male infertility through a comprehensive literature search. All case-control studies related to partial DAZ1/2 and DAZ3/4 deletions and male infertility risk were included in our study. Odd ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the association and its precision, respectively. Eleven partial DAZ1/2 deletion and nine partial DAZ3/4 deletion studies were included. Partial DAZ1/2 deletion was significantly associated with male infertility risk in the overall analysis (ORs=2.58, 95%CI: 1.60-4.18, I(2)=62.1%). Moreover, in the subgroup analysis stratified by ethnicity, partial DAZ1/2 deletion was significantly associated with male infertility risk in the East Asian populations under the random effect model (ORs=2.96, 95%CI: 1.87-4.71, I(2)=51.3%). Meanwhile, the analysis suggested that partial DAZ3/4 deletion was not associated with male infertility risk in East-Asian ethnicity (ORs=1.02, 95%CI: 0.54-1.92, I(2)=71.3%), but not in Non-East Asian under the random effect model (ORs=3.56, 95%CI: 1.13-11.23, I(2)=0.0%,). More interestingly, partial DAZ1/2 deletion was associated with azoospermia (ORs=2.63, 95%CI: 1.19-5.81, I(2)=64.7%) and oligozoospermia (ORs=2.53, 95%CI: 1.40-4.57, I(2)=51.8%), but partial DAZ3/4 deletion was not associated with azoospermia (ORs=0.71, 95%CI: 0.23-2.22, I(2)=71.7%,) and oligozoospermia (ORs=1.21, 95%CI: 0.65-2.24, I(2)=55.5%). In our meta-analysis, partial DAZ1/2 deletion is a risk factor for male infertility and different ethnicities have different influences, whereas partial DAZ3/4 deletion has no effect on fertility but partial DAZ3/4 deletion might have an impact on Non-East Asian male.

  8. Detection of genomic deletions in rice using oligonucleotide microarrays

    PubMed Central

    Bruce, Myron; Hess, Ann; Bai, Jianfa; Mauleon, Ramil; Diaz, M Genaleen; Sugiyama, Nobuko; Bordeos, Alicia; Wang, Guo-Liang; Leung, Hei; Leach, Jan E

    2009-01-01

    Background The induction of genomic deletions by physical- or chemical- agents is an easy and inexpensive means to generate a genome-saturating collection of mutations. Different mutagens can be selected to ensure a mutant collection with a range of deletion sizes. This would allow identification of mutations in single genes or, alternatively, a deleted group of genes that might collectively govern a trait (e.g., quantitative trait loci, QTL). However, deletion mutants have not been widely used in functional genomics, because the mutated genes are not tagged and therefore, difficult to identify. Here, we present a microarray-based approach to identify deleted genomic regions in rice mutants selected from a large collection generated by gamma ray or fast neutron treatment. Our study focuses not only on the utility of this method for forward genetics, but also its potential as a reverse genetics tool through accumulation of hybridization data for a collection of deletion mutants harboring multiple genetic lesions. Results We demonstrate that hybridization of labeled genomic DNA directly onto the Affymetrix Rice GeneChip® allows rapid localization of deleted regions in rice mutants. Deletions ranged in size from one gene model to ~500 kb and were predicted on all 12 rice chromosomes. The utility of the technique as a tool in forward genetics was demonstrated in combination with an allelic series of mutants to rapidly narrow the genomic region, and eventually identify a candidate gene responsible for a lesion mimic phenotype. Finally, the positions of mutations in 14 mutants were aligned onto the rice pseudomolecules in a user-friendly genome browser to allow for rapid identification of untagged mutations . Conclusion We demonstrate the utility of oligonucleotide arrays to discover deleted genes in rice. The density and distribution of deletions suggests the feasibility of a database saturated with deletions across the rice genome. This community resource can continue

  9. Performance of quantum cloning and deleting machines over coherence

    NASA Astrophysics Data System (ADS)

    Karmakar, Sumana; Sen, Ajoy; Sarkar, Debasis

    2017-10-01

    Coherence, being at the heart of interference phenomena, is found to be an useful resource in quantum information theory. Here we want to understand quantum coherence under the combination of two fundamentally dual processes, viz., cloning and deleting. We found the role of quantum cloning and deletion machines with the consumption and generation of quantum coherence. We establish cloning as a cohering process and deletion as a decohering process. Fidelity of the process will be shown to have connection with coherence generation and consumption of the processes.

  10. Ectrodactyly and proximal/intermediate interstitial deletion 7q

    SciTech Connect

    McElveen, C.; Carvajal, M.V.; Moscatello, D.

    1995-03-13

    We report on an individual with severe mental retardation, seizures, microcephaly, unusual face, scoliosis, and cleft feet and cleft right hand. The chromosomal study showed a proximal interstitial deletion 7q (q11.23q22). From our review of the literature, 11 patients have been reported with ectrodactyly (split hand/split foot malformation) and proximal/intermediate interstitial deletions or rearrangements of 7q. The critical segment for ectrodactyly seems to be located between 7q21.2 and 7q22.1. This malformation is present in 41% of the patients whose deletion involves the critical segment. 37 refs., 3 figs., 1 tab.

  11. 22q11.2 deletion syndrome

    PubMed Central

    McDonald-McGinn, Donna M.; Sullivan, Kathleen E.; Marino, Bruno; Philip, Nicole; Swillen, Ann; Vorstman, Jacob A. S.; Zackai, Elaine H.; Emanuel, Beverly S.; Vermeesch, Joris R.; Morrow, Bernice E.; Scambler, Peter J.; Bassett, Anne S.

    2016-01-01

    22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal microdeletion disorder, estimated to result mainly from de novo non-homologous meiotic recombination events occurring in approximately 1 in every 1,000 fetuses. The first description in the English language of the constellation of findings now known to be due to this chromosomal difference was made in the 1960s in children with DiGeorge syndrome, who presented with the clinical triad of immunodeficiency, hypoparathyroidism and congenital heart disease. The syndrome is now known to have a heterogeneous presentation that includes multiple additional congenital anomalies and later-onset conditions, such as palatal, gastrointestinal and renal abnormalities, autoimmune disease, variable cognitive delays, behavioural phenotypes and psychiatric illness — all far extending the original description of DiGeorge syndrome. Management requires a multidisciplinary approach involving paediatrics, general medicine, surgery, psychiatry, psychology, interventional therapies (physical, occupational, speech, language and behavioural) and genetic counselling. Although common, lack of recognition of the condition and/or lack of familiarity with genetic testing methods, together with the wide variability of clinical presentation, delays diagnosis. Early diagnosis, preferably prenatally or neonatally, could improve outcomes, thus stressing the importance of universal screening. Equally important, 22q11.2DS has become a model for understanding rare and frequent congenital anomalies, medical conditions, psychiatric and developmental disorders, and may provide a platform to better understand these disorders while affording opportunities for translational strategies across the lifespan for both patients with 22q11.2DS and those with these associated features in the general population. PMID:27189754

  12. Genetic Deletion of NADPH Oxidase 1 Rescues Microvascular Function in Mice With Metabolic Disease.

    PubMed

    Thompson, Jennifer A; Larion, Sebastian; Mintz, James D; Belin de Chantemèle, Eric J; Fulton, David J; Stepp, David W

    2017-08-18

    Early vascular changes in metabolic disease that precipitate the development of cardiovascular complications are largely driven by reactive oxygen species accumulation, yet the extent to which excess reactive oxygen species derive from specific NADPH oxidase isoforms remains ill defined. Identify the role of Nox1 in the development of microvascular dysfunction in metabolic disease. Four genotypes were generated by breeding Nox1 knockout mice with db/db mice: lean (HdbWnox1), lean Nox1 knockout (HdbKnox1), obese (KdbWnox1), and obese KK (KdbKnox1). The degree of adiposity, insulin resistance, and dyslipidemia in KW mice was not influenced by Nox1 deletion as determined by nuclear magnetic resonance spectroscopy, glucose tolerance tests, and plasma analyses. Endothelium-dependent responses to acetylcholine in pressurized mesenteric arteries were reduced in KW versus HW (P<0.01), whereas deletion of Nox1 in KW mice normalized dilation. Vasodilator responses after inhibition of NO synthase blunted acetylcholine responses in KK and lean controls, but had no impact in KW, attributing recovered dilatory capacity in KK to normalization of NO. Acetylcholine responses were improved (P<0.05) with Tempol, and histochemistry revealed oxidative stress in KW animals, whereas Tempol had no impact and reactive oxygen species staining was negligible in KK. Blunted dilatory responses to an NO donor and loss of myogenic tone in KW animals were also rescued with Nox1 deletion. Nox1 deletion reduces oxidant load and restores microvascular health in db/db mice without influencing the degree of metabolic dysfunction. Therefore, targeted Nox1 inhibition may be effective in the prevention of vascular complications. © 2017 The Authors.

  13. Distinctive Phenotype in 9 Patients with Deletion of Chromosome 1q24-q25

    PubMed Central

    Burkardt, Deepika D’Cunha; Rosenfeld, Jill A.; Helgeson, Maria; Angle, Brad; Banks, Valerie; Smith, Wendy; Gripp, Karen W.; Moline, Jessica; Moran, Rocio; Niyazov, Dmitriy M.; Stevens, Cathy; Zackai, Elaine; Lebel, Robert Roger; Ashley, Douglas; Kramer, Nancy; Lachman, Ralph S.; Graham, John M.

    2011-01-01

    Reports of individuals with deletions of 1q24→q25 share common features of prenatal onset growth deficiency, microcephaly, small hands and feet, dysmorphic face and severe cognitive deficits. We report nine individuals with 1q24q25 deletions, who show distinctive features of a clinically recognizable 1q24q25 microdeletion syndrome: prenatal-onset microcephaly and proportionate growth deficiency, severe cognitive disability, small hands and feet with distinctive brachydactyly, single transverse palmar flexion creases, fifth finger clinodactyly and distinctive facial features: upper eyelid fullness, small ears, short nose with bulbous nasal tip, tented upper lip, and micrognathia. Radiographs demonstrate disharmonic osseous maturation with markedly delayed bone age. Occasional features include cleft lip and/or palate, cryptorchidism, brain and spinal cord defects, and seizures. Using oligonucleotide-based array comparative genomic hybridization, we defined the critical deletion region as 1.9 Mb at 1q24.3q25.1 (chr1: 170135865–172099327, hg18 coordinates), containing 13 genes and including CENPL, which encodes centromeric protein L, a protein essential for proper kinetochore function and mitotic progression. The growth deficiency in this syndrome is similar to what is seen in other types of primordial short stature with microcephaly, such as Majewski osteodysplastic primordial dwarfism, type II (MOPD2) and Seckel syndrome, which result from loss-of-function mutations in genes coding for centrosomal proteins. DNM3 is also in the deleted region and expressed in the brain, where it participates in the Shank-Homer complex and increases synaptic strength. Therefore, DNM3 is a candidate for the cognitive disability, and CENPL is a candidate for growth deficiency in this 1q24q25 microdeletion syndrome. PMID:21548129

  14. Deletion of Drosophila Nopp140 induces subcellular ribosomopathies.

    PubMed

    He, Fang; James, Allison; Raje, Himanshu; Ghaffari, Helya; DiMario, Patrick

    2015-06-01

    The nucleolar and Cajal body phosphoprotein of 140 kDa (Nopp140) is considered a ribosome assembly factor, but its precise functions remain unknown. To approach this problem, we deleted the Nopp140 gene in Drosophila using FLP-FRT recombination. Genomic PCR, reverse transcriptase-PCR (RT-PCR), and immunofluorescence microscopy confirmed the loss of Nopp140, its messenger RNA (mRNA), and protein products from all tissues examined. Nopp140-/- larvae arrested in the second instar stage and most died within 8 days. While nucleoli appeared intact in Nopp140-/- cells, the C/D small nucleolar ribonucleoprotein (snoRNP) methyltransferase, fibrillarin, redistributed to the nucleoplasm in variable amounts depending on the cell type; RT-PCRs showed that 2'-O-methylation of ribosomal RNA (rRNA) in Nopp140-/- cells was reduced at select sites within both the 18S and 28S rRNAs. Ultrastructural analysis showed that Nopp140-/- cells were deficient in cytoplasmic ribosomes, but instead contained abnormal electron-dense cytoplasmic granules. Immunoblot analysis showed a loss of RpL34, and metabolic labeling showed a significant drop in protein translation, supporting the loss of functional ribosomes. Northern blots showed that pre-RNA cleavage pathways were generally unaffected by the loss of Nopp140, but that R2 retrotransposons that naturally reside within the 28S region of normally silent heterochromatic Drosophila ribosomal DNA (rDNA) genes were selectively expressed in Nopp140-/- larvae. Unlike copia elements and the related R1 retrotransposon, R2 expression appeared to be preferentially dependent on the loss of Nopp140 and not on environmental stresses. We believe the phenotypes described here define novel intracellular ribosomopathies resulting from the loss of Nopp140.

  15. Catalytic properties of ADAM12 and its domain deletion mutants.

    PubMed

    Jacobsen, Jonas; Visse, Robert; Sørensen, Hans Peter; Enghild, Jan J; Brew, Keith; Wewer, Ulla M; Nagase, Hideaki

    2008-01-15

    Human ADAM12 (a disintegrin and metalloproteinase) is a multidomain zinc metalloproteinase expressed at high levels during development and in human tumors. ADAM12 exists as two splice variants: a classical type 1 membrane-anchored form (ADAM12-L) and a secreted splice variant (ADAM12-S) consisting of pro, catalytic, disintegrin, cysteine-rich, and EGF domains. Here we present a novel activity of recombinant ADAM12-S and its domain deletion mutants on S-carboxymethylated transferrin (Cm-Tf). Cleavage of Cm-Tf occurred at multiple sites, and N-terminal sequencing showed that the enzyme exhibits restricted specificity but a consensus sequence could not be defined as its subsite requirements are promiscuous. Kinetic analysis revealed that the noncatalytic C-terminal domains are important regulators of Cm-Tf activity and that ADAM12-PC consisting of the pro domain and catalytic domain is the most active on this substrate. It was also observed that NaCl inhibits ADAM12. Among the tissue inhibitors of metalloproteinases (TIMP) examined, the N-terminal domain of TIMP-3 (N-TIMP-3) inhibits ADAM12-S and ADAM12-PC with low nanomolar Ki(app) values while TIMP-2 inhibits them with a slightly lower affinity (9-44 nM). However, TIMP-1 is a much weaker inhibitor. N-TIMP-3 variants that lack MMP inhibitory activity but retained the ability to inhibit ADAM17/TACE failed to inhibit ADAM12. These results indicate unique enzymatic properties of ADAM12 among the members of the ADAM family of metalloproteinases.

  16. Loss of Wave1 gene defines a subtype of lethal prostate cancer

    PubMed Central

    Sowalsky, Adam G.; Sager, Rebecca; Schaefer, Rachel J.; Bratslavsky, Gennady; Pandolfi, Pier Paolo; Balk, Steven P.; Kotula, Leszek

    2015-01-01

    Genetic alterations involving TMPRSS2-ERG alterations and deletion of key tumor suppressor genes are associated with development and progression of prostate cancer (PCa). However, less defined are early events that may contribute to the development of high-risk metastatic prostate cancer. Bioinformatic analysis of existing tumor genomic data from PCa patients revealed that WAVE complex gene alterations are associated with a greater likelihood of prostate cancer recurrence. Further analysis of primary vs. castration resistant prostate cancer indicate that disruption of WAVE complex gene expression, and particularly WAVE1 gene (WASF1) loss, is also associated with castration resistance, where WASF1 is frequently co-deleted with PTEN and resists androgen deprivation therapy (ADT). Hence, we propose that WASF1 status defines a subtype of ADT-resistant patients. Better understanding of the effects of WAVE pathway disruption will lead to development of better diagnostic and treatment modalities. PMID:25906751

  17. Patient Self-Defined Goals.

    PubMed

    Schellinger, Sandra Ellen; Anderson, Eric Worden; Frazer, Monica Schmitz; Cain, Cindy Lynn

    2017-01-01

    This research, a descriptive qualitative analysis of self-defined serious illness goals, expands the knowledge of what goals are important beyond the physical-making existing disease-specific guidelines more holistic. Integration of goals of care discussions and documentation is standard for quality palliative care but not consistently executed into general and specialty practice. Over 14 months, lay health-care workers (care guides) provided monthly supportive visits for 160 patients with advanced heart failure, cancer, and dementia expected to die in 2 to 3 years. Care guides explored what was most important to patients and documented their self-defined goals on a medical record flow sheet. Using definitions of an expanded set of whole-person domains adapted from the National Consensus Project (NCP) Clinical Practice Guidelines for Quality Palliative Care, 999 goals and their associated plans were deductively coded and examined. Four themes were identified-medical, nonmedical, multiple, and global. Forty percent of goals were coded into the medical domain; 40% were coded to nonmedical domains-social (9%), ethical (7%), family (6%), financial/legal (5%), psychological (5%), housing (3%), legacy/bereavement (3%), spiritual (1%), and end-of-life care (1%). Sixteen percent of the goals were complex and reflected a mix of medical and nonmedical domains, "multiple" goals. The remaining goals (4%) were too global to attribute to an NCP domain. Self-defined serious illness goals express experiences beyond physical health and extend into all aspects of whole person. It is feasible to elicit and record serious illness goals. This approach to goals can support meaningful person-centered care, decision-making, and planning that accords with individual preferences of late life.

  18. Defining and Achieving Decisive Victory

    DTIC Science & Technology

    2002-04-01

    developing a long-term strategy. In this process, nothing is more important than defining victory. In this monograph, Dr. Colin Gray, one of the world’s...Dr. Gray has written 17 books , most recently Modern Strategy (1999). In 2002 he will publish Strategy for Chaos: RMA Theory and the Evidence of...aims.4 But on the first page of Book One, Chapter 1, Clausewitz insists that “War is thus an act of force to compel our enemy to do our will.”5 He rams

  19. Genetics Home Reference: 22q13.3 deletion syndrome

    MedlinePlus

    ... and symptoms include developmental delay, moderate to profound intellectual disability, decreased muscle tone (hypotonia), and absent or delayed ... the syndrome's characteristic signs (such as developmental delay, intellectual disability, and impaired speech). Additional genes in the deleted ...

  20. Report: Observed Conditions at Five Deleted Superfund Sites

    EPA Pesticide Factsheets

    Report #11-P-0433, August 3, 2011. Conditions at two of the five sites we visited in EPA Region 3, which had been remediated and deleted from the National Priorities List, may warrant additional attention from EPA.

  1. Genetics Home Reference: 17q12 deletion syndrome

    MedlinePlus

    ... spectrum disorder (which affects social interaction and communication), schizophrenia , anxiety, and bipolar disorder . Less commonly, 17q12 deletion ... Encyclopedia: Autism Spectrum Disorder Encyclopedia: Bipolar Disorder Encyclopedia: ... Topic: Developmental Disabilities Health Topic: Diabetes Health ...

  2. Genetics Home Reference: 19p13.13 deletion syndrome

    MedlinePlus

    ... Resources (1 link) National Human Genome Research Institute: Chromosome Abnormalities Educational Resources (5 links) MalaCards: chromosome 19p13.13 deletion syndrome March of Dimes: Chromosomal ...

  3. Directly repeated sequences associated with pathogenic mitochondrial DNA deletions.

    PubMed Central

    Johns, D R; Rutledge, S L; Stine, O C; Hurko, O

    1989-01-01

    We determined the nucleotide sequences of junctional regions associated with large deletions of mitochondrial DNA found in four unrelated individuals with a phenotype of chronic progressive external ophthalmoplegia. In each patient, the deletion breakpoint occurred within a directly repeated sequence of 13-18 base pairs, present in different regions of the normal mitochondrial genome-separated by 4.5-7.7 kilobases. In two patients, the deletions were identical. When all four repeated sequences are compared, a consensus sequence of 11 nucleotides emerges, similar to putative recombination signals, suggesting the involvement of a recombinational event. Partially deleted and normal mitochondrial DNAs were found in all tissues examined, but in very different proportions, indicating that these mutations originated before the primary cell layers diverged. Images PMID:2813377

  4. Additions and deletions to the known cerambycidae (Coleoptera) of Bolivia

    USDA-ARS?s Scientific Manuscript database

    An additional 137 species and two tribes are added to the known cerambycid fauna of Bolivia while 12 species are deleted. Comments and statistics regarding the growth of knowledge on the Bolivian Cerambycid fauna and species endemicity are included....

  5. Genetics Home Reference: proximal 18q deletion syndrome

    MedlinePlus

    ... B, O'Donnell L, Gelfond J, Lancaster J, Fox PT, Hale DE. Consequences of chromsome18q deletions. Am ... Cody CM, Hardies LJ, Li J, Lancaster J, Fox PT, Stratton RF, Perry B, Hale DE. Recurrent ...

  6. 78 FR 17641 - Procurement List; Proposed Addition and Deletion

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-22

    ...The Committee is proposing to add a service to the Procurement List that will be provided by a nonprofit agency employing persons who are blind or have other severe disabilities and, deletes a product previously furnished by such...

  7. Characterization of a lymphoblastoid line deleted for lambda immunoglobulin genes

    SciTech Connect

    Hough, C.A., White, B.N., Holden, J.A.

    1995-04-01

    While characterizing the cat eye syndrome (CES) supernumerary chromosome for the presence of {lambda} immunoglobulin gene region sequences, a lymphoblastoid cell line from one CES patient was identified in which there was selection of cells deleted from some IGLC and IGLV genes. Two distinct deletions, one on each chromosome 22, were identified, presumably arising from independent somatic recombination events occurring during B-lymphocyte differentiation. The extent of the deleted regions was determined using probes from the various IGLV subgroups and they each covered at least 82 kilobases. The precise definition of the deletions was not possible because of conservation of some restriction sites in the IGLV region. The cell line was used to map putative IGLV genes within the recombinant phage {lambda}V{lambda}135 to the distal part of the IGLV gene region. 35 refs., 4 figs.

  8. 75 FR 41451 - Procurement List; Proposed Additions and Deletion

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-07-16

    ...The Committee is proposing to add services to the Procurement List that will be furnished by nonprofit agencies employing persons who are blind or have other severe disabilities and to delete a product previously furnished by such...

  9. Large mitochondrial DNA deletion in an infant with addison disease.

    PubMed

    Duran, Gloria P; Martinez-Aguayo, A; Poggi, H; Lagos, M; Gutierrez, D; Harris, P R

    2012-01-01

    Mitochondrial diseases are a group of disorders caused by mutations in nuclear DNA or mitochondrial DNA, usually involving multiple organ systems. Primary adrenal insufficiency due to mitochondrial disease is extremely infrequent and has been reported in association with mitochondrial DNA deletion syndromes such as Kearns-Sayre syndrome. To report a 3-year-old boy with Addison disease, congenital glaucoma, chronic pancreatitis, and mitochondrial myopathy due to large mitochondrial DNA deletion. Molecular analysis of mitochondrial DNA samples obtained from peripheral blood, oral mucosa, and muscle tissue. A novel large mitochondrial DNA deletion of 7,372bp was identified involving almost all genes on the big arch of mtDNA. This case reaffirms the association of adrenal insufficiency and mitochondrial DNA deletions and presents new evidence that glaucoma is another manifestation of mitochondrial diseases. Due to the genetic and clinical heterogeneity of mitochondrial disorders, molecular analysis is crucial to confirm diagnosis and to allow accurate genetic counseling.

  10. 75 FR 70909 - Procurement List Proposed Additions and Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-11-19

    ... Division II, Kansas City, MO. Barry S. Lineback, Director, Business Operations. BILLING CODE 6353-01-P ..., Division of Procurement, Washington, DC. Deletions Regulatory Flexibility Act Certification I certify that...

  11. 37 CFR 2.35 - Adding, deleting, or substituting bases.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... delete a basis at any time. (2) After publication, an applicant may add or substitute a basis in an application that is not the subject of an inter partes proceeding before the Trademark Trial and Appeal Board...

  12. Detection of submicroscopic deletions in band 17p13 in patients with the Miller-Dieker syndrome

    PubMed Central

    Schwartz, Charles E.; Johnson, John P.; Holycross, Bridget; Mandeville, Tracy M.; Sears, Tena S.; Graul, Elizabeth A.; Carey, John C.; Schroer, Richard J.; Phelan, Mary C.; Szollar, Judith; Flannery, David B.; Stevenson, Roger E.

    1988-01-01

    The Miller-Dieker syndrome (MDS), a syndrome with lissencephaly, distinctive craniofacial features, growth impairment, and profound developmental failure, has been associated with a deletion of the distal part of chromosome band 17p13. A minority of patients with the syndrome do not have a deletion detectable with current cytogenetic techniques. Using three highly polymorphic DNA probes (pYNZ22, pYNH37.3, and p144D6) we have detected microdeletions in three MDS patients, two of whom had no visible abnormalities of chromosome 17. Loci defined by two of the DNA probes, pYNZ22 and pYNH37.3, were deleted in all three patients. The most distal locus, defined by p144D6, was present in one MDS patient, possibly defining the distal limits of the MDS region in band 17pl3.3. None of these loci were absent in one case of lissencephaly without MDS. ImagesFigure 1Figure 2Figure 3Figure 4 PMID:2903661

  13. Chassis organism from Corynebacterium glutamicum--a top-down approach to identify and delete irrelevant gene clusters.

    PubMed

    Unthan, Simon; Baumgart, Meike; Radek, Andreas; Herbst, Marius; Siebert, Daniel; Brühl, Natalie; Bartsch, Anna; Bott, Michael; Wiechert, Wolfgang; Marin, Kay; Hans, Stephan; Krämer, Reinhard; Seibold, Gerd; Frunzke, Julia; Kalinowski, Jörn; Rückert, Christian; Wendisch, Volker F; Noack, Stephan

    2015-02-01

    For synthetic biology applications, a robust structural basis is required, which can be constructed either from scratch or in a top-down approach starting from any existing organism. In this study, we initiated the top-down construction of a chassis organism from Corynebacterium glutamicum ATCC 13032, aiming for the relevant gene set to maintain its fast growth on defined medium. We evaluated each native gene for its essentiality considering expression levels, phylogenetic conservation, and knockout data. Based on this classification, we determined 41 gene clusters ranging from 3.7 to 49.7 kbp as target sites for deletion. 36 deletions were successful and 10 genome-reduced strains showed impaired growth rates, indicating that genes were hit, which are relevant to maintain biological fitness at wild-type level. In contrast, 26 deleted clusters were found to include exclusively irrelevant genes for growth on defined medium. A combinatory deletion of all irrelevant gene clusters would, in a prophage-free strain, decrease the size of the native genome by about 722 kbp (22%) to 2561 kbp. Finally, five combinatory deletions of irrelevant gene clusters were investigated. The study introduces the novel concept of relevant genes and demonstrates general strategies to construct a chassis suitable for biotechnological application. © 2014 The Authors. Biotechnology Journal published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. This is an open access article under the terms of the Creative Commons Attribution-Non-Commercial-NoDerivs Licence, which permits use and distribution in any medium, provided the original work is properly cited, the use is non- commercial and no modifications or adaptations are made.

  14. Biasing genome-editing events toward precise length deletions with an RNA-guided TevCas9 dual nuclease.

    PubMed

    Wolfs, Jason M; Hamilton, Thomas A; Lant, Jeremy T; Laforet, Marcon; Zhang, Jenny; Salemi, Louisa M; Gloor, Gregory B; Schild-Poulter, Caroline; Edgell, David R

    2016-12-27

    The CRISPR/Cas9 nuclease is commonly used to make gene knockouts. The blunt DNA ends generated by cleavage can be efficiently ligated by the classical nonhomologous end-joining repair pathway (c-NHEJ), regenerating the target site. This repair creates a cycle of cleavage, ligation, and target site regeneration that persists until sufficient modification of the DNA break by alternative NHEJ prevents further Cas9 cutting, generating a heterogeneous population of insertions and deletions typical of gene knockouts. Here, we develop a strategy to escape this cycle and bias events toward defined length deletions by creating an RNA-guided dual active site nuclease that generates two noncompatible DNA breaks at a target site, effectively deleting the majority of the target site such that it cannot be regenerated. The TevCas9 nuclease, a fusion of the I-TevI nuclease domain to Cas9, functions robustly in HEK293 cells and generates 33- to 36-bp deletions at frequencies up to 40%. Deep sequencing revealed minimal processing of TevCas9 products, consistent with protection of the DNA ends from exonucleolytic degradation and repair by the c-NHEJ pathway. Directed evolution experiments identified I-TevI variants with broadened targeting range, making TevCas9 an easy-to-use reagent. Our results highlight how the sequence-tolerant cleavage properties of the I-TevI homing endonuclease can be harnessed to enhance Cas9 applications, circumventing the cleavage and ligation cycle and biasing genome-editing events toward defined length deletions.

  15. Defining the fundamentals of care.

    PubMed

    Kitson, Alison; Conroy, Tiffany; Wengstrom, Yvonne; Profetto-McGrath, Joanne; Robertson-Malt, Suzi

    2010-08-01

    A three-stage process is being undertaken to investigate the fundamentals of care. Stage One (reported here) involves the use of a met a-narrative review methodology to undertake a thematic analysis, categorization and synthesis of selected contents extracted from seminal texts relating to nursing practice. Stage Two will involve a search for evidence to inform the fundamentals of care and a refinement of the review method. Stage Three will extend the reviews of the elements defined as fundamentals of care. This introductory paper covers the following aspects: the conceptual basis upon which nursing care is delivered; how the fundamentals of care have been defined in the literature and in practice; an argument that physiological aspects of care, self-care elements and aspects of the environment of care are central to the conceptual refinement of the term fundamentals of care; and that efforts to systematize such information will enhance overall care delivery through improvements in patient safety and quality initiatives in health systems.

  16. Defining life: the virus viewpoint.

    PubMed

    Forterre, Patrick

    2010-04-01

    Are viruses alive? Until very recently, answering this question was often negative and viruses were not considered in discussions on the origin and definition of life. This situation is rapidly changing, following several discoveries that have modified our vision of viruses. It has been recognized that viruses have played (and still play) a major innovative role in the evolution of cellular organisms. New definitions of viruses have been proposed and their position in the universal tree of life is actively discussed. Viruses are no more confused with their virions, but can be viewed as complex living entities that transform the infected cell into a novel organism-the virus-producing virions. I suggest here to define life (an historical process) as the mode of existence of ribosome encoding organisms (cells) and capsid encoding organisms (viruses) and their ancestors. I propose to define an organism as an ensemble of integrated organs (molecular or cellular) producing individuals evolving through natural selection. The origin of life on our planet would correspond to the establishment of the first organism corresponding to this definition.

  17. Mitochondrial DNA deletions in patients with chronic suppurative otitis media.

    PubMed

    Tatar, Arzu; Tasdemir, Sener; Sahin, Ibrahim; Bozoglu, Ceyda; Erdem, Haktan Bagis; Yoruk, Ozgur; Tatar, Abdulgani

    2016-09-01

    The aim of this study was to investigate the 4977 and 7400 bp deletions of mitochondrial DNA in patients with chronic suppurative otitis media and to indicate the possible association of mitochondrial DNA deletions with chronic suppurative otitis media. Thirty-six patients with chronic suppurative otitis media were randomly selected to assess the mitochondrial DNA deletions. Tympanomastoidectomy was applied for the treatment of chronic suppurative otitis media, and the curettage materials including middle ear tissues were collected. The 4977 and 7400 bp deletion regions and two control regions of mitochondrial DNA were assessed by using the four pair primers. DNA was extracted from middle ear tissues and peripheral blood samples of the patients, and then polymerase chain reactions (PCRs) were performed. PCR products were separated in 2 % agarose gel. Seventeen of 36 patients had the heterozygote 4977 bp deletion in the middle ear tissue but not in peripheral blood. There wasn't any patient who had the 7400 bp deletion in mtDNA of their middle ear tissue or peripheral blood tissue. The patients with the 4977 bp deletion had a longer duration of chronic suppurative otitis media and a higher level of hearing loss than the others (p < 0.01). Long time chronic suppurative otitis media and the reactive oxygen species can cause the mitochondrial DNA deletions and this may be a predisposing factor to sensorineural hearing loss in chronic suppurative otitis media. An antioxidant drug as a scavenger agent may be used in long-term chronic suppurative otitis media.

  18. Evolution models with base substitutions, insertions, deletions, and selection

    NASA Astrophysics Data System (ADS)

    Saakian, D. B.

    2008-12-01

    The evolution model with parallel mutation-selection scheme is solved for the case when selection is accompanied by base substitutions, insertions, and deletions. The fitness is assumed to be either a single-peak function (i.e., having one finite discontinuity) or a smooth function of the Hamming distance from the reference sequence. The mean fitness is calculated exactly in large-genome limit. In the case of insertions and deletions the evolution characteristics depend on the choice of reference sequence.

  19. Germline CDH1 deletions in hereditary diffuse gastric cancer families

    PubMed Central

    Oliveira, Carla; Senz, Janine; Kaurah, Pardeep; Pinheiro, Hugo; Sanges, Remo; Haegert, Anne; Corso, Giovanni; Schouten, Jan; Fitzgerald, Rebecca; Vogelsang, Holger; Keller, Gisela; Dwerryhouse, Sarah; Grimmer, Donna; Chin, Suet-Feung; Yang, Han-Kwang; Jackson, Charles E.; Seruca, Raquel; Roviello, Franco; Stupka, Elia; Caldas, Carlos; Huntsman, David

    2009-01-01

    Germline CDH1 point or small frameshift mutations can be identified in 30–50% of hereditary diffuse gastric cancer (HDGC) families. We hypothesized that CDH1 genomic rearrangements would be found in HDGC and identified 160 families with either two gastric cancers in first-degree relatives and with at least one diffuse gastric cancer (DGC) diagnosed before age 50, or three or more DGC in close relatives diagnosed at any age. Sixty-seven carried germline CDH1 point or small frameshift mutations. We screened germline DNA from the 93 mutation negative probands for large genomic rearrangements by Multiplex Ligation-Dependent Probe Amplification. Potential deletions were validated by RT–PCR and breakpoints cloned using a combination of oligo-CGH-arrays and long-range-PCR. In-silico analysis of the CDH1 locus was used to determine a potential mechanism for these rearrangements. Six of 93 (6.5%) previously described mutation negative HDGC probands, from low GC incidence populations (UK and North America), carried genomic deletions (UK and North America). Two families carried an identical deletion spanning 193 593 bp, encompassing the full CDH3 sequence and CDH1 exons 1 and 2. Other deletions affecting exons 1, 2, 15 and/or 16 were identified. The statistically significant over-representation of Alus around breakpoints indicates it as a likely mechanism for these deletions. When all mutations and deletions are considered, the overall frequency of CDH1 alterations in HDGC is ∼46% (73/160). CDH1 large deletions occur in 4% of HDGC families by mechanisms involving mainly non-allelic homologous recombination in Alu repeat sequences. As the finding of pathogenic CDH1 mutations is useful for management of HDGC families, screening for deletions should be offered to at-risk families. PMID:19168852

  20. Behavioral Features of Williams Beuren Syndrome Compared to Fragile X Syndrome and Subjects with Intellectual Disability without Defined Etiology

    ERIC Educational Resources Information Center

    Perez-Garcia, D.; Granero, R.; Gallastegui, F.; Perez-Jurado, L. A.; Brun-Gasca, C.

    2011-01-01

    Williams-Beuren syndrome (WBS) is a genetically determined neurodevelopmental disorder caused by a heterozygous deletion of 26-28 genes on chromosome band 7q11.23. During the past few years, researchers and clinicians have significantly contributed to define the phenotype of the syndrome, including its cognitive and behavioral aspects. However, it…

  1. Behavioral Features of Williams Beuren Syndrome Compared to Fragile X Syndrome and Subjects with Intellectual Disability without Defined Etiology

    ERIC Educational Resources Information Center

    Perez-Garcia, D.; Granero, R.; Gallastegui, F.; Perez-Jurado, L. A.; Brun-Gasca, C.

    2011-01-01

    Williams-Beuren syndrome (WBS) is a genetically determined neurodevelopmental disorder caused by a heterozygous deletion of 26-28 genes on chromosome band 7q11.23. During the past few years, researchers and clinicians have significantly contributed to define the phenotype of the syndrome, including its cognitive and behavioral aspects. However, it…

  2. Xp22. 3 deletions in isolated familial Kallmann's syndrome

    SciTech Connect

    Hardelin, J.P.; Levilliers, J.; Legouis, R.; Petit, C. ); Young, J.; Pholsena, M.; Schaison, G. ); Kirk, J.; Bouloux, P. )

    1993-04-01

    Several familial cases of Kallmann's syndrome (KS) have been reported, among which the X-chromosome-linked mode of inheritance is the most frequent. The gene responsible for the X-linked KS has been localized to the terminal part of the X-chromosome short arm (Xp22.3 region), immediately proximal to the steroid sulfatase gene responsible for X-linked ichthyosis. Large deletions of this region have been previously shown in patients affected with both X-linked ichthyosis and KS. The authors report here the search for Xp22.3 deletions in 20 unrelated males affected with isolated X-linked KS. Only 2 deletions were found using Southern blot analysis, indicating that large deletions are uncommon in patients affected with KS alone. Both deletions were shown to include the entire KAL gene responsible for X-linked KS. The patients carrying these deletions exhibit additional clinical anomalies, which are discussed: unilateral renal aplasia, unilateral absence of vas deferens, mirror movements, and sensory neural hearing loss. 47 refs., 2 figs., 1 tab.

  3. PolyA Deletions in Hereditary Nonpolyposis Colorectal Cancer

    PubMed Central

    Kim, Kyoung-Mee; Salovaara, Reijo; Mecklin, Jukka-Pekka; Järvinen, Heikki J.; Aaltonen, Lauri A.; Shibata, Darryl

    2002-01-01

    Microsatellite instability (MSI) secondary to loss of DNA mismatch repair (MMR) is present in adenomas and colorectal carcinomas from individuals with hereditary nonpolyposis colorectal cancer (HNPCC). To better characterize when MMR loss occurs during HNPCC progression, the extent of deletions in noncoding polyA sequences were compared between 6 adenomas (all ≤1.0 cm in size) and 10 cancers. Numbers of deleted bases reflect time since loss of MMR because polyA deletions are stepwise. Adenoma deletions were nearly the same (85%) as the cancers with sum total deletions at four different polyA loci of −32.7 bases in adenomas and −38.4 bases in cancers. Intervals between negative clinical examinations and tumor removal (average of 2.1 years) were known for six tumors. There were no significant differences in the extent of deletions in tumors removed under clinical surveillance (−34.8 bases) versus tumors removed without prior negative examinations (−36.5 bases). These findings illustrate that MSI is extensive in both small adenomas, and tumors which appear after negative clinical examinations, consistent with an early loss of MMR in HNPCC, even before a gatekeeper mutation. PMID:11943734

  4. Chromosome 8 deletions in colorectal carcinoma (CRC): Localization and clinical significance

    SciTech Connect

    Takanishi, D.M. Jr.; Kelemen, P.R.; Kim, A.H.

    1994-09-01

    Loss of heterozygosity (LOH) from the short arm of chromosome 8 (8p) is common in a number of epithelial malignancies, including CRC, lung, hepatoma, prostate, and breast. We and others demonstrated that there are two discrete regions of 8p LOH in CRC, suggesting the possible existence of two independent tumor suppressor genes. To better define the deletion region, we examined 41 cases of CRC and matched normal tissue with a panel of thirteen microsatellite polymorphisms from 8p, including 30 paraffin-embedded samples enriched by slide microdissection, and 11 primary explant tissue cultures (passage 3 or higher). Of these 41 cases, 25 were noted to have LOH (61%). Most tumors had large deletions, but several had localized interstitial losses, enabling us to specify two non-overlapping regions of LOH; the proximal region is defined by markers D8S137 to D8S259 at 8p21, while the distal region is contained with LPL5{prime} and D8S262 at 8p22. Correlation with clinical features suggests a trend toward association with microinvasion (p=.057, Fisher exact test) but this could not be related to proximal or distal LOH because of the small numbers. Microinvasion (invasion of lymphatics, vessels, or nerves ascertained by light microscopy) is a stage-independent indicator of poor prognosis. We conclude that 8p LOH is a common occurrence in CRC which may be associated with more aggressive biologic behavior, and that there are two discrete chromosomal regions involved.

  5. Defining Life: Synthesis and Conclusions

    NASA Astrophysics Data System (ADS)

    Gayon, Jean

    2010-04-01

    The first part of the paper offers philosophical landmarks on the general issue of defining life. §1 defends that the recognition of “life” has always been and remains primarily an intuitive process, for the scientist as for the layperson. However we should not expect, then, to be able to draw a definition from this original experience, because our cognitive apparatus has not been primarily designed for this. §2 is about definitions in general. Two kinds of definition should be carefully distinguished: lexical definitions (based upon current uses of a word), and stipulative or legislative definitions, which deliberately assign a meaning to a word, for the purpose of clarifying scientific or philosophical arguments. The present volume provides examples of these two kinds of definitions. §3 examines three traditional philosophical definitions of life, all of which have been elaborated prior to the emergence of biology as a specific scientific discipline: life as animation (Aristotle), life as mechanism, and life as organization (Kant). All three concepts constitute a common heritage that structures in depth a good deal of our cultural intuitions and vocabulary any time we try to think about “life”. The present volume offers examples of these three concepts in contemporary scientific discourse. The second part of the paper proposes a synthesis of the major debates developed in this volume. Three major questions have been discussed. A first issue (§4) is whether we should define life or not, and why. Most authors are skeptical about the possibility of defining life in a strong way, although all admit that criteria are useful in contexts such as exobiology, artificial life and the origins of life. §5 examines the possible kinds of definitions of life presented in the volume. Those authors who have explicitly defended that a definition of life is needed, can be classified into two categories. The first category (or standard view) refers to two conditions

  6. Defining life: synthesis and conclusions.

    PubMed

    Gayon, Jean

    2010-04-01

    The first part of the paper offers philosophical landmarks on the general issue of defining life. Section 1 defends that the recognition of "life" has always been and remains primarily an intuitive process, for the scientist as for the layperson. However we should not expect, then, to be able to draw a definition from this original experience, because our cognitive apparatus has not been primarily designed for this. Section 2 is about definitions in general. Two kinds of definition should be carefully distinguished: lexical definitions (based upon current uses of a word), and stipulative or legislative definitions, which deliberately assign a meaning to a word, for the purpose of clarifying scientific or philosophical arguments. The present volume provides examples of these two kinds of definitions. Section 3 examines three traditional philosophical definitions of life, all of which have been elaborated prior to the emergence of biology as a specific scientific discipline: life as animation (Aristotle), life as mechanism, and life as organization (Kant). All three concepts constitute a common heritage that structures in depth a good deal of our cultural intuitions and vocabulary any time we try to think about "life". The present volume offers examples of these three concepts in contemporary scientific discourse. The second part of the paper proposes a synthesis of the major debates developed in this volume. Three major questions have been discussed. A first issue (Section 4) is whether we should define life or not, and why. Most authors are skeptical about the possibility of defining life in a strong way, although all admit that criteria are useful in contexts such as exobiology, artificial life and the origins of life. Section 5 examines the possible kinds of definitions of life presented in the volume. Those authors who have explicitly defended that a definition of life is needed, can be classified into two categories. The first category (or standard view) refers

  7. Defining motility in the Staphylococci.

    PubMed

    Pollitt, Eric J G; Diggle, Stephen P

    2017-08-01

    The ability of bacteria to move is critical for their survival in diverse environments and multiple ways have evolved to achieve this. Two forms of motility have recently been described for Staphylococcus aureus, an organism previously considered to be non-motile. One form is called spreading, which is a type of sliding motility and the second form involves comet formation, which has many observable characteristics associated with gliding motility. Darting motility has also been observed in Staphylococcus epidermidis. This review describes how motility is defined and how we distinguish between passive and active motility. We discuss the characteristics of the various forms of Staphylococci motility, the molecular mechanisms involved and the potential future research directions.

  8. Defining biocultural approaches to conservation.

    PubMed

    Gavin, Michael C; McCarter, Joe; Mead, Aroha; Berkes, Fikret; Stepp, John Richard; Peterson, Debora; Tang, Ruifei

    2015-03-01

    We contend that biocultural approaches to conservation can achieve effective and just conservation outcomes while addressing erosion of both cultural and biological diversity. Here, we propose a set of guidelines for the adoption of biocultural approaches to conservation. First, we draw lessons from work on biocultural diversity and heritage, social-ecological systems theory, integrated conservation and development, co-management, and community-based conservation to define biocultural approaches to conservation. Second, we describe eight principles that characterize such approaches. Third, we discuss reasons for adopting biocultural approaches and challenges. If used well, biocultural approaches to conservation can be a powerful tool for reducing the global loss of both biological and cultural diversity.

  9. Energy Velocity Defined by Brillouin

    NASA Astrophysics Data System (ADS)

    Hosono, Hiroyuki; Hosono, Toshio

    The physical meaning of the energy velocity in lossy Lorentz media is clarified. First, two expressions for the energy velocity, one by Brillouin and another by Diener, are examined. We show that, while Diener's is disqualified, Brillouin's is acceptable as energy velocity. Secondly, we show that the signal velocity defined by Brillouin and Baerwald is exactly identical with the Brillouin's energy velocity. Thirdly, by using triangle-modulated harmonic wave, we show that the superluminal group velocity plays its role as a revelator only after the arrival of the signal traveling at the subluminal energy velocity. In short, nothing moves at the group velocity, and every frequency component of a signal propagates at its own energy velocity.

  10. Defining groundwater age: Chapter 3

    USGS Publications Warehouse

    Torgersen, T.; Purtschert, R.; Phillips, F.M.; Plummer, L.N.; Sanford, W.E.; Suckow, A.

    2013-01-01

    This book investigates applications of selected chemical and isotopic substances that can be used to recognize and interpret age information pertaining to ‘old’ groundwater (defined as water that was recharged on a timescale from approximately 1000 to more than 1 000 000 a). However, as discussed below, only estimates of the ‘age’ of water extracted from wells can be inferred. These groundwater age estimates are interpreted from measured concentrations of chemical and isotopic substances in the groundwater. Even then, there are many complicating factors, as discussed in this book. In spite of these limitations, much can be learned about the physics of groundwater flow and about the temporal aspects of groundwater systems from age interpretations of measured concentrations of environmental tracers in groundwater systems. This chapter puts the concept of ‘age’ into context, including its meaning and interpretation, and attempts to provide a unifying usage for the rest of the book.

  11. Hamiltonians defined by biorthogonal sets

    NASA Astrophysics Data System (ADS)

    Bagarello, Fabio; Bellomonte, Giorgia

    2017-04-01

    In some recent papers, studies on biorthogonal Riesz bases have found renewed motivation because of their connection with pseudo-Hermitian quantum mechanics, which deals with physical systems described by Hamiltonians that are not self-adjoint but may still have real point spectra. Also, their eigenvectors may form Riesz, not necessarily orthonormal, bases for the Hilbert space in which the model is defined. Those Riesz bases allow a decomposition of the Hamiltonian, as already discussed in some previous papers. However, in many physical models, one has to deal not with orthonormal bases or with Riesz bases, but just with biorthogonal sets. Here, we consider the more general concept of G -quasi basis, and we show a series of conditions under which a definition of non-self-adjoint Hamiltonian with purely point real spectra is still possible.

  12. Miniature EVA Software Defined Radio

    NASA Technical Reports Server (NTRS)

    Pozhidaev, Aleksey

    2012-01-01

    As NASA embarks upon developing the Next-Generation Extra Vehicular Activity (EVA) Radio for deep space exploration, the demands on EVA battery life will substantially increase. The number of modes and frequency bands required will continue to grow in order to enable efficient and complex multi-mode operations including communications, navigation, and tracking applications. Whether conducting astronaut excursions, communicating to soldiers, or first responders responding to emergency hazards, NASA has developed an innovative, affordable, miniaturized, power-efficient software defined radio that offers unprecedented power-efficient flexibility. This lightweight, programmable, S-band, multi-service, frequency- agile EVA software defined radio (SDR) supports data, telemetry, voice, and both standard and high-definition video. Features include a modular design, an easily scalable architecture, and the EVA SDR allows for both stationary and mobile battery powered handheld operations. Currently, the radio is equipped with an S-band RF section. However, its scalable architecture can accommodate multiple RF sections simultaneously to cover multiple frequency bands. The EVA SDR also supports multiple network protocols. It currently implements a Hybrid Mesh Network based on the 802.11s open standard protocol. The radio targets RF channel data rates up to 20 Mbps and can be equipped with a real-time operating system (RTOS) that can be switched off for power-aware applications. The EVA SDR's modular design permits implementation of the same hardware at all Network Nodes concept. This approach assures the portability of the same software into any radio in the system. It also brings several benefits to the entire system including reducing system maintenance, system complexity, and development cost.

  13. Asymptomatic Alzheimer disease: Defining resilience.

    PubMed

    Hohman, Timothy J; McLaren, Donald G; Mormino, Elizabeth C; Gifford, Katherine A; Libon, David J; Jefferson, Angela L

    2016-12-06

    To define robust resilience metrics by leveraging CSF biomarkers of Alzheimer disease (AD) pathology within a latent variable framework and to demonstrate the ability of such metrics to predict slower rates of cognitive decline and protection against diagnostic conversion. Participants with normal cognition (n = 297) and mild cognitive impairment (n = 432) were drawn from the Alzheimer's Disease Neuroimaging Initiative. Resilience metrics were defined at baseline by examining the residuals when regressing brain aging outcomes (hippocampal volume and cognition) on CSF biomarkers. A positive residual reflected better outcomes than expected for a given level of pathology (high resilience). Residuals were integrated into a latent variable model of resilience and validated by testing their ability to independently predict diagnostic conversion, cognitive decline, and the rate of ventricular dilation. Latent variables of resilience predicted a decreased risk of conversion (hazard ratio < 0.54, p < 0.0001), slower cognitive decline (β > 0.02, p < 0.001), and slower rates of ventricular dilation (β < -4.7, p < 2 × 10(-15)). These results were significant even when analyses were restricted to clinically normal individuals. Furthermore, resilience metrics interacted with biomarker status such that biomarker-positive individuals with low resilience showed the greatest risk of subsequent decline. Robust phenotypes of resilience calculated by leveraging AD biomarkers and baseline brain aging outcomes provide insight into which individuals are at greatest risk of short-term decline. Such comprehensive definitions of resilience are needed to further our understanding of the mechanisms that protect individuals from the clinical manifestation of AD dementia, especially among biomarker-positive individuals. © 2016 American Academy of Neurology.

  14. Characterization of a 5.8-Mb interstitial deletion of chromosome 3p in a girl with 46,XX,inv(7)dn karyotype and phenotypic abnormalities.

    PubMed

    Morales, C; Mademont-Soler, I; Armengol, L; Milà, M; Badenas, C; Andrés, S; Soler, A; Sánchez, A

    2009-01-01

    Interstitial deletions of the short arm of chromosome 3 are rare, and a specific clinical phenotype has not been defined. We report the first isolated cryptic proximal interstitial 3p deletion, del(3)(p12.3p13), assessed by array-based comparative genomic hybridization in a girl with an inversion of chromosome 7, whose phenotype includes neurodevelopmental delay, growth retardation, dysmorphic facial features, hypophysis hypoplasia, gastroesophageal reflux, clinodactyly, preauricular appendix, and myopia. Her features are similar to those observed in the previously reported cases of proximal 3p deletions overlapping with our imbalance, indicating that her clinical manifestations are likely to be due to the deletion. As our patient's imbalance is the first non-cytogenetically visible proximal interstitial 3p deletion uncomplicated by other imbalances, its characterization has allowed us to narrow the minimal deletion interval associated with growth retardation and neurodevelopmental delay to the 3p12.3-p13 region. Among the genes found in this region, ROBO1, ROBO2, PDZRN3 and CNTN3 might play a role in the neurodevelopmental delay of the patient. This study provides additional evidence that cryptic imbalances anywhere along the genome can be found in patients with phenotypic abnormalities and a balanced chromosome rearrangement. (c) 2009 S. Karger AG, Basel.

  15. Molecular analysis of 24 Alagille syndrome families identifies a single submicroscopic deletion and further localizes the Alagille region within 20p12

    SciTech Connect

    Rand, E.B.; Piccoli, D.A.; Spinner, N.B.

    1995-11-01

    Alagille syndrome (AGS) is a clinically defined disorder characterized by cholestatic liver disease with bile duct paucity, peculiar facies, structural heart defects, vertebral anomalies, and ocular abnormalities. Multiple patients with various cytogenetic abnormalities involving 20p12 have been identified, allowing the assignment of AGS to this region. The presence of interstitial deletions of varying size led to the hypothesis that AGS is a contiguous gene deletion syndrome. This molecular analysis of cytogenetically normal AGS patients was performed in order to test this hypothesis and to refine the localization of the known AGS region. Investigation of inheritance of simple tandem repeat polymorphism alleles in 67 members of 24 cytogenetically normal Alagille families led to the identification of a single submicroscopic deletion. The deletion included loci D20S61, D20S41, D20S186, and D20S188 and presumably intervening uninformative loci D20S189 and D20S27. The six deleted loci are contained in a single YAC of 1.9 Mb. The additional finding of multiple unrelated probands who are heterozygous at each locus demonstrates that microdeletions at known loci within the AGS region are rare in cytogenetically normal patients with this disorder. This suggests that the majority of cases of AGS may be the result of a single gene defect rather than a contiguous gene deletion syndrome. 29 refs., 4 figs., 1 tab.

  16. Correlations between long inverted repeat (LIR) features, deletion size and distance from breakpoint in human gross gene deletions

    PubMed Central

    Aygun, Nevim

    2015-01-01

    Long inverted repeats (LIRs) have been shown to induce genomic deletions in yeast. In this study, LIRs were investigated within ±10 kb spanning each breakpoint from 109 human gross deletions, using Inverted Repeat Finder (IRF) software. LIR number was significantly higher at the breakpoint regions, than in control segments (P < 0.001). In addition, it was found that strong correlation between 5′ and 3′ LIR numbers, suggesting contribution to DNA sequence evolution (r = 0.85, P < 0.001). 138 LIR features at ±3 kb breakpoints in 89 (81%) of 109 gross deletions were evaluated. Significant correlations were found between distance from breakpoint and loop length (r = −0.18, P < 0.05) and stem length (r = −0.18, P < 0.05), suggesting DNA strands are potentially broken in locations closer to bigger LIRs. In addition, bigger loops cause larger deletions (r = 0.19, P < 0.05). Moreover, loop length (r = 0.29, P < 0.02) and identity between stem copies (r = 0.30, P < 0.05) of 3′ LIRs were more important in larger deletions. Consequently, DNA breaks may form via LIR-induced cruciform structure during replication. DNA ends may be later repaired by non-homologous end-joining (NHEJ), with following deletion. PMID:25657065

  17. New patients with Temple syndrome caused by 14q32 deletion: Genotype-phenotype correlations and risk of thyroid cancer.

    PubMed

    Severi, Giulia; Bernardini, Laura; Briuglia, Silvana; Bigoni, Stefania; Buldrini, Barbara; Magini, Pamela; Dentici, Maria L; Cordelli, Duccio M; Arrigo, Teresa; Franzoni, Emilio; Fini, Sergio; Italyankina, Eleonora; Loddo, Italia; Novelli, Antonio; Graziano, Claudio

    2016-01-01

    Temple syndrome (TS) is caused by abnormal expression of genes at the imprinted locus 14q32. A subset of TS patients carry 14q32 deletions of paternal origin. We aimed to define possible genotype-phenotype correlations and to highlight the prevalence of thyroid dysfunction, which is a previously unreported feature of TS. We described four new patients who carry deletions of paternal origin at 14q32 detected by array-CGH and reviewed nine patients reported in the medical literature. We compared clinical features with respect to deletion size and position. Expression of DLK1 is altered in all the patients with TS, but intellectual disability (ID) is present only in patients with larger deletions extending proximally to the imprinted locus. This study led to the identification of an ID "critical region" containing four annotated genes including YY1 as the strongest candidate. Furthermore, we described three patients with thyroid dysfunction, which progressed to papillary carcinoma at a very young age in two of them. We conclude that DLK1 loss of function is likely to be responsible for the core features of TS, while haploinsufficiency of a gene outside the imprinted region causes ID. Thyroid cancer may be an unrecognized feature and monitoring for thyroid dysfunction should thus be considered in TS patients. © 2015 Wiley Periodicals, Inc.

  18. Two new beta-thalassemia deletions compromising prenatal diagnosis in an Italian and a Turkish couple seeking prevention.

    PubMed

    Phylipsen, Marion; Amato, Antonio; Cappabianca, Maria Pia; Traeger-Synodinos, Jan; Kanavakis, Emmanuel; Basak, Nazli; Galanello, Renzo; Tuveri, Teresa; Ivaldi, Giovanni; Harteveld, Cornelis L; Giordano, Piero C

    2009-09-01

    When the molecular background of couples requesting prevention is unclear, family analysis and tools to define rare mutations are essential. We report two novel deletion defects observed in an Italian and in a Turkish couple. The first proband presented with microcytic hypochromic parameters without iron deficiency, a normal HbA(2) and an elevated HbF (10.6%). His father presented with a similar phenotype and his wife was heterozygous for the common Mediterranean codon 39 (HBB:c.118C>T) mutation. Having excluded point mutations and common deletions, Multiplex Ligation-dependent Probe Amplification was performed revealing an unknown Ggamma(Agammadeltabeta)(0)-thalassemia defect spanning from the Agamma gene to downstream of the beta-globin gene provisionally named Leiden 69.5 kb deletion. In the second case, the wife presented with a mild thalassemic picture, normal HbA(2), elevated HbF (18.5%) and a beta/alpha globin chain synthesis ratio of 0.62, without iron deficiency or any known beta-thalassemia defect, while the husband was a simple carrier of the common Mediterranean IVS-I-110 (HBB:c.93-21 G>A) mutation. A new large deletion involving the beta-gene and part of the delta-gene was identified by Multiplex Ligation-dependent Probe Amplification provisionally named "Leiden 7.4 kb".

  19. Transient expression of a mouse alpha-fetoprotein minigene: deletion analyses of promoter function.

    PubMed Central

    Scott, R W; Tilghman, S M

    1983-01-01

    The constitutive transcription of a mouse alpha-fetoprotein (AFP) minigene was examined during the transient expression of AFP-simian virus 40-pBR322 recombinant DNAs introduced into HeLa cells by Ca3(PO4)2 precipitation. We tested three constructs, each of which contains the AFP minigene and pBR322 DNAs inserted in the late region of simian virus 40 and found that the relative efficiency of AFP gene expression was dependent on the arrangement of the three DNA elements in the vector. The transcripts begin at the authentic AFP cap site and are properly spliced and polyadenylated. To define a sequence domain in the 5' flanking region of the AFP gene required for constitutive expression, sequential 5' deletion mutants of the AFP minigene were constructed and introduced into HeLa cells. All AFP deletion mutants which retained at least the TATA motif located 30 base pairs upstream from the cap site were capable of directing accurate and efficient AFP transcription. However, when the TATA sequence was deleted, no accurately initiated AFP transcripts were detected. These results are identical to those obtained from in vitro transcription of truncated AFP 5' deletion mutant templates assayed in HeLa cell extracts. The rate of AFP transcription in vivo was unaffected by deletion of DNA upstream of the AFP TATA box but was greatly affected by the distance between the simian virus 40 control region and the 5' end of the gene. The absence of any promoter activity upstream of the TATA box in this assay system is in contrast to what has been reported for several other eucaryotic structural genes in a variety of in vivo systems. A sequence comparison between the 5' flanking region of the AFP gene and these genes suggested that the AFP gene lacks those structural elements found to be important for constitutive transcription in vivo. Either the AFP gene lacks upstream promoter function in the 5' flanking DNA contained within the minigene, or the use of a viral vector in a

  20. Recurrent deletions of IKZF1 in pediatric acute myeloid leukemia.

    PubMed

    de Rooij, Jasmijn D E; Beuling, Eva; van den Heuvel-Eibrink, Marry M; Obulkasim, Askar; Baruchel, André; Trka, Jan; Reinhardt, Dirk; Sonneveld, Edwin; Gibson, Brenda E S; Pieters, Rob; Zimmermann, Martin; Zwaan, C Michel; Fornerod, Maarten

    2015-09-01

    IKAROS family zinc finger 1/IKZF1 is a transcription factor important in lymphoid differentiation, and a known tumor suppressor in acute lymphoid leukemia. Recent studies suggest that IKZF1 is also involved in myeloid differentiation. To investigate whether IKZF1 deletions also play a role in pediatric acute myeloid leukemia, we screened a panel of pediatric acute myeloid leukemia samples for deletions of the IKZF1 locus using multiplex ligation-dependent probe amplification and for mutations using direct sequencing. Three patients were identified with a single amino acid variant without change of IKZF1 length. No frame-shift mutations were found. Out of 11 patients with an IKZF1 deletion, 8 samples revealed a complete loss of chromosome 7, and 3 cases a focal deletion of 0.1-0.9Mb. These deletions included the complete IKZF1 gene (n=2) or exons 1-4 (n=1), all leading to a loss of IKZF1 function. Interestingly, differentially expressed genes in monosomy 7 cases (n=8) when compared to non-deleted samples (n=247) significantly correlated with gene expression changes in focal IKZF1-deleted cases (n=3). Genes with increased expression included genes involved in myeloid cell self-renewal and cell cycle, and a significant portion of GATA target genes and GATA factors. Together, these results suggest that loss of IKZF1 is recurrent in pediatric acute myeloid leukemia and might be a determinant of oncogenesis in acute myeloid leukemia with monosomy 7. Copyright© Ferrata Storti Foundation.

  1. The phenotype associated with a large deletion on MECP2

    PubMed Central

    Bebbington, Ami; Downs, Jenny; Percy, Alan; Pineda, Mercé; Zeev, Bruria Ben; Bahi-Buisson, Nadia; Leonard, Helen

    2012-01-01

    Multiplex ligation-dependent Probe Amplification (MLPA) has become available for the detection of a large deletion on the MECP2 gene allowing genetic confirmation of previously unconfirmed cases of clinical Rett syndrome. This study describes the phenotype of those with a large deletion and compares with those with other pathogenic MECP2 mutations. Individuals were ascertained from the Australian Rett Syndrome and InterRett databases with data sourced from family and clinician questionnaires, and two case studies were constructed from the longitudinal Australian data. Regression and survival analysis were used to compare severity and age of onset of symptoms in those with and without a large deletion. Data were available for 974 individuals including 51 with a large deletion and ages ranged from 1 year 4 months to 49 years (median 9 years). Those with a large deletion were more severely affected than those with other mutation types. Specifically, individuals with large deletions were less likely to have learned to walk (OR 0.42, 95% CI: 0.22–0.79, P=0.007) and to be currently walking (OR 0.53, 95% CI: 0.26–1.10, P=0.089), and were at higher odds of being in the most severe category of gross motor function (OR 1.84, 95% CI: 0.98–3.48, P=0.057) and epilepsy (OR 2.72, 95% CI: 1.38–5.37, P=0.004). They also developed epilepsy, scoliosis, hand stereotypies and abnormal breathing patterns at an earlier age. We have described the disorder profile associated with a large deletion from the largest sample to date and have found that the phenotype is severe with motor skills particularly affected. PMID:22473088

  2. Defining the Stimulus - A Memoir

    PubMed Central

    Terrace, Herbert

    2010-01-01

    The eminent psychophysicist, S. S. Stevens, once remarked that, “the basic problem of psychology was the definition of the stimulus” (Stevens, 1951, p. 46). By expanding the traditional definition of the stimulus, the study of animal learning has metamorphosed into animal cognition. The main impetus for that change was the recognition that it is often necessary to postulate a representation between the traditional S and R of learning theory. Representations allow a subject to re-present a stimulus it learned previously that is currently absent. Thus, in delayed-matching-to-sample, one has to assume that a subject responds to a representation of the sample during test if it responds correctly. Other examples, to name but a few, include concept formation, spatial memory, serial memory, learning a numerical rule, imitation and metacognition. Whereas a representation used to be regarded as a mentalistic phenomenon that was unworthy of scientific inquiry, it can now be operationally defined. To accommodate representations, the traditional discriminative stimulus has to be expanded to allow for the role of representations. The resulting composite can account for a significantly larger portion of the variance of performance measures than the exteroceptive stimulus could by itself. PMID:19969047

  3. 31 CFR 363.144 - May I delete a pending transaction involving a certificate of indebtedness?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 31 Money and Finance: Treasury 2 2010-07-01 2010-07-01 false May I delete a pending transaction... I delete a pending transaction involving a certificate of indebtedness? (a) You may delete a pending purchase of a certificate of indebtedness initiated from your TreasuryDirect ® account. (b) You may delete...

  4. 10 CFR 9.19 - Segregation of exempt information and deletion of identifying details.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ...) For records required to be made available under 5 U.S.C. 552(a)(2), the NRC shall delete information that is exempt under one or more of the exemptions cited in § 9.17. The amount of information deleted... deletions are made from parts of the record by computer, the amount of information deleted will be indicated...

  5. Genomic variability of Mycobacterium tuberculosis strains of the Euro-American lineage based on large sequence deletions and 15-locus MIRU-VNTR polymorphism.

    PubMed

    Rindi, Laura; Medici, Chiara; Bimbi, Nicola; Buzzigoli, Andrea; Lari, Nicoletta; Garzelli, Carlo

    2014-01-01

    A sample of 260 Mycobacterium tuberculosis strains assigned to the Euro-American family was studied to identify phylogenetically informative genomic regions of difference (RD). Mutually exclusive deletions of regions RD115, RD122, RD174, RD182, RD183, RD193, RD219, RD726 and RD761 were found in 202 strains; the RD(Rio) deletion was detected exclusively among the RD174-deleted strains. Although certain deletions were found more frequently in certain spoligotype families (i.e., deletion RD115 in T and LAM, RD174 in LAM, RD182 in Haarlem, RD219 in T and RD726 in the "Cameroon" family), the RD-defined sublineages did not specifically match with spoligotype-defined families, thus arguing against the use of spoligotyping for establishing exact phylogenetic relationships between strains. Notably, when tested for katG463/gyrA95 polymorphism, all the RD-defined sublineages belonged to Principal Genotypic Group (PGG) 2, except sublineage RD219 exclusively belonging to PGG3; the 58 Euro-American strains with no deletion were of either PGG2 or 3. A representative sample of 197 isolates was then analyzed by standard 15-locus MIRU-VNTR typing, a suitable approach to independently assess genetic relationships among the strains. Analysis of the MIRU-VNTR typing results by using a minimum spanning tree (MST) and a classical dendrogram showed groupings that were largely concordant with those obtained by RD-based analysis. Isolates of a given RD profile show, in addition to closely related MIRU-VNTR profiles, related spoligotype profiles that can serve as a basis for better spoligotype-based classification.

  6. Functional Genomics Using the Saccharomyces cerevisiae Yeast Deletion Collections.

    PubMed

    Nislow, Corey; Wong, Lai Hong; Lee, Amy Huei-Yi; Giaever, Guri

    2016-09-01

    Constructed by a consortium of 16 laboratories, the Saccharomyces genome-wide deletion collections have, for the past decade, provided a powerful, rapid, and inexpensive approach for functional profiling of the yeast genome. Loss-of-function deletion mutants were systematically created using a polymerase chain reaction (PCR)-based gene deletion strategy to generate a start-to-stop codon replacement of each open reading frame by homologous recombination. Each strain carries two molecular barcodes that serve as unique strain identifiers, enabling their growth to be analyzed in parallel and the fitness contribution of each gene to be quantitatively assessed by hybridization to high-density oligonucleotide arrays or through the use of next-generation sequencing technologies. Functional profiling of the deletion collections, using either strain-by-strain or parallel assays, provides an unbiased approach to systematically survey the yeast genome. The Saccharomyces yeast deletion collections have proved immensely powerful in contributing to the understanding of gene function, including functional relationships between genes and genetic pathways in response to diverse genetic and environmental perturbations. © 2016 Cold Spring Harbor Laboratory Press.

  7. Scalable Design of Paired CRISPR Guide RNAs for Genomic Deletion

    PubMed Central

    Polidori, Taisia; Palumbo, Emilio; Guigo, Roderic

    2017-01-01

    CRISPR-Cas9 technology can be used to engineer precise genomic deletions with pairs of single guide RNAs (sgRNAs). This approach has been widely adopted for diverse applications, from disease modelling of individual loci, to parallelized loss-of-function screens of thousands of regulatory elements. However, no solution has been presented for the unique bioinformatic design requirements of CRISPR deletion. We here present CRISPETa, a pipeline for flexible and scalable paired sgRNA design based on an empirical scoring model. Multiple sgRNA pairs are returned for each target, and any number of targets can be analyzed in parallel, making CRISPETa equally useful for focussed or high-throughput studies. Fast run-times are achieved using a pre-computed off-target database. sgRNA pair designs are output in a convenient format for visualisation and oligonucleotide ordering. We present pre-designed, high-coverage library designs for entire classes of protein-coding and non-coding elements in human, mouse, zebrafish, Drosophila melanogaster and Caenorhabditis elegans. In human cells, we reproducibly observe deletion efficiencies of ≥50% for CRISPETa designs targeting an enhancer and exonic fragment of the MALAT1 oncogene. In the latter case, deletion results in production of desired, truncated RNA. CRISPETa will be useful for researchers seeking to harness CRISPR for targeted genomic deletion, in a variety of model organisms, from single-target to high-throughput scales. PMID:28253259

  8. Mitochondrial DNA deletion analysis: a comparison of PCR quantitative methods.

    PubMed

    Hamblet, N S; Castora, F J

    1995-02-15

    The role of mitochondrial DNA (mtDNA) deletions in aging and in neurodegenerative diseases is often determined by measuring the amount of deleted mtDNA in the affected tissue. Upon examining brain autopsy tissue from a 59 year old individual with lung cancer we determined by serial dilution PCR and kinetic PCR that a greater ratio of deleted mtDNA was present in the caudate than in the parietal cortex. However, the magnitude difference for these two brain regions appeared to be technique dependent; by serial dilution PCR the caudate had 10 times more deleted mtDNA than the parietal cortex (0.0141 vs 0.0014) whereas kinetic PCR yielded a 4-fold difference (0.1258 vs 0.0316). These results indicate that although it is valid to compare the amount of deleted mtDNA in normal and diseased tissue and draw conclusions based on relative comparisons within one study, greater caution should be exercised when comparing absolute values from studies using different measurement techniques.

  9. TransFlip Mutations Produce Deletions in Pancreatic Cancer

    PubMed Central

    Norris, Alexis L.; Kamiyama, Hirohiko; Makohon-Moore, Alvin; Pallavajjala, Aparna; Morsberger, Laura A.; Lee, Kurt; Batista, Denise; Iacobuzio-Donahue, Christine A.; Lin, Ming-Tseh; Klein, Alison P.; Hruban, Ralph H.; Wheelan, Sarah J.; Eshleman, James R.

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is driven by the inactivation of the tumor suppressor genes (TSGs), CDKN2A (P16) and SMAD4 (DPC4), commonly by homozygous deletions (HDs). Using a combination of high density single-nucleotide polymorphism (SNP) microarray and whole genome sequencing (WGS), we fine-mapped novel breakpoints surrounding deletions of CDKN2A and SMAD4 and characterized them by their underlying structural variants (SVs). Only one third of CDKN2A and SMAD4 deletions (6 of 18) were simple interstitial deletions, rather, the majority of deletions were caused by complex rearrangements, specifically, a translocation on one side of the TSG in combination with an inversion on the other side. We designate these as “TransFlip” mutations. Characteristics of TransFlip mutations are: (1) a propensity to target the TSGs CDKN2A and SMAD4 (P < 0.005), (2) not present in the germline of the examined samples, (3) non-recurrent breakpoints, (4) relatively small (47 bp to 3.4 kb) inversions, (5) inversions can be either telomeric or centromeric to the TSG, and (6) non-reciprocal, and non-recurrent translocations. TransFlip mutations are novel complex genomic rearrangements with unique breakpoint signatures in pancreatic cancer. We hypothesize that they are a common but poorly understood mechanism of TSG inactivation in human cancer. PMID:26031834

  10. The Yeast Deletion Collection: A Decade of Functional Genomics

    PubMed Central

    Giaever, Guri; Nislow, Corey

    2014-01-01

    The yeast deletion collections comprise >21,000 mutant strains that carry precise start-to-stop deletions of ∼6000 open reading frames. This collection includes heterozygous and homozygous diploids, and haploids of both MATa and MATα mating types. The yeast deletion collection, or yeast knockout (YKO) set, represents the first and only complete, systematically constructed deletion collection available for any organism. Conceived during the Saccharomyces cerevisiae sequencing project, work on the project began in 1998 and was completed in 2002. The YKO strains have been used in numerous laboratories in >1000 genome-wide screens. This landmark genome project has inspired development of numerous genome-wide technologies in organisms from yeast to man. Notable spinoff technologies include synthetic genetic array and HIPHOP chemogenomics. In this retrospective, we briefly describe the yeast deletion project and some of its most noteworthy biological contributions and the impact that these collections have had on the yeast research community and on genomics in general. PMID:24939991

  11. Scalable Design of Paired CRISPR Guide RNAs for Genomic Deletion.

    PubMed

    Pulido-Quetglas, Carlos; Aparicio-Prat, Estel; Arnan, Carme; Polidori, Taisia; Hermoso, Toni; Palumbo, Emilio; Ponomarenko, Julia; Guigo, Roderic; Johnson, Rory

    2017-03-01

    CRISPR-Cas9 technology can be used to engineer precise genomic deletions with pairs of single guide RNAs (sgRNAs). This approach has been widely adopted for diverse applications, from disease modelling of individual loci, to parallelized loss-of-function screens of thousands of regulatory elements. However, no solution has been presented for the unique bioinformatic design requirements of CRISPR deletion. We here present CRISPETa, a pipeline for flexible and scalable paired sgRNA design based on an empirical scoring model. Multiple sgRNA pairs are returned for each target, and any number of targets can be analyzed in parallel, making CRISPETa equally useful for focussed or high-throughput studies. Fast run-times are achieved using a pre-computed off-target database. sgRNA pair designs are output in a convenient format for visualisation and oligonucleotide ordering. We present pre-designed, high-coverage library designs for entire classes of protein-coding and non-coding elements in human, mouse, zebrafish, Drosophila melanogaster and Caenorhabditis elegans. In human cells, we reproducibly observe deletion efficiencies of ≥50% for CRISPETa designs targeting an enhancer and exonic fragment of the MALAT1 oncogene. In the latter case, deletion results in production of desired, truncated RNA. CRISPETa will be useful for researchers seeking to harness CRISPR for targeted genomic deletion, in a variety of model organisms, from single-target to high-throughput scales.

  12. Mouse models for the Wolf-Hirschhorn deletion syndrome.

    PubMed

    Näf, D; Wilson, L A; Bergstrom, R A; Smith, R S; Goodwin, N C; Verkerk, A; van Ommen, G J; Ackerman, S L; Frankel, W N; Schimenti, J C

    2001-01-15

    Wolf-Hirschhorn syndrome (WHS) is a deletion syndrome caused by segmental haploidy of chromosome 4p16.3. Its hallmark features include a 'Greek warrior helmet' facial appearance, mental retardation, various midline defects and seizures. The WHS critical region (WHSCR) lies between the Huntington's disease gene, HD, and FGFR3. In mice, the homologs of these genes map to chromosome 5 in a region of conserved synteny with human 4p16.3. To derive mouse models of WHS and map genes responsible for subphenotypes of the syndrome, five mouse lines bearing radiation-induced deletions spanning the WHSCR syntenic region were generated and characterized. Similar to WHS patients, these animals were growth-retarded, were susceptible to seizures and showed midline (palate closure, tail kinks), craniofacial and ocular anomalies (colobomas, corneal opacities). Other phenotypes included cerebellar hypoplasia and a shortened cerebral cortex. Expression of WHS-like traits was variable and influenced by strain background and deletion size. These mice represent the first animal models for WHS. This collection of nested chromosomal deletions will be useful for mapping and identifying loci responsible for the various subphenotypes of WHS, and provides a paradigm for the dissection of other deletion syndromes using the mouse.

  13. Molecular mimicry and clonal deletion: A fresh look.

    PubMed

    Rose, Noel R

    2015-06-21

    In this article, I trace the historic background of clonal deletion and molecular mimicry, two major pillars underlying our present understanding of autoimmunity and autoimmune disease. Clonal deletion originated as a critical element of the clonal selection theory of antibody formation in order to explain tolerance of self. If we did have complete clonal deletion, there would be major voids, the infamous "black holes", in our immune repertoire. For comprehensive, protective adaptive immunity, full deletion is necessarily a rare event. Molecular mimicry, the sharing of epitopes among self and non-self antigens, is extraordinary common and provides the evidence that complete deletion of self-reactive clones is rare. If molecular mimicry were not common, protective adaptive immunity could not be all-encompassing. By taking a fresh look at these two processes together we can envision their evolutionary basis and understand the need for regulatory devices to prevent molecular mimicry from progressing to autoimmune disease. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. Functional Profiling Using the Saccharomyces Genome Deletion Project Collections.

    PubMed

    Nislow, Corey; Wong, Lai Hong; Lee, Amy Huei-Yi; Giaever, Guri

    2016-09-01

    The ability to measure and quantify the fitness of an entire organism requires considerably more complex approaches than simply using traditional "omic" methods that examine, for example, the abundance of RNA transcripts, proteins, or metabolites. The yeast deletion collections represent the only systematic, comprehensive set of null alleles for any organism in which such fitness measurements can be assayed. Generated by the Saccharomyces Genome Deletion Project, these collections allow the systematic and parallel analysis of gene functions using any measurable phenotype. The unique 20-bp molecular barcodes engineered into the genome of each deletion strain facilitate the massively parallel analysis of individual fitness. Here, we present functional genomic protocols for use with the yeast deletion collections. We describe how to maintain, propagate, and store the deletion collections and how to perform growth fitness assays on single and parallel screening platforms. Phenotypic fitness analyses of the yeast mutants, described in brief here, provide important insights into biological functions, mechanisms of drug action, and response to environmental stresses. It is important to bear in mind that the specific assays described in this protocol represent some of the many ways in which these collections can be assayed, and in this description particular attention is paid to maximizing throughput using growth as the phenotypic measure.

  15. The yeast deletion collection: a decade of functional genomics.

    PubMed

    Giaever, Guri; Nislow, Corey

    2014-06-01

    The yeast deletion collections comprise >21,000 mutant strains that carry precise start-to-stop deletions of ∼6000 open reading frames. This collection includes heterozygous and homozygous diploids, and haploids of both MAT A: and MATα mating types. The yeast deletion collection, or yeast knockout (YKO) set, represents the first and only complete, systematically constructed deletion collection available for any organism. Conceived during the Saccharomyces cerevisiae sequencing project, work on the project began in 1998 and was completed in 2002. The YKO strains have been used in numerous laboratories in >1000 genome-wide screens. This landmark genome project has inspired development of numerous genome-wide technologies in organisms from yeast to man. Notable spinoff technologies include synthetic genetic array and HIPHOP chemogenomics. In this retrospective, we briefly describe the yeast deletion project and some of its most noteworthy biological contributions and the impact that these collections have had on the yeast research community and on genomics in general. Copyright © 2014 by the Genetics Society of America.

  16. Deletion 2q37 syndrome: Cognitive-behavioral trajectories and autistic features related to breakpoint and deletion size.

    PubMed

    Fisch, Gene S; Falk, Rena E; Carey, John C; Imitola, Jaime; Sederberg, Maria; Caravalho, Karen S; South, Sarah

    2016-09-01

    Subtelomeric deletions have been reported in ∼2.5% of individuals with developmental disabilities. Subtelomeric deletion 2q37 has been detected in many individuals diagnosed with intellectual disabilities (ID) and autism spectrum disorders (ASD). Previously, genotype-phenotype correspondences were examined for their relationship to breakpoints 37.1, 37.2, or 37.3. Our purpose was to ascertain whether there were phenotypic differences at these breakpoints, elucidate the cognitive-behavioral phenotype in del2q37, and examine the genotype-phenotype association in the deletion with respect to cognitive-behavioral profiles and ASD. We administered a comprehensive cognitive-behavioral battery to nine children diagnosed with del 2q37, ages 3.9-17.75 years. ID for five tested with the Stanford-Binet (4th Edition) (SBFE) ranged from severe to mild [IQ Range: 36-59]. Adaptive behavior scores from the Vineland Adaptive Behavior Scale (VABS) were much below adequate levels (DQ Range: floor value ["19"] to 55). Autism scores from the Child Autism Rating Scale (CARS) ranged from 22 [non-autistic] to 56 [extremely autistic]; 5/8 [63%] children received scores on the autism spectrum. Participants with the largest deletions, 10.1 and 9.5 Mb, attained the highest IQ and DQ scores while those with the smallest deletions, 7.9 and 6.6 Mb, made the lowest IQ and DQ scores. No association between deletion breakpoint and phenotype were found. Assessment of the various deleted regions suggested histone deacetylase 4 gene (HDAC4) was a likely candidate gene for ASD in our sample. However, two earlier reports found no association between HDAC4 haploinsufficiency and ASD. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  17. Defining Tobacco Regulatory Science Competencies.

    PubMed

    Wipfli, Heather L; Berman, Micah; Hanson, Kacey; Kelder, Steven; Solis, Amy; Villanti, Andrea C; Ribeiro, Carla M P; Meissner, Helen I; Anderson, Roger

    2017-02-01

    In 2013, the National Institutes of Health and the Food and Drug Administration funded a network of 14 Tobacco Centers of Regulatory Science (TCORS) with a mission that included research and training. A cross-TCORS Panel was established to define tobacco regulatory science (TRS) competencies to help harmonize and guide their emerging educational programs. The purpose of this paper is to describe the Panel's work to develop core TRS domains and competencies. The Panel developed the list of domains and competencies using a semistructured Delphi method divided into four phases occurring between November 2013 and August 2015. The final proposed list included a total of 51 competencies across six core domains and 28 competencies across five specialized domains. There is a need for continued discussion to establish the utility of the proposed set of competencies for emerging TRS curricula and to identify the best strategies for incorporating these competencies into TRS training programs. Given the field's broad multidisciplinary nature, further experience is needed to refine the core domains that should be covered in TRS training programs versus knowledge obtained in more specialized programs. Regulatory science to inform the regulation of tobacco products is an emerging field. The paper provides an initial list of core and specialized domains and competencies to be used in developing curricula for new and emerging training programs aimed at preparing a new cohort of scientists to conduct critical TRS research. © The Author 2016. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  18. Chromosome 13q deletion with Cornelia de Lange syndrome phenotype.

    PubMed

    Ngo, C T; Alhady, M; Tan, A K; Norlasiah, I Siti; Ong, G B; Chua, C N

    2007-03-01

    A 3-year-old girl with facial dysmorphic features suggestive of Cornelia de Lange syndrome was seen in the ophthalmology unit for a right leukocoria. The leukocoria was found to be caused by a large retinoblastoma and the right eye was enucleated. Chromosomal analysis revealed partial chromosome 13q deletion involving band 14 which is associated with a high risk of retinoblastoma. This case shows that patient with chromosome 13q deletion syndrome cannot be diagnosed based on dysmorphic features only. Chromosomal analysis is warranted in all infants with facial dysmorphism suggestive of Cornelia de Lange syndrome so that those with chromosome 13q deletion can be referred early for early detection of retinoblastoma.

  19. Mitochondrial DNA deletions in Alzheimer’s brains: A review

    PubMed Central

    Phillips, Nicole R.; Simpkins, James W.; Roby, Rhonda K.

    2013-01-01

    Mitochondrial dysfunction and increased oxidative stress have been associated with normal aging and possibly implicated in the etiology of late onset Alzheimer’s disease. DNA deletions, as well as other alterations, can result from oxidative damage to nucleic acids. Many studies in the last two decades have investigated the incidence of mitochondrial DNA deletions in post-mortem brain tissues of late onset Alzheimer’s disease patients as compared to age-matched normal controls. Published studies are not entirely concordant, but their differences might shed light on the heterogeneity of Alzheimer’s disease itself. Our understanding the role that mitochondrial DNA deletions plays in disease progression may provide valuable information that could someday lead to a treatment. PMID:23850329

  20. Semilobar holoprosencephaly with 21q22 deletion: an autopsy report.

    PubMed

    Mallick, Saumyaranjan; Panda, Shasanka Shekhar; Ray, Ruma; Shukla, Rashmi; Kabra, Madhulika; Agarwal, Ramesh

    2014-03-13

    Holoprosencephaly (HPE) is the most common forebrain developmental anomaly with a prevalence of 1:16 000 live-births. Possible aetiological agents include environmental factors and genetic defects such as trisomies (13, 18) and deletions (18p, 7q, 2p and 21q). This complex malformation is due to incomplete division of the cerebral hemisphere. The phenotypes of HPE include alobar, semilobar, lobar and midline interhemispheric fusion variants. Craniofacial anomalies occur in 80% of cases. Severely affected babies die in the neonatal period. Here we report an autopsied case of semilobar HPE with pituitary and adrenal agenesis with 21q22 deletion. Additional findings are noted that would help expand the spectrum of 21q22 deletion.

  1. Specific deletion of DNA sequences between preselected bases.

    PubMed Central

    Panayotatos, N; Truong, K

    1981-01-01

    Blunt-end ligation of a "filled-in" HindIII, Sal I, Ava I or Bcl I restriction site with a DNA fragment having A, G, C, or T as the terminal 3' nucleotide regenerates the corresponding restriction site. A combination of this property with the action of BAL 31 nuclease which progressively removes base-pairs from the ends of linear DNA, can generate deletions extending to desired pre-selected nucleotides, and introduces unique restriction sites at those positions. Similarly other restriction sites can be used to select for the deletion of sequences between specific di-, tri-, tetra- and penta-nucleotides. Using this method, 10 base pairs were deleted from the end of a restriction fragment carrying the late promoter for bacteriophage T7 gene 1.1, to create a molecule with a unique restriction site at the initiation codon for translation. Images PMID:6273803

  2. Analysis of Terminal Deletions using a Generalized Time-Dependent Model of Radiation-Induced Formation of Chromosomal Aberrations

    NASA Technical Reports Server (NTRS)

    Ponomarev, Artem L.; George, K.; Cucinotta, Francis A.

    2011-01-01

    We have developed a model that can simulate different types of radiation induced chromosomal aberrations (CA's) and can provide predictions on the frequency and size of chromosomes with terminal deletions. Chromosomes with terminal deletions lack telomeres and this can elicit sister chromatid unions and the prolonged breakage/fusion/bridge (B/F/B) cycles that have been observed in mammalian tumors. The loss of a single telomere has been shown to cause extensive genomic instability through the B/F/B cycle process. Our model uses a stochastic process of DNA broken end joining, in which a realistic spectrum of CA's is created from improperly joined DNA free ends formed by DNA double strand breaks (DSBs). The distribution of the DNA free ends is given by a mechanistic model that takes into account the chromatin structure and track structure for high-LET radiation. The model allows for DSB clustering from high-LET radiation and simulates the formation of CA's in stages that correspond to the actual time after radiation exposure. The time scale for CA formation is derived from experimental data on DSB repair kinetics. At any given time a nucleus may have intact chromosomes, CA's, and/or unrepaired fragments, some of which are defined as terminal deletions, if they are capped by one telomere. The model produces a spectrum of terminal deletions with their corresponding probabilities and size distributions for different heavy ions exposures for the first division after exposure. This data provides valuable information because there is limited experimental data available in the literature on the on the actual size of terminal deletions. We compare our model output to the available experimental data and make a reasonable extrapolation on the number of chromosomes lacking telomeres in human lymphocytes exposed to heavy ions. This model generates data which may lead to predictions on the rate of genomic instability in cells after exposure to high charge and energy nuclei

  3. Neurobeachin (NBEA) is a target of recurrent interstitial deletions at 13q13 in patients with MGUS and multiple myeloma

    PubMed Central

    O’Neal, Julie; Gao, Feng; Hassan, Anjum; Monahan, Ryan; Barrios, Samantha; Kilimann, Manfred W.; Lee, Ian; Chng, Wee J.; Vij, Ravi; Tomasson, Michael H.

    2010-01-01

    Objective Chromosome 13 deletions (del[13]), detected by metaphase cytogenetics, predict poor outcome in multiple myeloma (MM), but the gene(s) responsible have not been conclusively identified. We sought to identify tumor suppressor genes on chromosome 13 using a novel array comparative genomic hybridization (aCGH) strategy. Methods We identified DNA copy number losses on chromosome 13 using genomic DNA isolated from CD138 enriched bone marrow cells (tumor) from twenty patients with MM, monoclonal gammopathy of undetermined significance (MGUS) or amyloidosis. We used matched skin biopsy (germline) genomic DNA to control for copy number polymorphisms and a novel aCGH array dedicated to chromosome 13 to map somatic DNA gains and losses at ultra-high resolution (>385,000 probes; median probe spacing 60bp). We analyzed microarray expression data from an additional 262 patient samples both with and without del[13]. Results Two distinct minimally deleted regions at 13q14 and 13q13 were defined that affected the RB1 and NBEA genes, respectively. RB1 is a canonical tumor suppressor previously implicated in MM. NBEA is implicated in membrane trafficking in neurons, PKA binding, and has no known role in cancer. Non-coding RNAs on chromosome 13 were not affected by interstitial deletions. Both the RB1 and NBEA genes were deleted in 40% of cases (8/20; 5 patients with del[13] detected by traditional methods and three patients with interstitial deletions detected by aCGH). Forty-one additional MM patient samples were used for complete exonic sequencing of RB1, but no somatic mutations were found. Along with RB1, NBEA gene expression was significantly reduced in cases with del[13]. Conclusions The NBEA gene at 13q13, and its expression, are frequently disrupted in MM. Additional studies are warranted to evaluate the role of NBEA as a novel candidate tumor suppressor gene. PMID:19135901

  4. Analysis of induced pluripotent stem cells carrying 22q11.2 deletion

    PubMed Central

    Toyoshima, M; Akamatsu, W; Okada, Y; Ohnishi, T; Balan, S; Hisano, Y; Iwayama, Y; Toyota, T; Matsumoto, T; Itasaka, N; Sugiyama, S; Tanaka, M; Yano, M; Dean, B; Okano, H; Yoshikawa, T

    2016-01-01

    Given the complexity and heterogeneity of the genomic architecture underlying schizophrenia, molecular analyses of these patients with defined and large effect-size genomic defects could provide valuable clues. We established human-induced pluripotent stem cells from two schizophrenia patients with the 22q11.2 deletion (two cell lines from each subject, total of four cell lines) and three controls (total of four cell lines). Neurosphere size, neural differentiation efficiency, neurite outgrowth, cellular migration and the neurogenic-to-gliogenic competence ratio were significantly reduced in patient-derived cells. As an underlying mechanism, we focused on the role of DGCR8, a key gene for microRNA (miRNA) processing and mapped in the deleted region. In mice, Dgcr8 hetero-knockout is known to show a similar phenotype of reduced neurosphere size (Ouchi et al., 2013). The miRNA profiling detected reduced expression levels of miRNAs belonging to miR-17/92 cluster and miR-106a/b in the patient-derived neurospheres. Those miRNAs are reported to target p38α, and conformingly the levels of p38α were upregulated in the patient-derived cells. p38α is known to drive gliogenic differentiation. The inhibition of p38 activity by SB203580 in patient-derived neurospheres partially restored neurogenic competence. Furthermore, we detected elevated expression of GFAP, a gliogenic (astrocyte) marker, in postmortem brains from schizophrenia patients without the 22q11.2 deletion, whereas inflammation markers (IL1B and IL6) remained unchanged. In contrast, a neuronal marker, MAP2 expressions were decreased in schizophrenia brains. These results suggest that a dysregulated balance of neurogenic-to-gliogenic competence may underlie neurodevelopmental disorders such as schizophrenia. PMID:27801899

  5. Replication of HIV-1 deleted Nef mutants in chronically immune activated human T cells.

    PubMed

    Shapira-Nahor, Orit; Maayan, Shlomo; Peden, Keith W C; Rabinowitz, Ruth; Schlesinger, Michael; Alian, Akram; Panet, Amos

    2002-11-10

    Lymphocytes (PBMC) obtained from blood of HIV-sera negative Ethiopian immigrants (ETH) were highly susceptible to HIV-1 infection in vitro with no need for stimulation by mitogens. As the HIV nef gene product has been shown to enhance viral replication in stimulated primary lymphocytes, we investigated in this work the role of Nef in viral replication in the ETH cells. Lymphocytes obtained from ETH individuals supported high replication of wild-type HIV-1 and low but significant replication level of the two deleted Nef mutants (encode truncated Nef proteins consisting only of either the first 35 or the first 86 amino acids of Nef). In contrast, no replication was observed in nonactivated cells obtained from non-ETH individuals. After activation of the PBMC from ETH individuals with PHA, replication of both wild-type strains and the two deleted Nef mutant viruses further increased. The CD4(+) T cells of ETH individuals exhibited elevated levels of the surface activation markers CD45RO and HLA-DR, compared with T cells derived from non-ETH group. Likewise, expression of the chemokine receptors CCR5 and CXCR4 on these cells was higher in the ETH group than in the non-ETH group. Replication of HIV-1 wild-type and the isogenic-deleted Nef mutants was significantly correlated with the proportion of ETH cells expressing CD45RO and the chemokine receptors. This study suggests that HIV-1 may respond differently to several activation states characteristic of T cells. One activation state, defined by chronically activated lymphocytes from ETH individuals, is permissive to the wild-type HIV-1 and, to a lesser degree, to the Nef mutants. Further activation of these cells by exogenous stimuli enhances replication of the virus. Our results support the notion that Nef enhances the basal level of T cell activation and consequently, viral replication.

  6. Targeted deletion of Tsc1 causes fatal cardiomyocyte hyperplasia independently of afterload.

    PubMed

    Kayyali, Usamah S; Larsen, Christopher G; Bashiruddin, Sarah; Lewandowski, Sara L; Trivedi, Chinmay M; Warburton, Rod R; Parkhitko, Andrey A; Morrison, Tasha A; Henske, Elizabeth P; Chekaluk, Yvonne; Kwiatkowski, David J; Finlay, Geraldine A

    2015-01-01

    Despite high expression levels, the role of Tsc1 in cardiovascular tissue is ill defined. We launched this study to examine the role of Tsc1 in cardiac physiology and pathology. Mice in which Tsc1 was deleted in cardiac tissue and vascular smooth muscle (Tsc1c/cSM22cre(+/-)), developed progressive cardiomegaly and hypertension and died early. Hearts of Tsc1c/cSM22cre(+/-) mice displayed a progressive increase in cardiomyocyte number, and to a lesser extent, size between the ages of 1 and 6 weeks. In addition, compared to control hearts, proliferation markers (phospho-histone 3 and PCNA) were elevated in Tsc1c/cSM22cre(+/-) cardiomyocytes at 0-4 weeks, suggesting that cardiomyocyte proliferation was the predominant mechanism underlying cardiomegaly in Tsc1c/cSM22cre(+/-) mice. To examine the contribution of Tsc1 deletion in peripheral vascular smooth muscle to the cardiac phenotype, Tsc1c/cSM22cre(+/-) mice were treated with the antihypertensive, hydralazine. Prevention of hypertension had no effect on survival, cardiac size, or cardiomyocyte number in these mice. We furthermore generated mice in which Tsc1 was deleted only in vascular smooth muscle but not in cardiac tissue (Tsc1c/cSMAcre-ER(T2+/-)). The Tsc1c/cSMAcre-ER(T2+/-) mice also developed hypertension. However, their survival was normal and no cardiac abnormalities were observed. Our results suggest that loss of Tsc1 in the heart causes cardiomegaly, which is driven by increased cardiomyocyte proliferation that also appears to confer relative resistance to afterload reduction. These findings support a critical role for the Tsc1 gene as gatekeeper in the protection against uncontrolled cardiac growth.

  7. Prenatal diagnosis of a terminal chromosome 1 (q42-q44) deletion: original case report and review of the literature

    PubMed Central

    Van Linthout, C; Emonard, V; Gatot, JS; Capelle, X; Kridelka, F; Emonts, P; Segghaye, MC

    2016-01-01

    Abstract Terminal chromosome 1q deletion is rarely reported but causes typical malformations that have been well described in childhood. Clinical features include facial dysmorphy, growth and/or psychomotor retardation, brain agenesis or hypoplasia of the corpus callosum, epilepsy and occasional urogenital or cardiac malformations. The diagnosis of this condition is usually made at birth. The rare cases of antenatal diagnosis were based on microcephaly and growth retardation. In the present case, the foetus presented with an hypoplasia of the corpus callosum, a dysmorphic profile and a single umbilical artery. The foetal echocardiography suggested a non- compaction of the left ventricular myocardium. No microcephaly or growth retardation were noted. We compare our antenatal findings to those described in the literature with the aim to better define the antenatal phenotype of the terminal chromosome 1 deletion syndrome. PMID:27909566

  8. Deletion and deletion/insertion mutations in the juxtamembrane domain of the FLT3 gene in adult acute myeloid leukemia

    PubMed Central

    Deeb, Kristin K.; Smonskey, Matthew T.; DeFedericis, HanChun; Deeb, George; Sait, Sheila N.J.; Wetzler, Meir; Wang, Eunice S.; Starostik, Petr

    2014-01-01

    In contrast to FLT3 ITD mutations, in-frame deletions in the FLT3 gene have rarely been described in adult acute leukemia. We report two cases of AML with uncommon in-frame mutations in the juxtamembrane domain of the FLT3 gene: a 3-bp (c.1770_1774delCTACGinsGT; p.F590_V592delinsLF) deletion/insertion and a 12-bp (c.1780_1791delTTCAGAGAATAT; p.F594_Y597del) deletion. We verified by sequencing that the reading frame of the FLT3 gene was preserved and by cDNA analysis that the mRNA of the mutant allele was expressed in both cases. Given the recent development of FLT3 inhibitors, our findings may be of therapeutic value for AML patients harboring similar FLT3 mutations. PMID:25379410

  9. A deletion and a duplication in distal 22q11.2 deletion syndrome region. Clinical implications and review

    PubMed Central

    Fernández, Luis; Nevado, Julián; Santos, Fernando; Heine-Suñer, Damià; Martinez-Glez, Victor; García-Miñaur, Sixto; Palomo, Rebeca; Delicado, Alicia; Pajares, Isidora López; Palomares, María; García-Guereta, Luis; Valverde, Eva; Hawkins, Federico; Lapunzina, Pablo

    2009-01-01

    Background Individuals affected with DiGeorge and Velocardiofacial syndromes present with both phenotypic diversity and variable expressivity. The most frequent clinical features include conotruncal congenital heart defects, velopharyngeal insufficiency, hypocalcemia and a characteristic craniofacial dysmorphism. The etiology in most patients is a 3 Mb recurrent deletion in region 22q11.2. However, cases of infrequent deletions and duplications with different sizes and locations have also been reported, generally with a milder, slightly different phenotype for duplications but with no clear genotype-phenotype correlation to date. Methods We present a 7 month-old male patient with surgically corrected ASD and multiple VSDs, and dysmorphic facial features not clearly suggestive of 22q11.2 deletion syndrome, and a newborn male infant with cleft lip and palate and upslanting palpebral fissures. Karyotype, FISH, MLPA, microsatellite markers segregation studies and SNP genotyping by array-CGH were performed in both patients and parents. Results Karyotype and FISH with probe N25 were normal for both patients. MLPA analysis detected a partial de novo 1.1 Mb deletion in one patient and a novel partial familial 0.4 Mb duplication in the other. Both of these alterations were located at a distal position within the commonly deleted region in 22q11.2. These rearrangements were confirmed and accurately characterized by microsatellite marker segregation studies and SNP array genotyping. Conclusion The phenotypic diversity found for deletions and duplications supports a lack of genotype-phenotype correlation in the vicinity of the LCRC-LCRD interval of the 22q11.2 chromosomal region, whereas the high presence of duplications in normal individuals supports their role as polymorphisms. We suggest that any hypothetical correlation between the clinical phenotype and the size and location of these alterations may be masked by other genetic and/or epigenetic modifying factors. PMID

  10. A deletion and a duplication in distal 22q11.2 deletion syndrome region. Clinical implications and review.

    PubMed

    Fernández, Luis; Nevado, Julián; Santos, Fernando; Heine-Suñer, Damià; Martinez-Glez, Victor; García-Miñaur, Sixto; Palomo, Rebeca; Delicado, Alicia; Pajares, Isidora López; Palomares, María; García-Guereta, Luis; Valverde, Eva; Hawkins, Federico; Lapunzina, Pablo

    2009-06-02

    Individuals affected with DiGeorge and Velocardiofacial syndromes present with both phenotypic diversity and variable expressivity. The most frequent clinical features include conotruncal congenital heart defects, velopharyngeal insufficiency, hypocalcemia and a characteristic craniofacial dysmorphism. The etiology in most patients is a 3 Mb recurrent deletion in region 22q11.2. However, cases of infrequent deletions and duplications with different sizes and locations have also been reported, generally with a milder, slightly different phenotype for duplications but with no clear genotype-phenotype correlation to date. We present a 7 month-old male patient with surgically corrected ASD and multiple VSDs, and dysmorphic facial features not clearly suggestive of 22q11.2 deletion syndrome, and a newborn male infant with cleft lip and palate and upslanting palpebral fissures. Karyotype, FISH, MLPA, microsatellite markers segregation studies and SNP genotyping by array-CGH were performed in both patients and parents. Karyotype and FISH with probe N25 were normal for both patients. MLPA analysis detected a partial de novo 1.1 Mb deletion in one patient and a novel partial familial 0.4 Mb duplication in the other. Both of these alterations were located at a distal position within the commonly deleted region in 22q11.2. These rearrangements were confirmed and accurately characterized by microsatellite marker segregation studies and SNP array genotyping. The phenotypic diversity found for deletions and duplications supports a lack of genotype-phenotype correlation in the vicinity of the LCRC-LCRD interval of the 22q11.2 chromosomal region, whereas the high presence of duplications in normal individuals supports their role as polymorphisms. We suggest that any hypothetical correlation between the clinical phenotype and the size and location of these alterations may be masked by other genetic and/or epigenetic modifying factors.

  11. Interstitial deletion 5q14.3q21.3 with MEF2C haploinsufficiency and mild phenotype: when more is less.

    PubMed

    Tonk, Vijay; Kyhm, Jee Hong; Gibson, Caro E; Wilson, Golder N

    2011-06-01

    An 18-year-old female with mild mental disability (global IQ 69), febrile seizures with subsequent myoclonic/grand mal epilepsy, and subtle morphologic changes is described with del 5(q14.3q21.3) by karyotype and minimal DNA deletion of 21.08 Mb by array comparative genomic hybridization microarray analysis (arr chr5:83,592,798-104,671,993 X1) that encompasses at least 50 genes. Included in the deletion interval is the MEF2C gene that usually causes severe mental disability when haploinsufficient, illustrating the complexity of clinic-cytogenetic correlation even with defined segmental aneuploidy. Interaction of MEF2C with the deleted febrile seizure (FEB4) and juveline myoclonic epilepsy (EJM4) loci plus the G-protein receptor (GPR98/MASS1/Usher syndrome) gene may moderate the phenotype, perhaps through common regulation by calcium. Copyright © 2011 Wiley-Liss, Inc.

  12. Isolation of a putative transcriptional regulator from the region of 22q11 deleted in DiGeorge syndrome, Shprintzen syndrome and familial congenital heart disease.

    PubMed

    Halford, S; Wadey, R; Roberts, C; Daw, S C; Whiting, J A; O'Donnell, H; Dunham, I; Bentley, D; Lindsay, E; Baldini, A

    1993-12-01

    A wide spectrum of birth defects are caused by deletions of the DiGeorge syndrome critical region (DGCR) at human chromosome 22q11. Over one hundred such deletions have now been examined and a minimally deleted region of 300kb defined. Within these sequences we have identified a gene expressed during human and murine embryogenesis. The gene, named TUPLE1, and its murine homologue, encodes a protein containing repeated motifs similar to the WD40 domains found in the beta-transducin/enhancer of split (TLE) family. The TUPLE1 product has several features typical of transcriptional control proteins and in particular has homology with the yeast Tup1 transcriptional regulator. We propose that haploinsufficiency for TUPLE1 is at least partly responsible for DiGeorge syndrome and related abnormalities.

  13. A new gene encoding the ligand for deletion of T cells bearing Tcrb-V6 and V8.1 (Mtv-50)

    SciTech Connect

    Niimi, N.; Tomida, S.; Ueda, M.; Ando, Y.; Yoshikai, Y.; Wajjwalku, W.

    1994-12-31

    The minor lymphocyte-stimulating antigen (Mls), which is defined by the demonstration of a strong primary T-cell proliferative response in a mixed lymphocyte culture between major histocompatibility complex-identical strains, is a representative of self superantigens (Sags) which bind to certain Tcrb-V elements, and delete T cells bearing these elements. Mls-1 antigen encoded by Mtv-7 stimulates T cells bearing Tcrb-V6, V7, V8.1, or V9 in vitro, and delete these T cells in vivo. Recently, Mtv-43, Mtv-44, and exogenous MMTV (SW) have also been found to encode Mls-1-like antigens, which delete Tcrb-V6, V7 (except Mtv-44), V8.1- and/or V9-bearing T cells. In sharp contrast to Mls-1, Mls-1-like antigens encoded by Mtv-43 and MMTV(SW) show only a limited in vitro stimulatory capacity. 9 refs., 1 fig.

  14. DCJ path formulation for genome transformations which include insertions, deletions, and duplications.

    PubMed

    Yancopoulos, Sophia; Friedberg, Richard

    2009-10-01

    We extend the double cut and join operation (DCJ) paradigm to perform genome rearrangements on pairs of genomes having unequal gene content and/or multiple copies by permitting genes in one genome which are completely or partially unmatched in the other. The existence of unmatched gene ends introduces new kinds of paths in the adjacency graph, since some paths can now terminate internal to a chromosome and not on telomeres. We introduce "ghost adjacencies" to supply the missing gene ends in the genome not containing them. Ghosts enable us to close paths that were due to incomplete matching, just as null points enable us to close even paths terminating in telomeres. We define generalized DCJ operations on the generalized adjacency graph, and give a prescription for calculating the DCJ distance for the expanded repertoire of operations, which includes insertions, deletions, and duplications. For the case of insertions and deletions, with linear as well as circular chromosomes, we suggest permitting a "nugh" (half ghost, half null), which can shorten the distance. We give algorithms for the optimal closure, with and without nughs, and give the resulting distance formula in terms of paths. For certain simplest cases, we calculate the number of optimal ways to close the graph.

  15. Rubinstein-Taybi syndrome caused by submicroscopic deletions within 16p13.3

    PubMed Central

    Breuning, Martijn H.; Dauwerse, Hans G.; Fugazza, Gluseppina; Saris, Jasper J.; Spruit, Lia; Wijnen, Herman; Tommerup, Niels; van der Hagen, C. B.; Imaizumi, Kiyoshi; Kuroki, Yoshikazu; van den Boogaard, Marie-Jose; de Pater, Joke M.; Mariman, Edwin C. M.; Hamel, Ben C. J.; Himmelbauer, Heinz; Frischauf, Anne-Marie; Stallings, Raymond L.; Beverstock, Geoffrey C.; van Ommen, Gert-Jan B.; Hennekam, Raoul C. M.

    1993-01-01

    The Rubinstein-Taybi syndrome (RTS) is a well-defined complex of congenital malformations characterized by facial abnormalities, broad thumbs and big toes, and mental retardation. The breakpoint of two distinct reciprocal translocations occurring in patients with a clinical diagnosis of RTS was located to the same interval on chromosome 16, between the cosmids N2 and RT1, in band 16p13.3. By using two-color fluorescence in situ hybridization, the signal from RT1 was found to be missing from one chromosome 16 in 6 of 24 patients with RTS. The parents of five of these patients did not show a deletion of RT1, indicating a de novo rearrangement. RTS is caused by submicroscopic interstitial deletions within 16pl3.3 in approximately 25% of the patients. The detection of microdeletions will allow the objective confirmation of the clinical diagnosis in new patients and provides an excellent tool for the isolation of the gene causally related to the syndrome. ImagesFigure 2 PMID:8430691

  16. Distinctive Phenotypic Abnormalities Associated with Submicroscopic 21q22 Deletion Including DYRK1A

    PubMed Central

    Oegema, R.; de Klein, A.; Verkerk, A.J.; Schot, R.; Dumee, B.; Douben, H.; Eussen, B.; Dubbel, L.; Poddighe, P.J.; van der Laar, I.; Dobyns, W.B.; van der Spek, P.J.; Lequin, M.H.; de Coo, I.F.M.; de Wit, M.-C.Y.; Wessels, M.W.; Mancini, G.M.S.

    2010-01-01

    Partial monosomy 21 has been reported, but the phenotypes described are variable with location and size of the deletion. We present 2 patients with a partially overlapping microdeletion of 21q22 and a striking phenotypic resemblance. They both presented with severe psychomotor delay, behavioral problems, no speech, microcephaly, feeding problems with frequent regurgitation, idiopathic thrombocytopenia, obesity, deep set eyes, down turned corners of the mouth, dysplastic ears, and small chin. Brain MRI showed cerebral atrophy mostly evident in frontal and temporal lobes, widened ventricles and thin corpus callosum in both cases, and in one patient evidence of a migration disorder. The first patient also presented with epilepsy and a ventricular septum defect. The second patient had a unilateral Peters anomaly. Microarray analysis showed a partially overlapping microdeletion spanning about 2.5 Mb in the 21q22.1–q22.2 region including the DYRK1A gene and excluding RUNX1. These patients present with a recognizable phenotype specific for this 21q22.1–q22.2 locus. We searched the literature for patients with overlapping deletions including the DYRK1A gene, in order to define other genes responsible for this presentation. PMID:21031080

  17. IKAROS Gene Deleted B-Cell Acute Lymphoblastic Leukemia in Mexican Mestizos: Observations in Seven Patients and a Short Review of the Literature.

    PubMed

    Ruiz-Delgado, Guillermo José; Cantero-Fortiz, Yahveth; León-Peña, Andrés Aurelio; León-González, Mónica; Nuñez-Cortés, Ana Karen; Ruiz-Argüelles, Guillermo José

    2016-01-01

    In B-cell acute lymphoblastic leukemia, one of the most frequent cytogenetic alterations is the presence of the Philadelphia chromosome. Recently, newly identified genetic alterations have been studied, among them the IKZF1 deletion. IKZF1 encodes IKAROS, a zinc finger protein that plays an important role in hematopoiesis involving the regulation process of adhesion, cellular migration, and as a tumor suppressor. We aimed to study the impact of IKAROS deletion in the evolution and prognosis of B-cell acute lymphoblastic leukemia. At a single center we prospectively studied patients diagnosed with B-cell acute lymphoblastic leukemia and screened for IKZF1 deletion using the multiplex ligation-dependent probe amplification method. We did a descriptive analysis of patients positive for the IKZF1 deletion to determine its impact on the evolution of the disease and survival rate. Between 2010 and 2015, 16 Mexican mestizo patients with B-cell acute lymphoblastic leukemia were prospectively screened for IKZF1 deletion; seven (43%) were positive and were included for further analysis. The age range of patients was 13-60 years; six were males and one female. All cases had type B acute lymphoblastic leukemia. Of the seven patients, two died, three were lost to follow-up, and two continue in complete remission with treatment. Results are worse than those in a group of patients with non-mutated IKAROS B-cell acute lymphoblastic leukemia previously studied in our center. Although this is a small sample, the presence of IKAROS deletion in acute lymphoblastic leukemia patients could represent a poor-prognosis marker and was probably related to therapy failure. It is also possible that this variant of leukemia may be more prevalent in Mexico. More studies are needed to define the role of IKZF1 deletion in acute lymphoblastic leukemia and the real prevalence of the disease in different populations.

  18. Minimum prevalence of chromosome 22q11 deletions

    SciTech Connect

    Wilson, D.I.; Cross, I.E.; Burn, J.

    1994-09-01

    Submicroscopic deletions from within chromosome 22q11 are associated with DiGeorge (DGS), velocardiofacial (VCFS) and conotruncal anomaly syndromes and isolated congenital heart defects. In 1993 our pediatric cardiologists clinically referred all children in whom a chromosome 22q11 deletion was suspected for fluorescent in situ hybridization studies using probes from the DGS critical region. 10 affected individuals have been identified to date from the children born in 1993 in the Northern Region served exclusively by our center. A further case, the subsequent pregnancy in one of these families was affected and terminated on the basis of a major heart malformation. In the years 1988-92, for which we have complete ascertainment, there were 1009 heart defects among 191,700 births (mean 202 per annum). Thus we estimate that chromosome 22q11 deletions were the cause of at least 5% of congenital heart disease. As not all children with chromosome 22q11 deletions have a heart defect, this gives an estimated minimum prevalence of 1/4000 live births.

  19. 37 CFR 2.35 - Adding, deleting, or substituting bases.

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  20. 77 FR 26520 - Procurement List Additions and Deletions

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  10. Genetic Counseling for the 22q11.2 Deletion

    ERIC Educational Resources Information Center

    McDonald-McGinn, Donna M.; Zackai, Elaine H.

    2008-01-01

    Because of advances in palliative medical care, children with the 22q11.2 deletion syndrome are surviving into adulthood. An increase in reproductive fitness will likely follow necessitating enhanced access to genetic counseling for these patients and their families. Primary care physicians/obstetric practitioners are in a unique position to…

  11. Efficient sequential repetitive gene deletions in Neurospora crassa

    USDA-ARS?s Scientific Manuscript database

    Despite its long-standing history as a model organism, Neurospora crassa has limited tools for repetitive gene deletions utilizing recyclable self-excising marker systems. Here we describe, for the first time, the functionality of a bacterial recombination system employing ß-recombinase acting on si...

  12. Genetic Counseling for the 22q11.2 Deletion

    ERIC Educational Resources Information Center

    McDonald-McGinn, Donna M.; Zackai, Elaine H.

    2008-01-01

    Because of advances in palliative medical care, children with the 22q11.2 deletion syndrome are surviving into adulthood. An increase in reproductive fitness will likely follow necessitating enhanced access to genetic counseling for these patients and their families. Primary care physicians/obstetric practitioners are in a unique position to…

  13. 75 FR 27313 - Procurement List; Additions and Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-14

    ... products are deleted from the Procurement List: Products USB Flash Drive, Flip Style NSN: 7045-01-568-4206--1 GB, no encryption. NSN: 7045-01-568-4207--1GB, with encryption. USB Flash Drive with Password Protection NSN: 7045-01-558-4983--512MB. NSN: 7045-01-558-4984--USB Flash Drive. USB Flash Drive with...

  14. Genomic anatomy of the Tyrp1 (brown) deletion complex

    SciTech Connect

    Hunsicker, Patricia R; Johnson, Dabney K

    2006-01-01

    Chromosome deletions in the mouse have proven invaluable in the dissection of gene function. The brown deletion complex comprises >28 independent genome rearrangements, which have been used to identify several functional loci on chromosome 4 required for normal embryonic and postnatal development. We have constructed a 172-bacterial artificial chromosome contig that spans this 22- egabase (Mb) interval and have produced a contiguous, finished, and manually annotated sequence from these clones. The deletion complex is strikingly gene- oor, containing only 52 protein-coding genes (of which only 39 are supported by human homologues) and has several further notable genomic features, including several segments of >1 Mb, apparently devoid of a coding sequence. We have used sequence polymorphisms to finely map the deletion breakpoints and identify strong candidate genes for the known phenotypes that map to this region, including three lethal loci (l4Rn1, l4Rn2, and l4Rn3) and the fitness mutant brown-associated fitness (baf). We have also characterized misexpression of the basonuclin homologue, Bnc2, associated with the inversion-ediated coat color mutant white-based brown (Bw). This study provides a molecular insight into the basis of several characterized mouse mutants, which will allow further dissection of this region by targeted or chemical mutagenesis.

  15. Atm deletion with dual recombinase technology preferentially radiosensitizes tumor endothelium.

    PubMed

    Moding, Everett J; Lee, Chang-Lung; Castle, Katherine D; Oh, Patrick; Mao, Lan; Zha, Shan; Min, Hooney D; Ma, Yan; Das, Shiva; Kirsch, David G

    2014-08-01

    Cells isolated from patients with ataxia telangiectasia are exquisitely sensitive to ionizing radiation. Kinase inhibitors of ATM, the gene mutated in ataxia telangiectasia, can sensitize tumor cells to radiation therapy, but concern that inhibiting ATM in normal tissues will also increase normal tissue toxicity from radiation has limited their clinical application. Endothelial cell damage can contribute to the development of long-term side effects after radiation therapy, but the role of endothelial cell death in tumor response to radiation therapy remains controversial. Here, we developed dual recombinase technology using both FlpO and Cre recombinases to generate primary sarcomas in mice with endothelial cell-specific deletion of Atm to determine whether loss of Atm in endothelial cells sensitizes tumors and normal tissues to radiation. Although deletion of Atm in proliferating tumor endothelial cells enhanced the response of sarcomas to radiation, Atm deletion in quiescent endothelial cells of the heart did not sensitize mice to radiation-induced myocardial necrosis. Blocking cell cycle progression reversed the effect of Atm loss on tumor endothelial cell radiosensitivity. These results indicate that endothelial cells must progress through the cell cycle in order to be radiosensitized by Atm deletion.

  16. 75 FR 5970 - Procurement List: Proposed Additions and Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-02-05

    ...The Committee is proposing to add to the Procurement List a product and a service to be furnished by nonprofit agencies employing persons who are blind or have other severe disabilities, and to delete products previously furnished by such agencies. Comments Must Be Received on or Before: March 8, 2010.

  17. On Making a Distinguished Vertex Minimum Degree by Vertex Deletion

    NASA Astrophysics Data System (ADS)

    Betzler, Nadja; Bredereck, Robert; Niedermeier, Rolf; Uhlmann, Johannes

    For directed and undirected graphs, we study the problem to make a distinguished vertex the unique minimum-(in)degree vertex through deletion of a minimum number of vertices. The corresponding NP-hard optimization problems are motivated by applications concerning control in elections and social network analysis. Continuing previous work for the directed case, we show that the problem is W[2]-hard when parameterized by the graph's feedback arc set number, whereas it becomes fixed-parameter tractable when combining the parameters "feedback vertex set number" and "number of vertices to delete". For the so far unstudied undirected case, we show that the problem is NP-hard and W[1]-hard when parameterized by the "number of vertices to delete". On the positive side, we show fixed-parameter tractability for several parameterizations measuring tree-likeness, including a vertex-linear problem kernel with respect to the parameter "feedback edge set number". On the contrary, we show a non-existence result concerning polynomial-size problem kernels for the combined parameter "vertex cover number and number of vertices to delete", implying corresponding nonexistence results when replacing vertex cover number by treewidth or feedback vertex set number.

  18. Sperm mitochondrial DNA deletion in Iranian infertiles with asthenozoospermia.

    PubMed

    Bahrehmand Namaghi, I; Vaziri, H

    2017-04-01

    Asthenozoospermia is an important cause of male infertility. The mutations in sperm mitochondrial DNA (mtDNA) result in either functionless or malfunctioning some proteins, subsequently affecting sperm motility leading to asthenozoospermia. The purpose of this study was to investigate sperm mtDNA 4,977-bp deletion in infertile men with low sperm motility/immotile spermatozoa compared to healthy subjects with high sperm motility. Semen samples of 256 asthenozoospermic infertiles and 200 controls from northern Iran were collected. After extraction of spermatozoa total DNA, Gap-polymerase chain reaction (Gap-PCR) was performed. The deletion was observed in 85.93% of patients with asthenozoospermia compared with 14% in controls [OR = 37.5397, 95% confidence interval = 12.937-108.9276, p < .0001]. It is concluded that there is a strong association between sperm mtDNA 4,977-bp deletion and asthenozoospermia-induced infertility in the population examined. Large-scale mtDNA deletions in spermatozoa may induce bioenergetic disorders. Nevertheless, to validate our results broader research may be needed.

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