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Sample records for small consanguineous families

  1. Compound heterozygosity for three common MEFV mutations in a highly consanguineous family with familial Mediterranean fever.

    PubMed

    Seidel, H; Steinlein, O K

    2008-07-01

    Consanguinity is not the only factor influencing the occurrence of autosomal recessive disorders such as familial Mediterranean fever (FMF). The extended, multiple consanguineous Turkish pedigree presented here demonstrates that the population frequency of certain mutations (so-called "ancient" mutations) can be at least equally important. In high-risk populations different combinations of mutations can occur within the same family, increasing not only the intrafamilial clinical variability, but also causing considerable recurrence risks even in marriages with unrelated spouses.

  2. Loss of function mutations in RP1 are responsible for retinitis pigmentosa in consanguineous familial cases

    PubMed Central

    Kabir, Firoz; Ullah, Inayat; Ali, Shahbaz; Gottsch, Alexander D.H.; Naeem, Muhammad Asif; Assir, Muhammad Zaman; Khan, Shaheen N.; Akram, Javed; Riazuddin, Sheikh; Ayyagari, Radha; Hejtmancik, J. Fielding

    2016-01-01

    Purpose This study was undertaken to identify causal mutations responsible for autosomal recessive retinitis pigmentosa (arRP) in consanguineous families. Methods Large consanguineous families were ascertained from the Punjab province of Pakistan. An ophthalmic examination consisting of a fundus evaluation and electroretinography (ERG) was completed, and small aliquots of blood were collected from all participating individuals. Genomic DNA was extracted from white blood cells, and a genome-wide linkage or a locus-specific exclusion analysis was completed with polymorphic short tandem repeats (STRs). Two-point logarithm of odds (LOD) scores were calculated, and all coding exons and exon–intron boundaries of RP1 were sequenced to identify the causal mutation. Results The ophthalmic examination showed that affected individuals in all families manifest cardinal symptoms of RP. Genome-wide scans localized the disease phenotype to chromosome 8q, a region harboring RP1, a gene previously implicated in the pathogenesis of RP. Sanger sequencing identified a homozygous single base deletion in exon 4: c.3697delT (p.S1233Pfs22*), a single base substitution in intron 3: c.787+1G>A (p.I263Nfs8*), a 2 bp duplication in exon 2: c.551_552dupTA (p.Q185Yfs4*) and an 11,117 bp deletion that removes all three coding exons of RP1. These variations segregated with the disease phenotype within the respective families and were not present in ethnically matched control samples. Conclusions These results strongly suggest that these mutations in RP1 are responsible for the retinal phenotype in affected individuals of all four consanguineous families. PMID:27307693

  3. Single-nucleotide polymorphism arrays and unexpected consanguinity: considerations for clinicians when returning results to families.

    PubMed

    Delgado, Fernanda; Tabor, Holly K; Chow, Penny M; Conta, Jessie H; Feldman, Kenneth W; Tsuchiya, Karen D; Beck, Anita E

    2015-05-01

    The broad use of single-nucleotide polymorphism microarrays has increased identification of unexpected consanguinity. Therefore, guidelines to address reporting of consanguinity have been published for clinical laboratories. Because no such guidelines for clinicians exist, we describe a case and present recommendations for clinicians to disclose unexpected consanguinity to families. In a boy with multiple endocrine abnormalities and structural birth defects, single-nucleotide polymorphism array analysis revealed ~23% autosomal homozygosity suggestive of a first-degree parental relationship. We assembled an interdisciplinary health-care team, planned the most appropriate way to discuss results of the single-nucleotide polymorphism array with the adult mother, including the possibility of multiple autosomal recessive disorders in her child, and finally met with her as a team. From these discussions, we developed four major considerations for clinicians returning results of unexpected consanguinity, all guided by the child's best interests: (i) ethical and legal obligations for reporting possible abuse, (ii) preservation of the clinical relationship, (iii) attention to justice and psychosocial challenges, and (iv) utilization of the single-nucleotide polymorphism array results to guide further testing. As single-nucleotide polymorphism arrays become a common clinical diagnostic tool, clinicians can use this framework to return results of unexpected consanguinity to families in a supportive and productive manner.

  4. Parental consanguinity and family history of coronary artery disease strongly predict early stenosis.

    PubMed

    Youhanna, Sonia; Platt, Daniel E; Rebeiz, Abdallah; Lauridsen, Michael; Deeb, Mary E; Nasrallah, Antoine; Alam, Samir; Puzantian, Houry; Kabbani, Samer; Ghoul, Melanie; Zreik, Tony G; el Bayeh, Hamid; Abchee, Antoine; Zalloua, Pierre

    2010-10-01

    Coronary artery disease (CAD) is a multifactorial disease with acquired and inherited components. We investigated the roles of family history and consanguinity on CAD risk and age at diagnosis in 4284 patients. The compounded impact of diabetes, hyperlipidemia, hypertension, smoking, and BMI, which are known CAD risk factors, on CAD risk and age at diagnosis was also explored. CAD was determined by cardiac catheterization. Logistic regression and stratification were performed to determine the impact of family history and consanguinity on risk and onset of CAD, controlling for diabetes, hyperlipidemia, hypertension, smoking, and BMI. Family history of CAD and gender significantly increased the risk for young age at diagnosis of CAD (p<0.001). Consanguinity did not promote risk of CAD (p=0.38), but did affect age of disease diagnosis (p<0.001). The mean age at disease diagnosis was lowest, 54.8 years, when both family history of CAD and consanguinity were considered as unique risk factors for CAD, compared to 62.8 years for the no-risk-factor patient category (p<0.001). Family history of CAD and smoking are strongly associated with young age at diagnosis. Furthermore, parental consanguinity in the presence of family history lowers the age of disease diagnosis significantly for CAD, emphasizing the role of strong genetic and cultural CAD modifiers. These findings highlight the increased role of genetic determinants of CAD in some population subgroups, and suggest that populations and family structure influence genetic heterogeneity between patients with CAD. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  5. Familial Recurrence of 3MC Syndrome in Consanguineous Families: A Clinical and Molecular Diagnostic Approach With Review of the Literature.

    PubMed

    Gardner, Olivia K; Haynes, Karla; Schweitzer, Daniela; Johns, Alexis; Magee, William P; Urata, Mark M; Sanchez-Lara, Pedro A

    2016-06-29

    We report four individuals from two unrelated consanguineous families with 3MC syndrome. In the first family, chromosome microarray data revealed that the two affected sisters, born to first-cousin parents, shared a unique homozygous C-terminal deletion in the COLEC11 gene. Two affected brothers from a second family, also born to first-cousin parents, shared a region of homozygosity that included the second gene known to cause the 3MC syndrome, MASP1. We discuss the diagnostic approach of craniofacial disorders born to consanguineous parents and highlight a literature search and reference a helpful dysmorphology solution powered by FDNA (Facial Dysmorphology Novel Analysis) technology.

  6. Homozygosity Mapping and Genetic Analysis of Autosomal Recessive Retinal Dystrophies in 144 Consanguineous Pakistani Families

    PubMed Central

    Li, Lin; Chen, Yabin; Jiao, Xiaodong; Jin, Chongfei; Jiang, Dan; Tanwar, Mukesh; Ma, Zhiwei; Huang, Li; Ma, Xiaoyin; Sun, Wenmin; Chen, Jianjun; Ma, Yan; M'hamdi, Oussama; Govindarajan, Gowthaman; Cabrera, Patricia E.; Li, Jiali; Gupta, Nikhil; Naeem, Muhammad Asif; Khan, Shaheen N.; Riazuddin, Sheikh; Akram, Javed; Ayyagari, Radha; Sieving, Paul A.; Riazuddin, S. Amer; Hejtmancik, J. Fielding

    2017-01-01

    Purpose The Pakistan Punjab population has been a rich source for identifying genes causing or contributing to autosomal recessive retinal degenerations (arRD). This study was carried out to delineate the genetic architecture of arRD in the Pakistani population. Methods The genetic origin of arRD in a total of 144 families selected only for having consanguineous marriages and multiple members affected with arRD was examined. Of these, causative mutations had been identified in 62 families while only the locus had been identified for an additional 15. The remaining 67 families were subjected to homozygosity exclusion mapping by screening of closely flanking microsatellite markers at 180 known candidate genes/loci followed by sequencing of the candidate gene for pathogenic changes. Results Of these 67 families subjected to homozygosity mapping, 38 showed homozygosity for at least one of the 180 regions, and sequencing of the corresponding genes showed homozygous cosegregating mutations in 27 families. Overall, mutations were detected in approximately 61.8 % (89/144) of arRD families tested, with another 10.4% (15/144) being mapped to a locus but without a gene identified. Conclusions These results suggest the involvement of unmapped novel genes in the remaining 27.8% (40/144) of families. In addition, this study demonstrates that homozygosity mapping remains a powerful tool for identifying the genetic defect underlying genetically heterogeneous arRD disorders in consanguineous marriages for both research and clinical applications. PMID:28418496

  7. Mutations in GRM6 identified in consanguineous Pakistani families with congenital stationary night blindness

    PubMed Central

    Naeem, Muhammad Asif; Gottsch, Alexander D. H.; Ullah, Inayat; Khan, Shaheen N.; Husnain, Tayyab; Butt, Nadeem H.; Qazi, Zaheeruddin A.; Akram, Javed; Riazuddin, Sheikh; Ayyagari, Radha; Hejtmancik, J. Fielding

    2015-01-01

    Purpose This study was undertaken to investigate the causal mutations responsible for autosomal recessive congenital stationary night blindness (CSNB) in consanguineous Pakistani families. Methods Two consanguineous families with multiple individuals manifesting symptoms of stationary night blindness were recruited. Affected individuals underwent a detailed ophthalmological examination, including fundus examination and electroretinography. Blood samples were collected and genomic DNA was extracted. Exclusion analyses were completed by genotyping closely spaced microsatellite markers, and two-point logarithm of odds (LOD) scores were calculated. All coding exons, along with the exon–intron boundaries of GRM6, were sequenced bidirectionally. Results According to the medical history available to us, affected individuals in both families had experienced night blindness from the early years of their lives. Fundus photographs of affected individuals in both the families appeared normal, with no signs of attenuated arteries or bone spicule pigmentation. The scotopic electroretinogram (ERG) response were absent in all of the affected individuals, while the photopic measurements show reduced b-waves. During exclusion analyses, both families localized to a region on chromosome 5q that harbors GRM6, a gene previously associated with autosomal recessive CSNB. Bidirectional sequencing of GRM6 identified homozygous single base pair changes, specifically c.1336C>T (p.R446X) and c.2267G>A (p.G756D) in families PKRP170 and PKRP172, respectively. Conclusions We identified a novel nonsense and a previously reported missense mutation in GRM6 that were responsible for autosomal recessive CSNB in patients of Pakistani decent. PMID:26628857

  8. A founder splice site mutation underlies glycogen storage disease type 3 in consanguineous Saudi families.

    PubMed

    Basit, Sulman; Malibari, Omhani; Al Balwi, Alia Mahmood; Abdusamad, Firoz; Abu Ismail, Feras

    2014-01-01

    Glycogen storage disease type 3 (GSD III) is an autosomal recessive disorder caused by genetic mutations in the gene AGL. AGL encodes amylo-a-1, 6-glucosidase, 4-a-glucanotransferase, a glycogen debranching enzyme. GSD III is characterized by fasting hypoglycemia, hepatomegaly, growth retardation, progressive myopathy, and cardiomyopathy due to storage of abnormally structured glycogen in both skeletal and cardiac muscles and/or liver. The aim of this study is to detect mutations underlying GSD III in Saudi patients. A cross-sectional clinical genetic study of 5 Saudi consanguineous families examined at the metabolic clinic of the Madinah Maternity and Children Hospital. We present a biochemical and molecular analysis of 5 consanguineous Saudi families with GSD III. DNA was isolated from the peripheral blood of 31 individuals, including 12 patients, and the AGL gene was sequenced bidirectionally. DNA sequences were compared with the AGL reference sequence from the ensemble genome browser. Genotyping and sequence analysis identified a homozygous intronic splice acceptor site mutation (IVS32-12A > G) in 4 families perfectly segregating with the phenotype. Complementary (c)DNA sequence analysis of the AGL gene revealed an 11-bp sequence insertion between exon 32 and exon 33 due to the creation of a new 3' splice site. The predicted mutant enzyme was truncated by 112 carboxyl-terminal amino acids as a result of premature termination. Haplotype analysis revealed that the mutation arises as a result of founder effect, not an independent event. This is the first report of a genetic mutation in the AGL gene from Saudi Arabia. Screening for this mutation can improve genetic counseling and prenatal diagnosis of GSD III in Saudi Arabia.

  9. Genetic dissection of two Pakistani families with consanguineous localized autosomal recessive hypotrichosis (LAH).

    PubMed

    Abbas, Seyyedha; Naveed, Abdul Khaliq; Khan, Shakir; Yousaf, Muhammad Jawad; Azeem, Zahid; Razak, Suhail; Qaiser, Fatima

    2014-07-01

    Genetic analysis of two consanguineous Pakistani families with localized autosomal recessive hypotrichosis was performed with the goal to establish genotype-phenotype correlation. Genomic DNA extraction had been done from peripheral blood samples. Extracted DNA was then subjected to PCR (polymerase chain reaction) for amplification. Linkage analysis was performed using 8% polyacrylamide gel. Candidate gene was sequenced after gene linkage supported at highly polymorphic microsatellite markers of the diseased region. Both families were initially tested for linkage to known genes, which were involved in human hereditary hypotrichosis, by genotyping Highly polymorphic microsatellite markers. Family B showed partial linkage at P2RY5 gene on chromosome 13q14.11-q21.32; hence, all exonic regions and their introns boundaries were subjected to DNA sequencing for any pathogenic mutation. Both families were tested for linkage by genotyping polymorphic microsatellite markers linked to known alopecia loci. Family A excluded all known diseased regions that is suggestive of some novel chromosomal disorder. However, sequencing of P2RY5 gene in family B showed no pathogenic mutation.

  10. Genetic dissection of two Pakistani families with consanguineous localized autosomal recessive hypotrichosis (LAH)

    PubMed Central

    Abbas, Seyyedha; Naveed, Abdul Khaliq; Khan, Shakir; Yousaf, Muhammad Jawad; Azeem, Zahid; Razak, Suhail; Qaiser, Fatima

    2014-01-01

    Objective(s): Genetic analysis of two consanguineous Pakistani families with localized autosomal recessive hypotrichosis was performed with the goal to establish genotype-phenotype correlation. Materials and Methods: Genomic DNA extraction had been done from peripheral blood samples. Extracted DNA was then subjected to PCR (polymerase chain reaction) for amplification. Linkage analysis was performed using 8% polyacrylamide gel. Candidate gene was sequenced after gene linkage supported at highly polymorphic microsatellite markers of the diseased region. Results: Both families were initially tested for linkage to known genes, which were involved in human hereditary hypotrichosis, by genotyping Highly polymorphic microsatellite markers. Family B showed partial linkage at P2RY5 gene on chromosome 13q14.11-q21.32; hence, all exonic regions and their introns boundaries were subjected to DNA sequencing for any pathogenic mutation. Conclusion: Both families were tested for linkage by genotyping polymorphic microsatellite markers linked to known alopecia loci. Family A excluded all known diseased regions that is suggestive of some novel chromosomal disorder. However, sequencing of P2RY5 gene in family B showed no pathogenic mutation. PMID:25429336

  11. Novel C8orf37 mutations cause retinitis pigmentosa in consanguineous families of Pakistani origin

    PubMed Central

    Ravesh, Zeinab; El Asrag, Mohammed E.; Weisschuh, Nicole; McKibbin, Martin; Reuter, Peggy; Watson, Christopher M.; Baumann, Britta; Poulter, James A.; Sajid, Sundus; Panagiotou, Evangelia S.; O’Sullivan, James; Abdelhamed, Zakia; Bonin, Michael; Soltanifar, Mehdi; Black, Graeme C.M.; Din, Muhammad Amin-ud; Toomes, Carmel; Ansar, Muhammad; Inglehearn, Chris F.; Wissinger, Bernd

    2015-01-01

    Purpose To investigate the molecular basis of retinitis pigmentosa in two consanguineous families of Pakistani origin with multiple affected members. Methods Homozygosity mapping and Sanger sequencing of candidate genes were performed in one family while the other was analyzed with whole exome next-generation sequencing. A minigene splicing assay was used to confirm the splicing defects. Results In family MA48, a novel homozygous nucleotide substitution in C8orf37, c.244–2A>C, that disrupted the consensus splice acceptor site of exon 3 was found. The minigene splicing assay revealed that this mutation activated a cryptic splice site within exon 3, causing a 22 bp deletion in the transcript that is predicted to lead to a frameshift followed by premature protein truncation. In family MA13, a novel homozygous null mutation in C8orf37, c.555G>A, p.W185*, was identified. Both mutations segregated with the disease phenotype as expected in a recessive manner and were absent in 8,244 unrelated individuals of South Asian origin. Conclusions In this report, we describe C8orf37 mutations that cause retinal dystrophy in two families of Pakistani origin, contributing further data on the phenotype and the spectrum of mutations in this form of retinitis pigmentosa. PMID:25802487

  12. Sequence variants in four genes underlying Bardet-Biedl syndrome in consanguineous families

    PubMed Central

    Ullah, Asmat; Umair, Muhammad; Yousaf, Maryam; Khan, Sher Alam; Nazim-ud-din, Muhammad; Shah, Khadim; Ahmad, Farooq; Azeem, Zahid; Ali, Ghazanfar; Alhaddad, Bader; Rafique, Afzal; Jan, Abid; Haack, Tobias B.; Strom, Tim M.; Meitinger, Thomas; Ghous, Tahseen

    2017-01-01

    Purpose To investigate the molecular basis of Bardet-Biedl syndrome (BBS) in five consanguineous families of Pakistani origin. Methods Linkage in two families (A and B) was established to BBS7 on chromosome 4q27, in family C to BBS8 on chromosome 14q32.1, and in family D to BBS10 on chromosome 12q21.2. Family E was investigated directly with exome sequence analysis. Results Sanger sequencing revealed two novel mutations and three previously reported mutations in the BBS genes. These mutations include two deletions (c.580_582delGCA, c.1592_1597delTTCCAG) in the BBS7 gene, a missense mutation (p.Gln449His) in the BBS8 gene, a frameshift mutation (c.271_272insT) in the BBS10 gene, and a nonsense mutation (p.Ser40*) in the MKKS (BBS6) gene. Conclusions Two novel mutations and three previously reported variants, identified in the present study, further extend the body of evidence implicating BBS6, BBS7, BBS8, and BBS10 in causing BBS. PMID:28761321

  13. Pathogenic mutations in TULP1 responsible for retinitis pigmentosa identified in consanguineous familial cases

    PubMed Central

    Ullah, Inayat; Kabir, Firoz; Iqbal, Muhammad; Gottsch, Clare Brooks S.; Naeem, Muhammad Asif; Assir, Muhammad Zaman; Khan, Shaheen N.; Akram, Javed; Riazuddin, Sheikh; Ayyagari, Radha; Hejtmancik, J. Fielding

    2016-01-01

    Purpose To identify pathogenic mutations responsible for autosomal recessive retinitis pigmentosa (arRP) in consanguineous familial cases. Methods Seven large familial cases with multiple individuals diagnosed with retinitis pigmentosa were included in the study. Affected individuals in these families underwent ophthalmic examinations to document the symptoms and confirm the initial diagnosis. Blood samples were collected from all participating members, and genomic DNA was extracted. An exclusion analysis with microsatellite markers spanning the TULP1 locus on chromosome 6p was performed, and two-point logarithm of odds (LOD) scores were calculated. All coding exons along with the exon–intron boundaries of TULP1 were sequenced bidirectionally. We constructed a single nucleotide polymorphism (SNP) haplotype for the four familial cases harboring the K489R allele and estimated the likelihood of a founder effect. Results The ophthalmic examinations of the affected individuals in these familial cases were suggestive of RP. Exclusion analyses confirmed linkage to chromosome 6p harboring TULP1 with positive two-point LOD scores. Subsequent Sanger sequencing identified the single base pair substitution in exon14, c.1466A>G (p.K489R), in four families. Additionally, we identified a two-base deletion in exon 4, c.286_287delGA (p.E96Gfs77*); a homozygous splice site variant in intron 14, c.1495+4A>C; and a novel missense variation in exon 15, c.1561C>T (p.P521S). All mutations segregated with the disease phenotype in the respective families and were absent in ethnically matched control chromosomes. Haplotype analysis suggested (p<10−6) that affected individuals inherited the causal mutation from a common ancestor. Conclusions Pathogenic mutations in TULP1 are responsible for the RP phenotype in seven familial cases with a common ancestral mutation responsible for the disease phenotype in four of the seven families. PMID:27440997

  14. Exclusion of LCA5 locus in a consanguineous Turkish family with macular coloboma-type LCA.

    PubMed

    Ozgül, R K; Bozkurt, B; Kiratli, H; Oğüş, A

    2006-07-01

    Leber's congenital amaurosis (LCA) is an inherited retinal dystrophy, which causes severe visual impairment in early childhood. Recent molecular genetic studies have linked 11 loci (AIPL1, CRB1, CRX, GUCY2D, RPE65, RDH12, RPGRIP1, TULP1, LCA3, LCA5, and LCA9) to LCA. LCA5 is a new locus, which maps to the 6q11-q16 chromosomal region and was found to be associated with macular coloboma-type LCA in a Pakistani family. Herein, we describe the molecular genetic features of a consanguineous Turkish family in which four children have macular coloboma-type LCA. Haplotype analysis was performed on the DNA of the family members using microsatellite markers against GUCY2D, RPE65, and LCA5. Genomic DNA was screened for mutations by means of single-strand conformational polymorphism (SSCP) analysis in exons of the RPE65 and CRX genes. In haplotype analysis, no linkage to LCA5 or GUCY2D loci was detected. None of the tested markers showed homozygosity or segregation between affected siblings. PCR-SSCP mutation analysis revealed no mutations in the screened RPE65 and CRX genes. We excluded LCA5 as the genetic cause of macular coloboma-type LCA in this Turkish family. Macular coloboma-type LCA shows genetic heterogeneity and it is not possible to establish a phenotype-genotype correlation with LCA5 and macular coloboma.

  15. Autosomal recessive congenital cataract, intellectual disability phenotype linked to STX3 in a consanguineous Tunisian family.

    PubMed

    Chograni, M; Alkuraya, F S; Ourteni, I; Maazoul, F; Lariani, I; Chaabouni, H B

    2015-09-01

    The aim of this study is to investigate the genetic basis of autosomal recessive congenital cataract and intellectual disability phenotype in a consanguineous Tunisian family. The whole genome scan of the studied family was performed with single nucleotide polymorphisms (SNPs). The resulted runs of homozygosity (ROH) were analyzed through the integrated Systems Tool for Eye gene discovery (iSyTE) in order to prioritize candidate genes associated with congenital cataract. Selected genes were amplified and sequenced. Bioinformatic analysis was conducted to predict the function of the mutant gene. We identified a new specific lens gene named syntaxin 3 linked to the studied phenotype. The direct sequencing of this gene revealed a novel missense mutation c.122A>G which results in p.E41G. Bioinformatic analysis suggested a deleterious effect of this mutation on protein structure and function. Here, we report for the first time a missense mutation of a novel lens specific gene STX3 in a phenotype associating autosomal recessive congenital cataract and intellectual disability.

  16. WDR73 missense mutation causes infantile onset intellectual disability and cerebellar hypoplasia in a consanguineous family.

    PubMed

    Jiang, Chen; Gai, Nan; Zou, Yongyi; Zheng, Yu; Ma, Ruiyu; Wei, Xianda; Liang, Desheng; Wu, Lingqian

    2017-01-01

    Galloway-Mowat syndrome (GMS) is a very rare autosomal-recessive disorder characterized by nephrotic syndrome associated with microcephaly, and various central nervous system abnormalities, mostly cerebral hypoplasia or cerebellar atrophy, intellectual disability and neural-migration defects. WDR73 is the only gene known to cause GMS, and has never been implicated in other disease. Here we present a Chinese consanguineous family with infantile onset intellectual disability and cerebellar hypoplasia but no microcephaly. Whole exome sequencing identified a WDR73 p.W371G missense mutation. The mutation is confirmed to be segregated in this family by Sanger sequencing according to a recessive inheritance pattern. It is predicted to be deleterious by multiple algorithms and affect highly conserved site. Structural modeling revealed conformational differences between the wild type protein and the p.W371G protein. Real-time PCR and Western blotting revealed altered mRNA and protein levels in mutated samples. Our study indicates the novel WDR73 p.W371G missense mutation causes infantile onset intellectual disability and cerebellar hypoplasia in recessive mode of inheritance. Our findings imply that microcephaly is a variable phenotype in WDR73-related disease, suggest WDR73 to be a candidate gene of severe intellectual disability and cerebellar hypoplasia, and expand the molecular spectrum of WDR73-related disease.

  17. Exome sequencing of Pakistani consanguineous families identifies 30 novel candidate genes for recessive intellectual disability.

    PubMed

    Riazuddin, S; Hussain, M; Razzaq, A; Iqbal, Z; Shahzad, M; Polla, D L; Song, Y; van Beusekom, E; Khan, A A; Tomas-Roca, L; Rashid, M; Zahoor, M Y; Wissink-Lindhout, W M; Basra, M A R; Ansar, M; Agha, Z; van Heeswijk, K; Rasheed, F; Van de Vorst, M; Veltman, J A; Gilissen, C; Akram, J; Kleefstra, T; Assir, M Z; Grozeva, D; Carss, K; Raymond, F L; O'Connor, T D; Riazuddin, S A; Khan, S N; Ahmed, Z M; de Brouwer, A P M; van Bokhoven, H; Riazuddin, S

    2016-07-26

    Intellectual disability (ID) is a clinically and genetically heterogeneous disorder, affecting 1-3% of the general population. Although research into the genetic causes of ID has recently gained momentum, identification of pathogenic mutations that cause autosomal recessive ID (ARID) has lagged behind, predominantly due to non-availability of sizeable families. Here we present the results of exome sequencing in 121 large consanguineous Pakistani ID families. In 60 families, we identified homozygous or compound heterozygous DNA variants in a single gene, 30 affecting reported ID genes and 30 affecting novel candidate ID genes. Potential pathogenicity of these alleles was supported by co-segregation with the phenotype, low frequency in control populations and the application of stringent bioinformatics analyses. In another eight families segregation of multiple pathogenic variants was observed, affecting 19 genes that were either known or are novel candidates for ID. Transcriptome profiles of normal human brain tissues showed that the novel candidate ID genes formed a network significantly enriched for transcriptional co-expression (P<0.0001) in the frontal cortex during fetal development and in the temporal-parietal and sub-cortex during infancy through adulthood. In addition, proteins encoded by 12 novel ID genes directly interact with previously reported ID proteins in six known pathways essential for cognitive function (P<0.0001). These results suggest that disruptions of temporal parietal and sub-cortical neurogenesis during infancy are critical to the pathophysiology of ID. These findings further expand the existing repertoire of genes involved in ARID, and provide new insights into the molecular mechanisms and the transcriptome map of ID.Molecular Psychiatry advance online publication, 26 July 2016; doi:10.1038/mp.2016.109.

  18. Novel homozygous large deletion including the 5' part of the SPATA7 gene in a consanguineous Israeli Muslim Arab family.

    PubMed

    Mayer, Anja-Kathrin; Mahajnah, Muhammad; Zobor, Ditta; Bonin, Michael; Sharkia, Rajech; Wissinger, Bernd

    2015-01-01

    To identify the genetic defect in a consanguineous Israeli Muslim Arab family with juvenile retinitis pigmentosa (RP). DNA samples were collected from the index patient, her parents, her affected sister, and two non-affected siblings. Genome-wide linkage analysis with 250 K single nucleotide polymorphism (SNP) arrays was performed using DNA from the two affected patients. Owing to consanguinity in the family, we applied homozygosity mapping to identify the disease-causing gene. The candidate gene SPATA7 was screened for mutations with PCR amplifications and direct Sanger sequencing. Following high-density SNP arrays, we identified several homozygous genomic regions one of which included the SPATA7 gene. Several mutations in SPATA7 have been reported for various forms of retinal dystrophy, including Leber congenital amaurosis (LCA) and juvenile RP. PCR-based sequence content mapping, long-distance PCR amplifications, and subsequent sequencing analysis revealed a homozygous 63.4 kb large deletion that encompasses the 5' part of the SPATA7 gene including exons 1-5. The mutation showed concordant segregation with the phenotype in the family as expected for autosomal recessive mode of inheritance and is consistent with a diagnosis of juvenile RP. We report a novel homozygous large deletion in SPATA7 associated with juvenile RP in a consanguineous Israeli Muslim Arab family. This is the first larger deletion mutation reported for SPATA7.

  19. Association between Leptin gene polymorphisms and plasma leptin level in three consanguineous families with obesity.

    PubMed

    Fourati, Mouna; Mnif, Mouna; Kharrat, Najla; Charfi, Nédia; Kammoun, Mahdi; Fendri, Nourhène; Sessi, Salwa; Abid, Mohamed; Rebai, Ahmed; Fakhfakh, Faiza

    2013-09-15

    Leptin (LEP) gene is one of the most promising candidate genes for obesity. Previous studies have tested the association of polymorphisms in LEP gene with obesity and obesity-related metabolic biomarkers (anthropometric variables, glucose, insulin level, leptin level and lipid profile). However, the results of these studies were still controversial. To determine whether LEP gene is associated with obesity in Tunisian population, we performed a family-based association study between LEP polymorphisms and obesity and obesity-related metabolic biomarkers. Seven single nucleotide polymorphisms (SNPs) in 5' region of LEP gene were genotyped in three consanguineous families including 33 individuals. The previously reported LEP SNPs (H1328084, H1328082, rs10487506, H1328081, H1328080, G-2548A and A19G) were evaluated by PCR-RFLP and direct sequencing methods. Single SNP association and haplotype association analyses were performed using the family-based association test (FBAT). To determine allele frequencies of these SNPs in general population, 52 unrelated individuals from the general Tunisian population were also analyzed. Two SNPs showed significant associations with plasma leptin level (H1328084: A>G, Z=2.058, p=0.039; A19G: G>A, Z=2.058, p=0.039). When haplotypes were constructed with these two-markers, the risk AA haplotype (frequency 57.1%) was positively associated with plasma leptin level (Z=2.058, p=0.039). Moreover, SNPs H1328084 and A19G are predicted to modify transcription-factor binding sites. Our study provided that two functional variants in 5' regulatory region of LEP gene are associated with plasma leptin level as a quantitative trait. It suggested that H1328084 and A19G have an important role in regulating plasma leptin level. Copyright © 2013 Elsevier B.V. All rights reserved.

  20. Genome-scan for loci involved in cleft lip with or without cleft palate in consanguineous families from Turkey.

    PubMed

    Marazita, Mary L; Field, L Leigh; Tunçbilek, Gökhan; Cooper, Margaret E; Goldstein, Toby; Gürsu, K Gürler

    2004-04-15

    Cleft lip with or without cleft palate (CL/P) is a common congenital anomaly, with birth prevalence ranging from 1/500 to 1/1,000. A number of genetic loci have shown positive linkage or association results in European Caucasian populations. The purpose of the current study was to assess whether any of those loci have positive results in Turkish Caucasian CL/P families, and to perform a 10 cM genome scan to identify other regions potentially containing cleft susceptibility loci. Eighteen affected individuals with consanguineous parents were identified as part of our on-going studies of orofacial clefts in Ankara, Turkey. Genotyped were 383 genome-scan markers, and 70 additional markers, including markers in six candidate loci or regions on chromosomes 2, 4, 6, 14, 17, and 19 (TGFA, D4S175, F13A1, TGFB3, D17S250, and APOC2) that have been implicated in other studies of families with orofacial clefting. LOD scores (two point and multiple point) and family-based association statistics (TDT) were calculated between each of the markers and CL/P. For the LOD score calculations, an autosomal recessive model was assumed for the inheritance of CL/P. Of the six candidate markers, significant TDT results were obtained with TGFA (P = 0.05). The most statistically significant multipoint results from the linkage genome scan were between putative genes controlling risk of CL/P and regions on chromosomes 4, 10, 12, and 15 (maximum multipoint HLOD's of 1.25, 1.30, 2.73, and 1.28 respectively). These results demonstrate the power of small numbers of families with inbred probands to detect linkage and association. Copyright 2003 Wiley-Liss, Inc.

  1. Combining gene mapping and phenotype assessment for fast mutation finding in non-consanguineous autosomal recessive retinitis pigmentosa families.

    PubMed

    Hebrard, Maxime; Manes, Gaël; Bocquet, Béatrice; Meunier, Isabelle; Coustes-Chazalette, Delphine; Hérald, Emilie; Sénéchal, Audrey; Bolland-Augé, Anne; Zelenika, Diana; Hamel, Christian P

    2011-12-01

    Among inherited retinal dystrophies, autosomal recessive retinitis pigmentosa (arRP) is the most genetically heterogenous condition with 32 genes currently known that account for ~60 % of patients. Molecular diagnosis thus requires the tedious systematic sequencing of 506 exons. To rapidly identify the causative mutations, we devised a strategy that combines gene mapping and phenotype assessment in small non-consanguineous families. Two unrelated sibships with arRP had whole-genome scan using SNP microchips. Chromosomal regions were selected by calculating a score based on SNP coverage and genotype identity of affected patients. Candidate genes from the regions with the highest scores were then selected based on phenotype concordance of affected patients with previously described phenotype for each candidate gene. For families RP127 and RP1459, 33 and 40 chromosomal regions showed possible linkage, respectively. By comparing the scores with the phenotypes, we ended with one best candidate gene for each family, namely tubby-like protein 1 (TULP1) and C2ORF71 for RP127 and RP1459, respectively. We found that RP127 patients were compound heterozygous for two novel TULP1 mutations, p.Arg311Gln and p.Arg342Gln, and that RP1459 patients were compound heterozygous for two novel C2ORF71 mutations, p.Leu777PhefsX34 and p.Leu777AsnfsX28. Phenotype assessment showed that TULP1 patients had severe early onset arRP and that C2ORF71 patients had a cone rod dystrophy type of arRP. Only two affected individuals in each sibship were sufficient to lead to mutation identification by screening the best candidate gene selected by a combination of gene mapping and phenotype characterization.

  2. Mapping autosomal recessive intellectual disability: combined microarray and exome sequencing identifies 26 novel candidate genes in 192 consanguineous families.

    PubMed

    Harripaul, R; Vasli, N; Mikhailov, A; Rafiq, M A; Mittal, K; Windpassinger, C; Sheikh, T I; Noor, A; Mahmood, H; Downey, S; Johnson, M; Vleuten, K; Bell, L; Ilyas, M; Khan, F S; Khan, V; Moradi, M; Ayaz, M; Naeem, F; Heidari, A; Ahmed, I; Ghadami, S; Agha, Z; Zeinali, S; Qamar, R; Mozhdehipanah, H; John, P; Mir, A; Ansar, M; French, L; Ayub, M; Vincent, J B

    2017-04-11

    Approximately 1% of the global population is affected by intellectual disability (ID), and the majority receive no molecular diagnosis. Previous studies have indicated high levels of genetic heterogeneity, with estimates of more than 2500 autosomal ID genes, the majority of which are autosomal recessive (AR). Here, we combined microarray genotyping, homozygosity-by-descent (HBD) mapping, copy number variation (CNV) analysis, and whole exome sequencing (WES) to identify disease genes/mutations in 192 multiplex Pakistani and Iranian consanguineous families with non-syndromic ID. We identified definite or candidate mutations (or CNVs) in 51% of families in 72 different genes, including 26 not previously reported for ARID. The new ARID genes include nine with loss-of-function mutations (ABI2, MAPK8, MPDZ, PIDD1, SLAIN1, TBC1D23, TRAPPC6B, UBA7 and USP44), and missense mutations include the first reports of variants in BDNF or TET1 associated with ID. The genes identified also showed overlap with de novo gene sets for other neuropsychiatric disorders. Transcriptional studies showed prominent expression in the prenatal brain. The high yield of AR mutations for ID indicated that this approach has excellent clinical potential and should inform clinical diagnostics, including clinical whole exome and genome sequencing, for populations in which consanguinity is common. As with other AR disorders, the relevance will also apply to outbred populations.Molecular Psychiatry advance online publication, 11 April 2017; doi:10.1038/mp.2017.60.

  3. Molecular analysis of a consanguineous Iranian polycystic kidney disease family identifies a PKD2 mutation that aids diagnostics.

    PubMed

    Vazifehmand, Reza; Rossetti, Sandro; Saber, Sassan; Khorshid, Hamid Reza Khorram; Harris, Peter C

    2013-09-08

    Polycystic kidney diseases (PKD) are a group of monogenic disorders that are inherited dominantly (autosomal dominant PKD; ADPKD) or recessively, including, autosomal recessive PKD (ARPKD). A number of recessive, syndromic disorders also involve PKD but have a range of pleiotropic phenotypes beyond the kidney, and are enriched in consanguineous families. We describe here a consanguineous Iranian pedigree in which PKD was diagnosed in four generations, but also included cases with additional abnormalities, including mental retardation. We employed molecular screening to reveal the etiology of the PKD. Since the PKD seemed to be dominantly inherited, molecular diagnostics was performed by direct sequencing of the ADPKD genes, PKD1 and PKD2. Clinical and imaging data was collected on family members. The sequence analysis revealed a PKD2 single base-pair deletion, c.1142delG, and segregation was demonstrated in 16 PKD patients from different branches of the family. In keeping with other reports, the PKD2 phenotype in this family was overall mild, and characterized by conserved kidney function, although 12 cases had some evidence of renal insufficiency. Several younger mutation carriers had borderline or no clinical characteristics of ADPKD, while a patient that required a renal transplant at 14 y did not have the PKD2 mutation. The molecular analysis of an Iranian family showed that the PKD was due to a PKD2 mutation. The identification of the causative mutation allowed an accurate diagnosis in a number of individuals with equivocal imaging data. Consequently, these patients could be followed appropriately as at-risk individuals. In addition, the PKD2 diagnosis ruled out a syndromic form of PKD as the cause of the additional phenotypes in the family.

  4. Wolcott-Rallison Syndrome Is the Most Common Genetic Cause of Permanent Neonatal Diabetes in Consanguineous Families

    PubMed Central

    Rubio-Cabezas, Oscar; Patch, Ann-Marie; Minton, Jayne A. L.; Flanagan, Sarah E.; Edghill, Emma L.; Hussain, Khalid; Balafrej, Amina; Deeb, Asma; Buchanan, Charles R.; Jefferson, Ian G.; Mutair, Angham; Hattersley, Andrew T.; Ellard, Sian

    2009-01-01

    Context and Objective: Mutations in EIF2AK3 cause Wolcott-Rallison syndrome (WRS), a rare recessive disorder characterized by early-onset diabetes, skeletal abnormalities, and liver dysfunction. Although early diagnosis is important for clinical management, genetic testing is generally performed after the full clinical picture develops. We aimed to identify patients with WRS before any other abnormalities apart from diabetes are present and study the overall frequency of WRS among patients with permanent neonatal diabetes. Research Design and Methods: The coding regions of EIF2AK3 were sequenced in 34 probands with infancy-onset diabetes with a clinical phenotype suggestive of WRS (n = 28) or homozygosity at the WRS locus (n = 6). Results: Twenty-five probands (73.5%) were homozygous or compound heterozygous for mutations in EIF2AK3. Twenty of the 26 mutations identified were novel. Whereas a diagnosis of WRS was suspected before genetic testing in 22 probands, three patients with apparently isolated diabetes were diagnosed after identifying a large homozygous region encompassing EIF2AK3. In contrast to nonconsanguineous pedigrees, mutations in EIF2AK3 are the most common known genetic cause of diabetes among patients born to consanguineous parents (24 vs. < 2%). Age at diabetes onset and birth weight might be used to prioritize genetic testing in the latter group. Conclusions: WRS is the most common cause of permanent neonatal diabetes mellitus in consanguineous pedigrees. In addition to testing patients with a definite clinical diagnosis, EIF2AK3 should be tested in patients with isolated neonatal diabetes diagnosed after 3 wk of age from known consanguineous families, isolated populations, or countries in which inbreeding is frequent. PMID:19837917

  5. APOA5 Q97X Mutation Identified through homozygosity mapping causes severe hypertriglyceridemia in a Chilean consanguineous family

    PubMed Central

    2012-01-01

    Background Severe hypertriglyceridemia (HTG) has been linked to defects in LPL, APOC2, APOA5, LMF1 and GBIHBP1 genes. However, a number of severe HTG cases are probably caused by as yet unidentified mutations. Very high triglyceride plasma levels (>112 mmol/L at diagnosis) were found in two sisters of a Chilean consanguineous family, which is strongly suggestive of a recessive highly penetrant mutation. The aim of this study was to determine the genetic locus responsible for the severe HTG in this family. Methods We carried out a genome-wide linkage study with nearly 300,000 biallelic markers (Illumina Human CytoSNP-12 panel). Using the homozygosity mapping strategy, we searched for chromosome regions with excess of homozygous genotypes in the affected cases compared to non-affected relatives. Results A large homozygous segment was found in the long arm of chromosome 11, with more than 2,500 consecutive homozygous SNP shared by the proband with her affected sister, and containing the APOA5/A4/C3/A1 cluster. Direct sequencing of the APOA5 gene revealed a known homozygous nonsense Q97X mutation (p.Gln97Ter) found in both affected sisters but not in non-affected relatives nor in a sample of unrelated controls. Conclusion The Q97X mutation of the APOA5 gene in homozygous status is responsible for the severe hypertriglyceridemia in this family. We have shown that homozygosity mapping correctly pinpointed the genomic region containing the gene responsible for severe hypertriglyceridemia in this consanguineous Chilean family. PMID:23151256

  6. APOA5 Q97X mutation identified through homozygosity mapping causes severe hypertriglyceridemia in a Chilean consanguineous family.

    PubMed

    Dussaillant, Catalina; Serrano, Valentina; Maiz, Alberto; Eyheramendy, Susana; Cataldo, Luis Rodrigo; Chavez, Matías; Smalley, Susan V; Fuentes, Marcela; Rigotti, Attilio; Rubio, Lorena; Lagos, Carlos F; Martinez, José Alfredo; Santos, José Luis

    2012-11-15

    Severe hypertriglyceridemia (HTG) has been linked to defects in LPL, APOC2, APOA5, LMF1 and GBIHBP1 genes. However, a number of severe HTG cases are probably caused by as yet unidentified mutations. Very high triglyceride plasma levels (>112 mmol/L at diagnosis) were found in two sisters of a Chilean consanguineous family, which is strongly suggestive of a recessive highly penetrant mutation. The aim of this study was to determine the genetic locus responsible for the severe HTG in this family. We carried out a genome-wide linkage study with nearly 300,000 biallelic markers (Illumina Human CytoSNP-12 panel). Using the homozygosity mapping strategy, we searched for chromosome regions with excess of homozygous genotypes in the affected cases compared to non-affected relatives. A large homozygous segment was found in the long arm of chromosome 11, with more than 2,500 consecutive homozygous SNP shared by the proband with her affected sister, and containing the APOA5/A4/C3/A1 cluster. Direct sequencing of the APOA5 gene revealed a known homozygous nonsense Q97X mutation (p.Gln97Ter) found in both affected sisters but not in non-affected relatives nor in a sample of unrelated controls. The Q97X mutation of the APOA5 gene in homozygous status is responsible for the severe hypertriglyceridemia in this family. We have shown that homozygosity mapping correctly pinpointed the genomic region containing the gene responsible for severe hypertriglyceridemia in this consanguineous Chilean family.

  7. Pitfalls of homozygosity mapping: an extended consanguineous Bardet-Biedl syndrome family with two mutant genes (BBS2, BBS10), three mutations, but no triallelism.

    PubMed

    Laurier, Virginie; Stoetzel, Corinne; Muller, Jean; Thibault, Christelle; Corbani, Sandra; Jalkh, Nadine; Salem, Nabiha; Chouery, Eliane; Poch, Olivier; Licaire, Serge; Danse, Jean-Marc; Amati-Bonneau, Patricia; Bonneau, Dominique; Mégarbané, André; Mandel, Jean-Louis; Dollfus, Hélène

    2006-11-01

    The extensive genetic heterogeneity of Bardet-Biedl syndrome (BBS) is documented by the identification, by classical linkage analysis complemented recently by comparative genomic approaches, of nine genes (BBS1-9) that account cumulatively for about 50% of patients. The BBS genes appear implicated in cilia and basal body assembly or function. In order to find new BBS genes, we performed SNP homozygosity mapping analysis in an extended consanguineous family living in a small Lebanese village. This uncovered an unexpectedly complex pattern of mutations, and led us to identify a novel BBS gene (BBS10). In one sibship of the pedigree, a BBS2 homozygous mutation was identified, while in three other sibships, a homozygous missense mutation was identified in a gene encoding a vertebrate-specific chaperonine-like protein (BBS10). The single patient in the last sibship was a compound heterozygote for the above BBS10 mutation and another one in the same gene. Although triallelism (three deleterious alleles in the same patient) has been described in some BBS families, we have to date no evidence that this is the case in the present family. The analysis of this family challenged linkage analysis based on the expectation of a single locus and mutation. The very high informativeness of SNP arrays was instrumental in elucidating this case, which illustrates possible pitfalls of homozygosity mapping in extended families, and that can be explained by the rather high prevalence of heterozygous carriers of BBS mutations (estimated at one in 50 in Europeans).

  8. Reduced bone mineral density and hyaloid vasculature remnants in a consanguineous recessive FEVR family with a mutation in LRP5.

    PubMed

    Downey, L M; Bottomley, H M; Sheridan, E; Ahmed, M; Gilmour, D F; Inglehearn, C F; Reddy, A; Agrawal, A; Bradbury, J; Toomes, C

    2006-09-01

    Familial exudative vitreoretinopathy (FEVR) is an inherited blinding condition characterised by abnormal development of the retinal vasculature. FEVR has multiple modes of inheritance, and homozygous mutations in LRP5 have recently been reported as underlying the recessive form of this disease. The aim of this study was to examine LRP5 in a consanguineous recessive FEVR family and to clarify the eye and bone phenotype associated with recessive FEVR. All family members were examined by slit lamp biomicroscopy and indirect ophthalmoscopy. Linkage to LRP5 was determined by genotyping microsatellite markers, constructing haplotypes and calculating lod scores. Mutation screening of LRP5 was performed by polymerase chain reaction amplification of genomic DNA followed by direct sequencing. Bone mineral density (BMD) was evaluated in all family members using dual energy x ray absorptiometry (DEXA). The clinical features observed in this family were consistent with a diagnosis of recessive FEVR. A homozygous LRP5 missense mutation, G550R, was identified in all affected individuals and all unaffected family members screened were heterozygous carriers of this mutation. Reduced BMD, hyaloid vasculature remnants, and nystagmus were features of the phenotype. Recessive mutations in LRP5 can cause FEVR with reduced BMD and hyaloid vasculature remnants. Assessment of a patient with a provisional diagnosis of FEVR should therefore include investigation of BMD, with reduced levels suggestive of an underlying LRP5 mutation.

  9. Reduced bone mineral density and hyaloid vasculature remnants in a consanguineous recessive FEVR family with a mutation in LRP5

    PubMed Central

    Downey, L M; Bottomley, H M; Sheridan, E; Ahmed, M; Gilmour, D F; Inglehearn, C F; Reddy, A; Agrawal, A; Bradbury, J; Toomes, C

    2006-01-01

    Background/aims Familial exudative vitreoretinopathy (FEVR) is an inherited blinding condition characterised by abnormal development of the retinal vasculature. FEVR has multiple modes of inheritance, and homozygous mutations in LRP5 have recently been reported as underlying the recessive form of this disease. The aim of this study was to examine LRP5 in a consanguineous recessive FEVR family and to clarify the eye and bone phenotype associated with recessive FEVR. Methods All family members were examined by slit lamp biomicroscopy and indirect ophthalmoscopy. Linkage to LRP5 was determined by genotyping microsatellite markers, constructing haplotypes and calculating lod scores. Mutation screening of LRP5 was performed by polymerase chain reaction amplification of genomic DNA followed by direct sequencing. Bone mineral density (BMD) was evaluated in all family members using dual energy x ray absorptiometry (DEXA). Results The clinical features observed in this family were consistent with a diagnosis of recessive FEVR. A homozygous LRP5 missense mutation, G550R, was identified in all affected individuals and all unaffected family members screened were heterozygous carriers of this mutation. Reduced BMD, hyaloid vasculature remnants, and nystagmus were features of the phenotype. Conclusion Recessive mutations in LRP5 can cause FEVR with reduced BMD and hyaloid vasculature remnants. Assessment of a patient with a provisional diagnosis of FEVR should therefore include investigation of BMD, with reduced levels suggestive of an underlying LRP5 mutation. PMID:16929062

  10. Novel ADAM9 homozygous mutation in a consanguineous Egyptian family with severe cone-rod dystrophy and cataract.

    PubMed

    El-Haig, Wael M; Jakobsson, Cecilia; Favez, Tatiana; Schorderet, Daniel F; Abouzeid, Hana

    2014-12-01

    To genetically and phenotypically describe a new ADAM9 homozygous mutation in a consanguineous family from Egypt with autosomal recessive cone-rod dystrophy (arCRD), anterior polar and posterior subcapsular cataract. The parents and their six children were included. They underwent a complete ophthalmic examination with fundus photography and optical coherence tomography (OCT). DNA was extracted from peripheral blood from all family members. Screening for mutations in genes known to be implicated in retinal disorders was done with the IROme, an in-solution enrichment array, followed by high-throughput sequencing. Validation of the results was done by bidirectional Sanger sequencing of ADAM9 exon 14, including exon-intron junctions. Screening of normal controls was done by denaturing high-performance liquid chromatography. arCRD was diagnosed in the mother and two of her children. Bilateral anterior polar and posterior subcapsular cataract was observed in the mother and bilateral dot cataract was diagnosed in three of the four children not affected with arCRD, one of whom also had glaucoma. The characteristics of the arCRD were childhood-onset visual impairment, reorganisation of the retinal pigment epithelium with mid-periphery greyish-white discolouration, attenuated retinal vasculatur and optic disc pallor. A coloboma-like macular lesion was observed in one of the arCRD-affected children. IROme analysis identified a c.1396-2A>G homozygous mutation in the splice acceptor site of intron 13 of ADAM9. This mutation was homozygous in the two children affected by arCRD and in their affected mother. This mutation was heterozygous in the unaffected father and the four unaffected children. We identified a novel autosomal recessive ADAM9 mutation causing arCRD in a consanguineous Egyptian family. The percentage of arCRD cases caused by mutation in ADAM9 remains to be determined. Few families are reported in the literature to date; hence extensive clinical descriptions of

  11. Novel sequence variants in the LIPH and LPAR6 genes underlies autosomal recessive woolly hair/hypotrichosis in consanguineous families.

    PubMed

    Ahmad, Farooq; Sharif, Salma; Furqan Ubaid, Muhammad; Shah, Khadim; Khan, Muhammad Nasim; Umair, Muhammad; Azeem, Zahid; Ahmad, Wasim

    2017-04-19

    Autosomal-recessive woolly hair/hypotrichosis (ARWH/H) is a rare genetic disorder of hair caused by variants in the LIPH and LPAR6 genes. The disease is characterized by congenital tightly curled hair leading to sparse hair later in life. In the present report genetic characterization of three consanguineous families of Pakistani origin, displaying clinical features of ARWH/H, was performed. Haplotype and DNA sequence analysis of the LIPH gene revealed a novel homozygous nonsense variant (c.688C > T; p.Gln230*) in family A. In two other families, B and C, sequence analysis of the LPAR6 gene revealed a novel homozygous frameshift variant (c.68_69dupGCAT; p.Phe24Hisfs*29) and a previously reported missense variant (c.188A > T; p.Asp63Val), respectively. Taken together, our findings will expand the spectrum of variants reported in the LIPH and LPAR6 genes. © 2017 Japanese Teratology Society.

  12. A novel mutation in PGAP2 gene causes developmental delay, intellectual disability, epilepsy and microcephaly in consanguineous Saudi family.

    PubMed

    Naseer, Muhammad Imran; Rasool, Mahmood; Jan, Mohammed M; Chaudhary, Adeel G; Pushparaj, Peter Natesan; Abuzenadah, Adel M; Al-Qahtani, Mohammad H

    2016-12-15

    PGAP2 (Post-GPI Attachment to Proteins 2) gene is involved in lipid remodeling steps of Glycosylphosphatidylinositol (GPI)-anchor maturation. At the surface of the cell this gene is required for proper expression of GPI-anchored proteins. Hyperphosphatasia with mental retardation syndrome-3 is an autosomal recessive disorder usually characterized by severe mental retardation. Mutations in the PGAP2 gene cause hyperphosphatasia mental retardation syndrome-3. We have identified a large consanguineous family from Saudi origin segregating developmental delay, intellectual disability, epilepsy and microcephaly. Whole exome sequencing with 100× coverage was performed on two affected siblings of the family. Data analysis in the patient revealed a novel missense mutation c.191C>T in PGAP2 gene resulting in Alanine to Valine substitution (Ala64Val). The mutation was reconfirmed and validated by subsequent Sanger sequencing method. The mutation was ruled out in 100 unrelated healthy controls. We suggest that this pathogenic mutation disrupts the proper function of the gene proteins resulting in the disease state.

  13. Characterisation of severe rod-cone dystrophy in a consanguineous family with a splice site mutation in the MERTK gene.

    PubMed

    Charbel Issa, P; Bolz, H J; Ebermann, I; Domeier, E; Holz, F G; Scholl, H P N

    2009-07-01

    To characterise the ocular phenotype of a family segregating the splice site mutation c.2189+1G>T in the tyrosine kinase receptor gene MERTK. Five affected children of a consanguineous Moroccan family were investigated by ophthalmic examinations, including fundus photography, autofluorescence (FAF) imaging, optical coherence tomography (OCT), psychophysical and electrophysiological methods. Affected children were between 5 and 19 years of age, allowing an estimation of disease progression. Electroretinography demonstrated loss of scotopic and photopic function in the first decade of life. Younger siblings showed drusen-like deposits with focal relatively increased FAF in the macular area. With increasing age, a yellowish lesion with relatively increased FAF and subsequent macular atrophy developed. Visual acuity deteriorated with age and ranged between 20/50 in the best eye of the youngest affected and 20/400 in the worst eye of the oldest affected sibling. Spectral-domain OCT revealed debris-like material in the subneurosensory space. The splice site mutation c.2189+1G>T in MERTK causes rod-cone dystrophy with a distinct macular phenotype. The debris in the subneurosensory space resembles that in the Royal College of Surgeons (RCS) rat being the mertk animal model. Patients might therefore benefit from advances in gene therapy that were previously achieved in the RCS rat.

  14. Dystrophic Epidermolysis Bullosa: COL7A1 Mutation Landscape in a Multi-Ethnic Cohort of 152 Extended Families with High Degree of Customary Consanguineous Marriages.

    PubMed

    Vahidnezhad, Hassan; Youssefian, Leila; Zeinali, Sirous; Saeidian, Amir Hossein; Sotoudeh, Soheila; Mozafari, Nikoo; Abiri, Maryam; Kajbafzadeh, Abdol-Mohammad; Barzegar, Mohammadreza; Ertel, Adam; Fortina, Paolo; Uitto, Jouni

    2017-03-01

    Dystrophic epidermolysis bullosa is a heritable skin disease manifesting with sub-lamina densa blistering, erosions, and chronic ulcers. COL7A1, encoding type VII collagen, has been identified as the candidate gene for dystrophic epidermolysis bullosa. In this study, we have identified COL7A1 mutations in a large multi-ethnic cohort of 152 extended Iranian families with high degree of consanguinity. The patients were diagnosed by clinical manifestations, histopathology, and immunoepitope mapping. Mutation detection consisted of a combination of single nucleotide polymorphism-based whole-genome homozygosity mapping, Sanger sequencing, and gene-targeted next-generation sequencing. A total of 104 distinct mutations in COL7A1 were identified in 149 of 152 families (98%), 56 (53%) of them being previously unreported. Ninety percent of these mutations were homozygous recessive, reflecting consanguinity in these families. Three recurrent mutations were identified in five or more families, and haplotype analysis suggested a founder effect in two of them. In conclusion, COL7A1 harbored mutations in the overwhelming majority of patients with dystrophic epidermolysis bullosa, and most of them in this Iranian cohort were consistent with autosomal recessive inheritance. The mutation profile attests to the impact of consanguinity in these families. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  15. Consanguinity on Robinson Crusoe Island, an isolated Chilean population.

    PubMed

    Villanueva, Pia; Fernández, Maria A; De Barbieri, Zulema; Palomino, Hernán

    2014-07-01

    The population of Robinson Crusoe Island is estimated at 633 inhabitants. The current population has a common origin from the first eight families who colonized the island at the end of the 19th century. The objective of this study was to determine the rates of consanguinity, the average coefficients of inbreeding, the types of consanguineous marriages and the inbreeding evolution between 1900 and 2000 on the island. All marriages registered on the island, from the last colonization until 2000 (417 in total), were included in the analysis. In addition, extended genealogies were obtained. The consanguinity rate was 14.9% and the average coefficient of inbreeding (α) 54.05 × 10(-4). The most frequent type of consanguineous marriages was between second cousins, followed by first cousins. The average value of the first/second cousin ratio was 1.11. The population of Robinson Crusoe Island has a high rate of inbreeding. The unique characteristic of the island - its small current population, originating from just a few families, with small rate of gene flow - could explain the observed high and increasing consanguinity.

  16. Novel homozygous large deletion including the 5′ part of the SPATA7 gene in a consanguineous Israeli Muslim Arab family

    PubMed Central

    Mayer, Anja-Kathrin; Mahajnah, Muhammad; Zobor, Ditta; Bonin, Michael; Sharkia, Rajech

    2015-01-01

    Purpose To identify the genetic defect in a consanguineous Israeli Muslim Arab family with juvenile retinitis pigmentosa (RP). Methods DNA samples were collected from the index patient, her parents, her affected sister, and two non-affected siblings. Genome-wide linkage analysis with 250 K single nucleotide polymorphism (SNP) arrays was performed using DNA from the two affected patients. Owing to consanguinity in the family, we applied homozygosity mapping to identify the disease-causing gene. The candidate gene SPATA7 was screened for mutations with PCR amplifications and direct Sanger sequencing. Results Following high-density SNP arrays, we identified several homozygous genomic regions one of which included the SPATA7 gene. Several mutations in SPATA7 have been reported for various forms of retinal dystrophy, including Leber congenital amaurosis (LCA) and juvenile RP. PCR-based sequence content mapping, long-distance PCR amplifications, and subsequent sequencing analysis revealed a homozygous 63.4 kb large deletion that encompasses the 5′ part of the SPATA7 gene including exons 1–5. The mutation showed concordant segregation with the phenotype in the family as expected for autosomal recessive mode of inheritance and is consistent with a diagnosis of juvenile RP. Conclusions We report a novel homozygous large deletion in SPATA7 associated with juvenile RP in a consanguineous Israeli Muslim Arab family. This is the first larger deletion mutation reported for SPATA7. PMID:25814828

  17. A novel frameshift mutation in FGA (c.1846 del A) leading to congenital afibrinogenemia in a consanguineous Syrian family.

    PubMed

    Levrat, Emmanuel; Aboukhamis, Imad; de Moerloose, Philippe; Farho, Jaafar; Chamaa, Sahar; Reber, Guido; Fort, Alexandre; Neerman-Arbez, Marguerite

    2011-03-01

    Congenital afibrinogenemia is a rare autosomal recessive coagulation disorder characterized essentially by bleeding symptoms, but miscarriages and, paradoxically, thromboembolic events can also occur. Most reported mutations leading to congenital afibrinogenemia are located in FGA encoding the fibrinogen A α-chain. In this study, we analysed 12 individuals from a consanguineous Syrian family with reduced or absent fibrinogen levels: those with fibrinogen levels around 1 g/l (n = 7) were found to be heterozygous for a novel frameshift mutation in FGA exon 5 (c.1846 del A) and those with undetectable fibrinogen levels (n = 5) were homozygous for the same mutation. This novel frameshift mutation is the most C-terminal causative FGA mutation identified to date in afibrinogenemic patients. The resulting aberrant Aα-chain (p.Thr616HisfsX32) is most likely synthesized, but is less efficiently assembled and/or secreted into the circulation given the phenotype of asymptomatic hypofibrinogenemia in heterozygous individuals and bleeding diathesis in homozygous individuals.

  18. Increased Probability of Co-Occurrence of Two Rare Diseases in Consanguineous Families and Resolution of a Complex Phenotype by Next Generation Sequencing

    PubMed Central

    Lal, Dennis; Neubauer, Bernd A.; Toliat, Mohammad R.; Altmüller, Janine; Thiele, Holger; Nürnberg, Peter; Kamrath, Clemens; Schänzer, Anne; Sander, Thomas; Hahn, Andreas; Nothnagel, Michael

    2016-01-01

    Massively parallel sequencing of whole genomes and exomes has facilitated a direct assessment of causative genetic variation, now enabling the identification of genetic factors involved in rare diseases (RD) with Mendelian inheritance patterns on an almost routine basis. Here, we describe the illustrative case of a single consanguineous family where this strategy suffered from the difficulty to distinguish between two etiologically distinct disorders, namely the co-occurrence of hereditary hypophosphatemic rickets (HRR) and congenital myopathies (CM), by their phenotypic manifestation alone. We used parametric linkage analysis, homozygosity mapping and whole exome-sequencing to identify mutations underlying HRR and CM. We also present an approximate approach for assessing the probability of co-occurrence of two unlinked recessive RD in a single family as a function of the degree of consanguinity and the frequency of the disease-causing alleles. Linkage analysis and homozygosity mapping yielded elusive results when assuming a single RD, but whole-exome sequencing helped to identify two mutations in two genes, namely SLC34A3 and SEPN1, that segregated independently in this family and that have previously been linked to two etiologically different diseases. We assess the increase in chance co-occurrence of rare diseases due to consanguinity, i.e. under circumstances that generally favor linkage mapping of recessive disease, and show that this probability can increase by several orders of magnitudes. We conclude that such potential co-occurrence represents an underestimated risk when analyzing rare or undefined diseases in consanguineous families and should be given more consideration in the clinical and genetic evaluation. PMID:26789268

  19. Novel splice-site mutation in TTLL5 causes cone dystrophy in a consanguineous family

    PubMed Central

    Dias, Miguel de Sousa; Hamel, Christian P.; Meunier, Isabelle; Varin, Juliette; Blanchard, Steven; Boyard, Fiona; Sahel, José-Alain

    2017-01-01

    Purpose To report the clinical and genetic findings of one family with autosomal recessive cone dystrophy (CD) and to identify the causative mutation. Methods An institutional study of three family members from two generations. The clinical examination included best-corrected Snellen visual acuity measurement, fundoscopy, the Farnsworth D-15 color vision test, a full-field electroretinogram (ERG) that incorporated the International Society for Clinical Electrophysiology of Vision standards and methodology, fundus autofluorescence (FAF) and infrared (IR), and spectral-domain optical coherence tomography (SD-OCT). Genetic findings were achieved with DNA analysis using whole exome sequencing (WES) and Sanger sequencing. Results The proband, a 9-year-old boy, presented with a condition that appeared to be congenital and stationary. The clinical presentation initially reflected incomplete congenital stationary night blindness (icCSNB) because of myopia, a decrease in visual acuity, abnormal oscillatory potentials, and reduced amplitudes on the 30 Hz flicker ERG but was atypical because there were no clear electronegative responses. However, no disease-causing mutations in the genes underlying icCSNB were identified. Following WES analysis of family members, a homozygous splice-site mutation in intron 3 of TTLL5 (c.182–3_182–1delinsAA) was found cosegregating within the phenotype in the family. Conclusions The distinction between icCSNB and CD phenotypes is not always straightforward in young patients. The patient was quite young, which most likely explains why the progression of the CD was not obvious. WES analysis provided prompt diagnosis for this family; thus, the use of this technique to refine the diagnosis is highlighted in this study. PMID:28356705

  20. Utility of large consanguineous family-based model for investigating the genetics of type 2 diabetes mellitus.

    PubMed

    Al-Sinani, Sawsan; Hassan, Mohammed Othman; Zadjali, Fahad; Al-Yahyaee, Said; Albarwani, Sulayma; Rizvi, Syed; Jaju, Deepali; Comuzzie, Anthony; Voruganti, Venkata Saroja; Bayoumi, Riad

    2014-09-10

    This study examined the utility of a family-based model for replicating the results of genome-wide association studies (GWAS) of type 2 diabetes (T2D). In a total of 232 members of a large consanguineous Omani Arab pedigree (age: 16-80years), there were 27 diabetics and 50 prediabetics (17 with impaired fasting glucose and 33 with impaired glucose tolerance). All 232 individuals underwent anthropometric and biochemical investigations and genotyped for 14 known common gene variants of modest effect on T2D risk. Power analysis at a LOD score of 3, gave 80% power to locate a single specific locus that accounts for 52% of the total phenotypic variation. Measured genotype analysis (MGA) was used to determine heritability of various quantitative traits (QTs) which ranged 25-56%. Using MGA, some common gene variants were found to have little (<5%) but significant impact on the heritability of T2D related QTs [KCNJ11 (rs5219), p=0.004]; [IGF2BP2 (rs4402960), p=0.02]; [SLC30A8 (rs13266634), p=0.05]; [CAPN10 (rs2975760), p=0.031]; [FTO (rs8050136), p=0.023]; [FTO (rs9939609), p=0.018] and [SLC30A8 (rs13266634), p=0.05]. Sib-TDT analysis showed that some gene variants were significantly associated with T2D risk but didn't reach the level of significance after Bonferroni correction [KCNJ11 (rs5219), p=0.047] and [CAPN10 (rs41266971), p=0.035]. We have demonstrated that, in principle, a family-based model with minor limitations could be used to replicate some of the results of large GWAS case-control studies. This model could successfully be applied for the future discovery, by deep sequencing, of rare gene variants. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Novel nonsense mutation in the PTRF gene underlies congenital generalized lipodystrophy in a consanguineous Saudi family.

    PubMed

    Jelani, Musharraf; Ahmed, Saleem; Almramhi, Mona Mohammad; Mohamoud, Hussein Sheikh Ali; Bakur, Khadijah; Anshasi, Waseem; Wang, Jun; Al-Aama, Jumana Yousuf

    2015-04-01

    Congenital generalized lipodystrophies (CGLs) are a heterogeneous group of rare, monogenic disorders characterized by loss of sub-cutaneous fat, muscular hypertrophy, acanthosis nigricans, hepatomegaly, cardiac arrhythmias, impaired metabolism and mental retardation. Four different but overlapping phenotypes (CGL1-4) have been identified, which are caused by mutations in AGPAT2 at 9q34.3, BSCL2 at 11q13, CAV1 at 7q31.1, and PTRF at 17q21.2. In this study, we performed genome-wide homozygosity mapping of two affected and one unaffected subject in a Saudi family using a 300K HumanCytoSNPs12v12.1 array with the Illumina iScan system. A common homozygous region at chromosome 17q22.1, from 34.4 to 45.3 Mb, was identified in both the affected individuals. The region is flanked by SNPs rs139433362 and rs185263326, which encompass the PTRF gene. Bidirectional DNA sequencing of the PTRF gene covering all of the coding exons and exon-intron boundaries was performed in all family members. Sequencing analysis identified a novel homozygous nonsense mutation in the PTRF gene (c.550G>T; p.Glu184*), leading to a premature stop codon. To the best of our knowledge, we present a novel mutation of PTRF from Saudi Arabia and our findings broaden the mutation spectrum of PTRF in the familial CGL4 phenotype. Homozygosity mapping coupled with candidate gene sequencing is an effective tool for identifying the causative pathogenic variants in familial cases. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  2. An exceptional mutational event leading to Chanarin-Dorfman syndrome in a large consanguineous family.

    PubMed

    Samuelov, L; Fuchs-Telem, D; Sarig, O; Sprecher, E

    2011-06-01

    Chanarin-Dorfman syndrome (CDS) is a rare autosomal recessive metabolic disorder featuring congenital ichthyosis combined with pleiomorphic visceral manifestations associated with tissue accumulation of cytoplasmic lipid droplets. Mutations in the ABHD5 gene, encoding a crucial cofactor for adipose triglyceride lipase, have been found to underlie all CDS cases reported to date. The purposed of this study was to ascertain the genetic defect underlying CDS in a large multigenerational family. We used a combination of direct sequencing, reverse transcriptase-polymerase chain reaction (RT-PCR) and microsatellite marker genotyping to identify a novel CDS-causing mutation in ABHD5. Although no pathogenic mutation could be identified in the coding sequence of the ABHD5 gene, polymorphic marker genotyping analysis supported linkage to this gene locus. Accordingly, direct sequencing of RT-PCR amplification products generated from patient skin-derived total RNA, revealed in all four patients the presence of a 101 bp insertion between exon 3 and exon 4. Bioinformatic analysis and direct sequencing indicated that this insertion resulted from an exceptional mutational event, namely, the insertion of a LINE element into intron 3 of the ABHD5 gene, leading to aberrant splicing out of the mutant intron 3. Our results confirm genetic homogeneity in CDS and underscore the importance of RNA studies in the molecular diagnosis of genodermatoses. © 2011 The Authors. BJD © 2011 British Association of Dermatologists.

  3. A novel mutation in FGD4/FRABIN causes Charcot Marie Tooth disease type 4H in patients from a consanguineous Tunisian family.

    PubMed

    Boubaker, Chokri; Hsairi-Guidara, Inès; Castro, Christel; Ayadi, Ines; Boyer, Amandine; Kerkeni, Emna; Courageot, Joël; Abid, Imen; Bernard, Rafaëlle; Bonello-Palot, Nathalie; Kamoun, Fatma; Cheikh, Hassen Ben; Lévy, Nicolas; Triki, Chahnez; Delague, Valérie

    2013-07-01

    Charcot-Marie-Tooth (CMT) disease constitutes a clinically and genetically heterogeneous group of hereditary neuropathies characterized by progressive muscular and sensory loss in the distal extremities with chronic distal weakness, deformation of the feet, and loss of deep tendon reflexes. CMT4H is an autosomal recessive demyelinating subtype of CMT, due to mutations in FGD4/FRABIN, for which nine mutations are described to date. In this study, we describe three patients from a consanguineous Tunisian family, presenting with severe, early onset, slowly progressive, autosomal recessive demyelinating CMT, complicated by mild to severe kyphoscoliosis, consistent with CMT4H. In these patients, we report the identification of a novel homozygous frameshift mutation in FGD4: c.514_515insG; p.Ala172Glyfs*27. Our study reports the first mutation identified in FGD4 in Tunisian patients affected with CMT. It further confirms the important clinical heterogeneity observed in patients with mutations in FGD4 and the lack of phenotype/genotype correlations in CMT4H. Our results suggest that FGD4 should be screened in other early-onset CMT subtypes, regardless of the severity of the phenotype, and particularly in patients of consanguineous descent. In Tunisians, as in other populations with high consanguinity rates, screening of genes responsible for rare autosomal recessive CMT subtypes should be prioritized. © 2013 John Wiley & Sons Ltd/University College London.

  4. Consanguinity, human evolution, and complex diseases

    PubMed Central

    Bittles, A. H.; Black, M. L.

    2010-01-01

    There is little information on inbreeding during the critical early years of human existence. However, given the small founding group sizes and restricted mate choices it seems inevitable that intrafamilial reproduction occurred and the resultant levels of inbreeding would have been substantial. Currently, couples related as second cousins or closer (F ≥ 0.0156) and their progeny account for an estimated 10.4% of the global population. The highest rates of consanguineous marriage occur in north and sub-Saharan Africa, the Middle East, and west, central, and south Asia. In these regions even couples who regard themselves as unrelated may exhibit high levels of homozygosity, because marriage within clan, tribe, caste, or biraderi boundaries has been a long-established tradition. Mortality in first-cousin progeny is ≈3.5% higher than in nonconsanguineous offspring, although demographic, social, and economic factors can significantly influence the outcome. Improving socioeconomic conditions and better access to health care will impact the effects of consanguinity, with a shift from infant and childhood mortality to extended morbidity. At the same time, a range of primarily social factors, including urbanization, improved female education, and smaller family sizes indicate that the global prevalence of consanguineous unions will decline. This shift in marriage patterns will initially result in decreased homozygosity, accompanied by a reduction in the expression of recessive single-gene disorders. Although the roles of common and rare gene variants in the etiology of complex disease remain contentious, it would be expected that declining consanguinity would also be reflected in reduced prevalence of complex diseases, especially in population isolates. PMID:19805052

  5. Pendred syndrome in a large consanguineous Brazilian family caused by a homozygous mutation in the SLC26A4 gene.

    PubMed

    Lofrano-Porto, Adriana; Barra, Gustavo B; Nascimento, Paula P; Costa, Patrícia G G; Garcia, Erica C; Vaz, Rodrigo F; Batista, Ana R T; Freitas, Ana C R de; Cherulli, Bruno L B; Bahmad, Fayez; Figueiredo, Larissa G; Neves, Francisco A R; Casulari, Luiz Augusto

    2008-11-01

    Pendred Syndrome (PS) is an autossomal recessive disorder characterized by sensorineural deafness, goiter and iodide organification defect. The hearing loss is associated with inner ear abnormalities, ranging from an isolated enlarged vestibular aqueduct (EVA) to a typical coclear dysplasia. Mutations in the gene that encodes pendrin (SLC26A4), a chloride/iodide transporter, have been shown to be associated with PS. We describe the clinical and molecular characteristics of a large consanguineous family harboring a mutation in the SLC26A4 gene. The proband was a 26-year-old deaf Brazilian woman who presented a bulky multinodular goiter and hypothyroidism since puberty. Five other siblings were deaf: one brother had a similar phenotype, three siblings also had goiters but normal thyroid function tests, and one brother had only a subtle thyroid enlargement. Other 4 siblings had no thyroid or hearing disorder. Parents were first degree cousins and had normal hearing. The mother was healthy, except for subclinical hypothyroidism; the father was deceased. A perchlorate test in the proband showed a discharge of 21% of the incorporated iodide 2h after the administration of 1g of KClO4. Audiological examinations showed profound hearing loss in all deaf subjects; CT and MRI of the temporal bones showed EVA in all of them. Genomic DNA was isolated from whole blood, from the 6 affected and 4 unaffected siblings, the mother and control. The coding region of the PDS gene (exons 2-21), including exon/intron boundaries, were amplified by PCR and sequenced. A single base-pair (T) deletion at position 1197 of exon 10 was detected in homozygous state in the 6 deaf siblings. The mother and 2 unaffected siblings were heterozygous for this mutation, which has been described by Everett et al. The 1197delT mutation is predicted to result in a frameshift and a truncated protein. The existence of PS phenocopies and intrafamilial phenotypic variability are well documented. The definite

  6. Trends in consanguinity in South India.

    PubMed

    Krishnamoorthy, S; Audinarayana, N

    2001-04-01

    This study uses data from the 1992-93 National Family Health Survey to assess trends in consanguinity in the South Indian states of Andhra Pradesh, Karnataka, Kerala and Tamil Nadu. In Kerala, the frequency of consanguineous marriages is very low and one type of preferred marriage of the Dravidian marriage system uncle niece marriage--is conspicuously absent. In the other states of South India, consanguinity and the coefficient of inbreeding are high. While no change in consanguinity is observed during the past three to four decades in Karnataka, a definite decline is observed in Andhra Pradesh and Tamil Nadu. Due to recent changes in the demographic and social situation in these states, this decline in consanguinity is likely to continue.

  7. Novel homozygous mutations in the EVC and EVC2 genes in two consanguineous families segregating autosomal recessive Ellis-van Creveld syndrome.

    PubMed

    Aziz, Abdul; Raza, Syed I; Ali, Salman; Ahmad, Wasim

    2016-01-01

    Ellis-van Creveld syndrome (EVC) is a rare developmental disorder characterized by short limbs, short ribs, postaxial polydactyly, dysplastic nails, teeth, oral and cardiac abnormalities. It is caused by biallelic mutations in the EVC or EVC2 gene, separated by 2.6 kb of genomic sequence on chromosome 4p16. In the present study, we have investigated two consanguineous families of Pakistani origin, segregating EVC in autosomal recessive manner. Linkage in the families was established to chromosome 4p16. Subsequently, sequence analysis identified a novel nonsense mutation (p.Trp234*) in exon 8 of the EVC2 gene and 15 bp duplication in exon 14 of the EVC gene in the two families. This further expands the mutations in the EVC or EVC2 genes resulting in the EVC syndrome.

  8. Identification of a novel mutation in FOXL2 gene that leads to blepharophimosis ptosis epicanthus inversus and telecanthus syndrome in a Tunisian consanguineous family.

    PubMed

    Chouchene, Ibtissem; Derouiche, Kaouthar; Chaabouni, Afif; Cherif, Lamia; Amouri, Ahlem; Largueche, Leila; Abdelhak, Sonia; El Matri, Leila

    2010-02-01

    Mutations in FOXL2 gene are responsible for blepharophimosis ptosis epicanthus inversus and telecanthus syndrome (BPES). The BPES syndrome is a rare autosomal dominant genetic disease characterized by eyelid malformations associated with premature ovarian failure (BPES type I) or not (BPES type II). The human FOXL2 protein (376 aa) contains a 100 amino-acid DNA-binding forkhead domain (residues 52-152) and a polyalanine tract (residues 221-234). In the present study, we report the molecular investigation of four affected members with BPES syndrome in a Tunisian consanguineous family. To identify the causative mutation, we performed a direct sequencing of the FOXL2 gene. The sequence analysis of the coding exon revealed a novel frameshift mutation g.1113 dup C, c.876 dup C, p.P292 Fs. The mutation is located downstream of the polyalanine tract and causes the protein extension to 532 aa. This study reports for the first time a novel frameshift mutation in two-generation consanguineous Tunisian family with BPES. Our results expand the spectrum of FOXL2 mutations.

  9. Consanguinity in Kahramanmaras city, Turkey, and its medical impact.

    PubMed

    Donbak, Lale

    2004-12-01

    Recently, several studies have indicated the rate of consanguinity ranging between 20 and 70% in the Middle East. Turkey is one of the countries with a high rate of consanguineous unions in the Middle East. In this study, the rate of consanguinity and its effects on spontaneous abortus, stillbirth, infant mortality, and birth defects were investigated in a population sample residing in Kahramanmaras city, Turkey. For this study, 1000 randomly selected women, aboriginals of Kahramanmaras city, Turkey, were interviewed at their home and the concerning information was obtained by administration of a questionnaire between April 2002 and March 2003. The prevalence of consanguinity was found to be 30.6% with the mean inbreeding coefficient of 0.015373. The most common type of consanguineous mating was first cousin marriages with the frequency of 22.6%. The family pressure and love were the main reasons for marrying with a relative. The mean age at marriage of women and men were lower in consanguineous marriages than that of non-consanguineous unions. There was a negative correlation between the consanguinity and educational level of both sexes. The results revealed differences between consanguineous and non-consanguineous matings, in terms of stillbirth, infant mortality and birth defects whereas the rate of spontaneous abortus was found to be the same in 2 kinds of marriages. The incidence of consanguinity and of first cousin marriages is found to be very high in the Kahramanmaras city. A reduction of consanguinity rate is necessary for the health quality of the population.

  10. Bloom syndrome: An analysis of consanguineous families assigns the locus mutated to chromosome band 15q26. 1

    SciTech Connect

    German, J.; Roe, A.M.; Ellis, N.A. ); Leppert, M.F. )

    1994-07-05

    By the principle of identity by descent, parental consanguinity in individuals with rare recessively transmitted disorders dictates homozygosity not just at the mutated disease-associated locus but also at sequences that flank that locus closely. In 25 of 26 individuals with Bloom syndrome examined whose parents were related, a polymorphic tetranucleotide repeat in an intron of the protooncogene FES was homozygous far more often than expected (P < 0.0001 by x[sup 2]). Therefore, BLM, the gene that when mutated gives rise to Bloom syndrome, is tightly linked to FES, a gene whose chromosome position is known to be 15q26.1. This successful approach to the assignment of the Bloom syndrome locus to one short segment of the human genome simultaneously (i) demonstrates the power of homozygosity mapping and (ii) becomes the first step in a [open quotes]reverse[close quotes] genetics definition of the primary defect in Bloom syndrome.

  11. Novel homozygous mutations in the WNT10B gene underlying autosomal recessive split hand/foot malformation in three consanguineous families.

    PubMed

    Aziz, Abdul; Irfanullah; Khan, Saadullah; Zimri, Faridullah Khan; Muhammad, Noor; Rashid, Sajid; Ahmad, Wasim

    2014-01-25

    Split-hand/split-foot malformation (SHFM), representing variable degree of median clefts of hands and feet, is a genetically heterogeneous group of limb malformations with seven loci mapped on different human chromosomes. However, only 3 genes (TP63, WNT10B, DLX5) for the seven loci have been identified. The study, presented here, described three consanguineous Pakistani families segregating SHFM in autosomal recessive manner. Linkage in the families was searched by genotyping microsatellite markers and mutation screening of candidate gene was performed by Sanger DNA sequencing. Clinical features of affected members of these families exhibited SHFM phenotype with involvement of hands and feet. Genotyping using microsatellite markers mapped the families to WNT10B gene at SHFM6 on chromosome 12q13.11-q13. Subsequently, sequence analysis of WNT10B gene revealed a novel 4-bp deletion mutation (c.1165_1168delAAGT) in one family and 7-bp duplication (c.300_306dupAGGGCGG) in two other families. Structure-based analysis showed a significant conformational shift in the active binding site of mutated WNT10B (p.Lys388Glufs*36), influencing binding with Fzd8. The mutations identified in the WNT10B gene extend the body of evidence implicating it in the pathogenesis of SHFM.

  12. A community genetics perspective on consanguineous marriage.

    PubMed

    Bittles, A H

    2008-01-01

    Consanguineous marriage has long been a controversial topic, with particular attention focused on adverse health outcomes. Unfortunately, the studies that have been conducted on consanguinity to date have usually lacked control for important sociodemographic variables, such as maternal age and birth intervals, and in estimating specific disease gene frequency, they have ignored the influence of population sub-division. Inadequate attention has also been paid to the social benefits associated with intra-familial marriage, resulting in a biased overall cost-benefit assessment. Worldwide, some 1,000 million people live in countries where 20 to more than 50% of marriages are consanguineous, and large migrant communities from these regions are now resident in Western Europe, North America and Oceania. The need for comprehensive and more balanced investigations into all aspects of consanguineous marriage is pressing and merits a substantial international collaborative research effort.

  13. Consanguinity and deafness in Omani children.

    PubMed

    Khabori, Mazin Al; Patton, Michael A

    2008-01-01

    This study was based on a national retrospective analysis of 1400 questionnaires on the causes of deafness in Omani children, collected from 1986 to 2000. It was found that 70% of the deaf children were from parents of consanguineous marriages, and 30% from non-consanguineous unions. In those with consanguineous families 70.16% were first cousin marriages, 17.54% were second cousins, and 10.86% were from the same tribe. The proportion arising from first cousin marriages was higher than the background rate of first cousin marriages in Oman. In the total cohort, 45% had other family members with hearing loss. There was a greater chance of other relatives being affected in the consanguineous group as opposed to the non-consanguineous group (29.7% versus 15.3%). In most cases the affected relative was a deaf sibling (67.8%). We have demonstrated a higher rate of consanguinity amongst parents of deaf children in Oman and suggest this is associated with a higher frequency of autosomal recessive deafness in this paediatric population.

  14. [Consanguinity and congenital abnormalities].

    PubMed

    Søgaard, Marie; Vedsted-Jakobsen, Agnete

    2003-04-28

    Knowledge of consanguinity is relevant for employees in the Danish national health service, since about 7.5% of the Danish population has another ethnic background than Danish and the majority comes from cultures where consanguineous marriages are not unusual. In the literature it is found that consanguineous couples have a higher risk of having children with congenital malformations. The risk is increased by a factor 2 to 2 1/2. The average risk in Denmark is about 3%. Primarily, the autosomal recessive diseases are expressed in children with consanguineous parents. In order to advise and diagnose it is essential to clarify the consanguinity state. In case of pregnancy with consanguineous parents, we recommend: 1) Counselling to estimate the risk of foetal illness and information about possible examination possibilities. 2) An ultrasound scan at the gestational age of 11-14 weeks in order to measure nuchal translucency and an early malformation scan. 3) An ultrasound scan for malformations at the gestational age of 18-20 weeks. 4) An ultrasound scan especially in order to detect foetal heart malformations at the gestational age of 20-24 weeks.

  15. [Endogamy and consanguinity in Mauritania].

    PubMed

    Hammami, Abdelmajid; Elgazzeh, Mohamed; Chalbi, Noureddine; Mansour, Ben Abdallah

    2005-01-01

    We examined the types of marriage between husband and wife and their frequency as well as the intensity of consanguinity for the Mauritanian ethnic groups. Then we evaluated for all the population, the variations of each of these dimensions according to the dates of marriage. The analisys of a sample of 2413 couples obtained according to the quota method showed that the Mauritanian population presents a strong family endogamy of about 47.20%. The Wolofs and the Poulards present pourcentages of marriages between blood relations of about 74.47% and of 55.74% respectively. On the other hand, for the Maures, black Maures and Soninkes, the proportions of marriages between blood relations are of the order of 41.25%, 30.52% and 46.99% respectively. This same analysis has also shown that the Mauritanian ethnic groupes present high apparent coefficient of consanguinity. They are of a level of unions between unequal cousins (1 /32) for (1/64) for others. The evaluation of endogamy practices in function of marriage dates (from 1921 to 1991) shows and for all the population a decline tendency in the pourcentages of consanguine marriages, and at the level of a whole Mauritanian population.

  16. Endogamy, consanguinity and community genetics.

    PubMed

    Bittles, A H

    2002-12-01

    The population of India is composed of many thousands of subpopulations, divided by geography, language, religion and caste or biraderi (patrilineage) boundaries, with endogamous marriage the norm. The net effect has been the creation of multiple genetic isolates with individual mutation profiles, but to date the clinical consequences of this highly complex differentiation have been largely ignored. In contrast, the topic of consanguinity continues to attract attention among medical and population geneticists, clinicians and social scientists. The significant progress made in India in improving childhood nutritional status and combating infectious disease means that genetic disorders have assumed ever-increasing importance. In populations where consanguineous marriage is widely practised, recessive genetic disorders will continue to gain greater prominence in the overall spectrum of ill health. At the same time this increase will in part be negated by urbanization and the move to smaller family sizes, which predictably will result in a decline in the prevalence of consanguineous unions. Developing an understanding of these changes will require a wide-ranging and multidisciplinary investigative approach for which community genetics is ideally suited.

  17. Clinical and molecular effect on offspring of a marriage of consanguineous spinocerebellar ataxia type 7 mutation carriers: a family case report

    PubMed Central

    Magaña, Jonathan J; Tapia-Guerrero, Yessica S; Velázquez-Pérez, Luis; Cruz-Mariño, Tania; Cerecedo-Zapata, Cesar M; Gómez, Rocío; Murillo-Melo, Nadia M; González-Piña, Rigoberto; Hernández-Hernández, Oscar; Cisneros, Bulmaro

    2014-01-01

    Spinocerebellar ataxia type 7 (SCA7) is a genetic disorder characterized by degeneration of the cerebellum, brainstem, and retina that is caused by abnormal expansion of a CAG repeat located in the ATXN7 gene encoding sequence on chromosome 3p21.1. Although SCA7 is an uncommon autosomal dominant ataxia, we previously found increased prevalence of the disease in a Southeastern Mexican population. In this study, we described to our knowledge for the first time a marriage of consanguineous SCA7 mutation carriers and their offspring effect. We characterized a severely affected infantile-onset female patient whose parents and two siblings exhibited no symptoms of the disease at time of diagnosis. A comprehensive clinical analysis of the proband showed a progressive cerebellar syndrome, including gait ataxia, movement disorders, and saccadic movements, as well as hyperreflexia, visual deterioration, urinary and cardiovascular dysfunction, and impaired nerve conduction. The SCA7 mutation was detected in the proband patient. Subsequently, genetic examination using four ATXN7 gene-linked markers (three centromeric microsatellite markers [D3S1228, D3S1287, and D3S3635] and an intragenic Single Nucleotide Polymorphism [SNP-3145G/A]) revealed that the proband descends from a couple of consanguineous SCA7 mutation carriers. Genotyping analysis demonstrated that all offspring inherited only one mutant allele, and that the severe infantile-onset phenotype is caused by germinal expansion (from 37 to 72 CAG repeats) of the paternal mutant allele. Interestingly, the couple also referred a miscarriage. Finally, we found no CAA interruptions in the ATXN7 gene CAG repeats tract in this family, which might explain, at least in part, the triplet instability in the proband. PMID:25664129

  18. Novel SIL1 nonstop mutation in a Chinese consanguineous family with Marinesco-Sjögren syndrome and Dandy-Walker syndrome.

    PubMed

    Gai, Nan; Jiang, Chen; Zou, Yong-Yi; Zheng, Yu; Liang, De-Sheng; Wu, Ling-Qian

    2016-07-01

    Marinesco-Sjögren syndrome (MSS) is a rare autosomal recessive disorder, which is characterized by congenital cataracts, cerebellar ataxia, progressive muscle weakness, and delayed psychomotor development. SIL1, which is located at 5q31.2, is the only gene known to cause MSS. Dandy-Walker syndrome (DWS) is defined by hypoplasia, upward rotation of the cerebellar vermis, and cystic dilation of the fourth ventricle; however, its genetic pathogeny remains unclear. Here, we report a Chinese consanguineous family with MSS and DWS. Whole exome sequencing identified a novel nonstop mutation in SIL1. Sanger sequencing revealed that the mutation was segregated in this family according to a recessive mode of inheritance. We found that the mutation changed a stop codon (TGA) to an arginine codon (CGA), and no in-frame termination codon in the 3' untranslated region (UTR) of SIL1 could be found. The mRNA levels of SIL1 were decreased by 56.6% and 37.5% in immortalized lymphoblasts of the patients respectively; the protein levels of SIL1 were substantially decreased. This case study is the first report on Chinese MSS patients, MSS complicated by DWS, and a nonstop mutation in SIL1. Our findings imply the pathogenetic association between DWS and MSS. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. Mutations in the LPAR6 and LIPH genes underlie autosomal recessive hypotrichosis/woolly hair in 17 consanguineous families from Pakistan.

    PubMed

    Khan, S; Habib, R; Mir, H; Umm-e-Kalsoom; Naz, G; Ayub, M; Shafique, S; Yamin, T; Ali, N; Basit, S; Wasif, N; Kamran-Ul-Hassan Naqvi, S; Ali, G; Wali, A; Ansar, M; Ahmad, W

    2011-08-01

    Autosomal recessive hypotrichosis/woolly hair is a rare genetic hair loss disorder characterized by sparse scalp hair/woolly hair, sparse to absent eyebrows and eyelashes, sparse axillary and body hair in affected individuals. This form of hair loss results from mutations in either LPAR6 or LIPH gene. To identify mutations in LPAR6 and LIPH genes in 17 consanguineous Pakistani families showing features of hypotrichosis/woolly hair. Genotyping in 17 families was carried out using polymorphic microsatellite markers linked to genes causing autosomal recessive hypotrichosis/woolly hair phenotype. To screen for mutations in LPAR6 and LIPH genes, all of their exons and splice junction sites were amplified by PCR and sequenced using an automated DNA sequencer. Genotyping with polymorphic microsatellite markers showed linkage in eight families to LPAR6 and in nine families to LIPH gene. Sequence analysis revealed four recurrent mutations (p.Phe24HisfsX28; p.Asp63Val; p.Gly146Arg; p.Ile188Phe) in LPAR6 and two recurrent mutations (p.Trp108Arg; p.Ile220ArgfsX29) in LIPH gene. Comparison of the haplotypes generated by typing LPAR6 and LIPH genes linked microsatellite markers in different families suggested common founder natures of the two mutations (c.66_69insCATG and c.659_660delTA). Mutations identified in the present study extend the body of evidence implicating LPAR6 and LIPH genes in pathogenesis of human hereditary hair loss. © The Author(s). CED © 2011 British Association of Dermatologists.

  20. Consanguinity and dysmorphology in Arabs.

    PubMed

    Al-Gazali, Lihadh; Hamamy, Hanan

    2014-01-01

    Incidence rates of congenital disorders among the 350 million inhabitants of Arab countries could be influenced via the people's demographic and cultural characteristics. Arabs usually marry at a young age and have large families. They share certain core cultural values and beliefs, with the family accepted as the central structure of society. Consanguineous marriage is favored and respected in most if not all Arab communities, and intrafamilial unions currently account for 20-50% of all marriages. First-cousin unions are especially popular and constitute almost one quarter of all marriages in many Arab countries. Consequently, autosomal recessive (AR) dysmorphic syndromes constitute a considerable proportion of all birth defects among Arabs. Arab geneticists, with their persistent commitment to advancing research, have contributed to the description of a number of rare and new AR syndromes with the identification of novel genes. The collaboration with research teams in high-income countries resulted in a plethora of data on pathogenic variants and their function in causing dysmorphic syndromes. There could still be a considerable number of rare dysmorphic syndromes that prevail among Arabs which are not hitherto described and whose underlying molecular pathologies are not yet defined. Arab countries should thus strive to deploy DNA diagnostics and to build research capability around local priorities. Furthermore, a characterization of the prevailing genetic disorders in each geographic location, together with their mutations, is needed to plan for appropriate screening and testing protocols. An overview of consanguinity in Arab countries and examples of dysmorphology syndromes associated with consanguinity with their available molecular bases will be discussed. © 2014 S. Karger AG, Basel

  1. Novel homozygous missense mutation in GAN associated with Charcot-Marie-Tooth disease type 2 in a large consanguineous family from Israel.

    PubMed

    Aharoni, Sharon; Barwick, Katy E S; Straussberg, Rachel; Harlalka, Gaurav V; Nevo, Yoram; Chioza, Barry A; McEntagart, Meriel M; Mimouni-Bloch, Aviva; Weedon, Michael; Crosby, Andrew H

    2016-11-16

    CMT-2 is a clinically and genetically heterogeneous group of peripheral axonal neuropathies characterized by slowly progressive weakness and atrophy of distal limb muscles resulting from length-dependent motor and sensory neurodegeneration. Classical giant axonal neuropathy (GAN) is an autosomal recessively inherited progressive neurodegenerative disorder of the peripheral and central nervous systems, typically diagnosed in early childhood and resulting in death by the end of the third decade. Distinctive phenotypic features are the presence of "kinky" hair and long eyelashes. The genetic basis of the disease has been well established, with over 40 associated mutations identified in the gene GAN, encoding the BTB-KELCH protein gigaxonin, involved in intermediate filament regulation. An Illumina Human CytoSNP-12 array followed by whole exome sequence analysis was used to identify the disease associated gene mutation in a large consanguineous family diagnosed with Charcot-Marie-Tooth disease type 2 (CMT-2) from which all but one affected member had straight hair. Here we report the identification of a novel GAN missense mutation underlying the CMT-2 phenotype observed in this family. Although milder forms of GAN, with and without the presence of kinky hair have been reported previously, a phenotype distinct from that was investigated in this study. All family members lacked common features of GAN, including ataxia, nystagmus, intellectual disability, seizures, and central nervous system involvement. Our findings broaden the spectrum of phenotypes associated with GAN mutations and emphasize a need to proceed with caution when providing families with diagnostic or prognostic information based on either clinical or genetic findings alone.

  2. Integration of Sequence Data from a Consanguineous Family with Genetic Data from an Outbred Population Identifies PLB1 as a Candidate Rheumatoid Arthritis Risk Gene

    PubMed Central

    Okada, Yukinori; Diogo, Dorothee; Greenberg, Jeffrey D.; Mouassess, Faten; Achkar, Walid A. L.; Fulton, Robert S.; Denny, Joshua C.; Gupta, Namrata; Mirel, Daniel; Gabriel, Stacy; Li, Gang; Kremer, Joel M.; Pappas, Dimitrios A.; Carroll, Robert J.; Eyler, Anne E.; Trynka, Gosia; Stahl, Eli A.; Cui, Jing; Saxena, Richa; Coenen, Marieke J. H.; Guchelaar, Henk-Jan; Huizinga, Tom W. J.; Dieudé, Philippe; Mariette, Xavier; Barton, Anne; Canhão, Helena; Fonseca, João E.; de Vries, Niek; Tak, Paul P.; Moreland, Larry W.; Bridges, S. Louis; Miceli-Richard, Corinne; Choi, Hyon K.; Kamatani, Yoichiro; Galan, Pilar; Lathrop, Mark; Raj, Towfique; De Jager, Philip L.; Raychaudhuri, Soumya; Worthington, Jane; Padyukov, Leonid; Klareskog, Lars; Siminovitch, Katherine A.; Gregersen, Peter K.; Mardis, Elaine R.; Arayssi, Thurayya; Kazkaz, Layla A.; Plenge, Robert M.

    2014-01-01

    Integrating genetic data from families with highly penetrant forms of disease together with genetic data from outbred populations represents a promising strategy to uncover the complete frequency spectrum of risk alleles for complex traits such as rheumatoid arthritis (RA). Here, we demonstrate that rare, low-frequency and common alleles at one gene locus, phospholipase B1 (PLB1), might contribute to risk of RA in a 4-generation consanguineous pedigree (Middle Eastern ancestry) and also in unrelated individuals from the general population (European ancestry). Through identity-by-descent (IBD) mapping and whole-exome sequencing, we identified a non-synonymous c.2263G>C (p.G755R) mutation at the PLB1 gene on 2q23, which significantly co-segregated with RA in family members with a dominant mode of inheritance (P = 0.009). We further evaluated PLB1 variants and risk of RA using a GWAS meta-analysis of 8,875 RA cases and 29,367 controls of European ancestry. We identified significant contributions of two independent non-coding variants near PLB1 with risk of RA (rs116018341 [MAF = 0.042] and rs116541814 [MAF = 0.021], combined P = 3.2×10−6). Finally, we performed deep exon sequencing of PLB1 in 1,088 RA cases and 1,088 controls (European ancestry), and identified suggestive dispersion of rare protein-coding variant frequencies between cases and controls (P = 0.049 for C-alpha test and P = 0.055 for SKAT). Together, these data suggest that PLB1 is a candidate risk gene for RA. Future studies to characterize the full spectrum of genetic risk in the PLB1 genetic locus are warranted. PMID:24520335

  3. Integration of sequence data from a Consanguineous family with genetic data from an outbred population identifies PLB1 as a candidate rheumatoid arthritis risk gene.

    PubMed

    Okada, Yukinori; Diogo, Dorothee; Greenberg, Jeffrey D; Mouassess, Faten; Achkar, Walid A L; Fulton, Robert S; Denny, Joshua C; Gupta, Namrata; Mirel, Daniel; Gabriel, Stacy; Li, Gang; Kremer, Joel M; Pappas, Dimitrios A; Carroll, Robert J; Eyler, Anne E; Trynka, Gosia; Stahl, Eli A; Cui, Jing; Saxena, Richa; Coenen, Marieke J H; Guchelaar, Henk-Jan; Huizinga, Tom W J; Dieudé, Philippe; Mariette, Xavier; Barton, Anne; Canhão, Helena; Fonseca, João E; de Vries, Niek; Tak, Paul P; Moreland, Larry W; Bridges, S Louis; Miceli-Richard, Corinne; Choi, Hyon K; Kamatani, Yoichiro; Galan, Pilar; Lathrop, Mark; Raj, Towfique; De Jager, Philip L; Raychaudhuri, Soumya; Worthington, Jane; Padyukov, Leonid; Klareskog, Lars; Siminovitch, Katherine A; Gregersen, Peter K; Mardis, Elaine R; Arayssi, Thurayya; Kazkaz, Layla A; Plenge, Robert M

    2014-01-01

    Integrating genetic data from families with highly penetrant forms of disease together with genetic data from outbred populations represents a promising strategy to uncover the complete frequency spectrum of risk alleles for complex traits such as rheumatoid arthritis (RA). Here, we demonstrate that rare, low-frequency and common alleles at one gene locus, phospholipase B1 (PLB1), might contribute to risk of RA in a 4-generation consanguineous pedigree (Middle Eastern ancestry) and also in unrelated individuals from the general population (European ancestry). Through identity-by-descent (IBD) mapping and whole-exome sequencing, we identified a non-synonymous c.2263G>C (p.G755R) mutation at the PLB1 gene on 2q23, which significantly co-segregated with RA in family members with a dominant mode of inheritance (P = 0.009). We further evaluated PLB1 variants and risk of RA using a GWAS meta-analysis of 8,875 RA cases and 29,367 controls of European ancestry. We identified significant contributions of two independent non-coding variants near PLB1 with risk of RA (rs116018341 [MAF = 0.042] and rs116541814 [MAF = 0.021], combined P = 3.2 × 10(-6)). Finally, we performed deep exon sequencing of PLB1 in 1,088 RA cases and 1,088 controls (European ancestry), and identified suggestive dispersion of rare protein-coding variant frequencies between cases and controls (P = 0.049 for C-alpha test and P = 0.055 for SKAT). Together, these data suggest that PLB1 is a candidate risk gene for RA. Future studies to characterize the full spectrum of genetic risk in the PLB1 genetic locus are warranted.

  4. A Homozygous Mutation in GPT2 Associated with Nonsyndromic Intellectual Disability in a Consanguineous Family from Costa Rica.

    PubMed

    Lobo-Prada, Tanya; Sticht, Heinrich; Bogantes-Ledezma, Sixto; Ekici, Arif; Uebe, Steffen; Reis, André; Leal, Alejandro

    2017-01-28

    Intellectual disability is a highly heterogeneous disease that affects the central nervous system and impairs patients' ability to function independently. Despite multiples genes involved in the etiology of disease, most of the genetic background is yet to be discovered. We used runs of homozygosity and exome sequencing to study a large Costa Rican family with four individuals affected with severe intellectual disability and found a novel homozygous missense mutation, p. 96G>R, c. 286G>A, in all affected individuals. This gene encodes for a pyridoxal enzyme involved in the production of the neurotransmitter glutamate and is highly expressed in the white matter of brain and cerebellum. Protein modeling of GPT2 predicted that the mutation is located in a loop where the substrate binds to the active site of the enzyme, therefore, suggesting that the catalytic activity is impaired. With our report of a second mutation we fortify the importance of GPT2 as a novel cause of autosomal recessive nonsyndromic intellectual disability and support the premise that GPT2 is highly important for the neurodevelopment of the central nervous system.

  5. Is consanguinity a risk factor for keratoconus?

    PubMed

    Gordon-Shaag, Ariela; Millodot, Michel; Essa, Maron; Garth, Jeanne; Ghara, Mohammed; Shneor, Einat

    2013-05-01

    To determine whether consanguinity is a risk factor for keratoconus (KC). A questionnaire was distributed to all patients presenting to St. John Eye Hospital, Jerusalem, Israel. Questionnaire included data on demographic characteristics and potential risk factors. Patients were divided into two groups: cases with KC, in at least one eye, who were diagnosed by the attending ophthalmologist on the basis of abnormal corneal topography and at least one of the common signs of the disease; and controls presenting for problems other than KC and free of systemic and ocular conditions associated with KC. Multivariate logistic analyses were performed to identify risk factors for KC. Seventy cases and 140 controls participated in the study. Groups were similar with respect to sex and age. Univariate analyses found a significant association between KC and parental first-cousin consanguinity, eye rubbing, allergy, positive family history, education (>12 years), and sunglass wear, whereas asthma, eczema, smoking, and second-cousin consanguinity were not. Multivariate analyses showed that total consanguinity (first-cousin and second-cousin) (adjusted odds ratio, 3.96; p = 0.001), eye rubbing and absence of sunglass wear were significant risk factors. Education was also associated with KC, but family history was not so in the multivariate analysis. This study supports the hypothesis that consanguinity is a significant risk factor for KC and provides strong support for a genetic contribution to the disease. Wearing sunglasses in this environment is beneficial, and the study confirmed that eye rubbing, allergy, and education are also significantly associated with KC after adjusting for other predictors.

  6. Survey of familial glaucoma shows a high incidence of cytochrome P450, family 1, subfamily B, polypeptide 1 (CYP1B1) mutations in non-consanguineous congenital forms in a Spanish population

    PubMed Central

    Millá, Elena; Mañé, Begoña; Duch, Susana; Hernan, Imma; Borràs, Emma; Planas, Ester; Dias, Miguel de Sousa; Carballo, Miguel

    2013-01-01

    Purpose To identify myocilin (MYOC) and cytochrome P450, family 1, subfamily B, polypeptide 1 (CYP1B1) mutations in a Spanish population with different clinical forms of familial glaucoma or ocular hypertension (OHT). Methods Index patients from 226 families participated in this study. Patients were diagnosed with familial glaucoma or OHT by complete ophthalmologic examination. Screening for MYOC mutations was performed in 207 index patients: 96 with adult-onset primary open-angle glaucoma (POAG), 21 with primary congenital glaucoma (PCG), 18 with juvenile-onset open-angle glaucoma (JOAG), five with Axenfeld-Rieger syndrome (ARS), and 67 with other types of glaucoma. One hundred two of the families (including all those in whom a MYOC mutation was detected) were also screened for CYP1B1 mutations: 45 POAG, 25 PCG, 21 JOAG, four ARS, and seven others. Results We examined 292 individuals (patients and relatives) with a positive family history of glaucoma or OHT. We identified two novel MYOC variants, p.Lys39Arg and p.Glu218Lys, in two families with POAG, and six previously reported MYOC mutations in seven families with POAG (four), JOAG (one), PCG (one), and normotensive glaucoma (one). CYP1B1 mutations were found in 16 index patients with PCG (nine), POAG (three), JOAG (two), and ARS (two). Conclusions The high percentage (9/25=36%) of mutations in CYP1B1 found in non-consanguineous patients with congenital glaucoma mandates genetic testing. However, the percentage of mutations (9/207=4.4%) in MYOC associated with glaucoma is relatively low in our population. The variable phenotype expression of glaucoma, even in families, cannot be explained with a digenic mechanism between MYOC and CYP1B1. PMID:23922489

  7. Specific aspects of consanguinity: some examples from the Tunisian population.

    PubMed

    Romdhane, Lilia; Ben Halim, Nizar; Rejeb, Insaf; Kefi, Rym; Bouyacoub, Yosra; Ben Rekaya, Mariem; Messai, Habib; Messaoud, Olfa; Riahi, Zied; Bonnet, Crystel; Ben Rhouma, Faten; Nagara, Majdi; Petit, Christine; McElreavey, Ken; Romeo, Giovanni; Abdelhak, Sonia

    2014-01-01

    Located at the cross-road between Europe and Africa, Tunisia is a North African country of 11 million inhabitants. Throughout its history, it has been invaded by different ethnic groups. These historical events, and consanguinity, have impacted on the spectrum and frequency of genetic diseases in Tunisia. Investigations of Tunisian families have significantly contributed to elucidation of the genetic bases of rare disorders, providing an invaluable resource of cases due to particular familial structures (large family size, consanguinity and share of common ancestors). In the present study, we report on and review different aspects of consanguinity in the Tunisian population as a case study, representing several features common to neighboring or historically related countries in North Africa and the Middle East. Despite the educational, demographic and behavioral changes that have taken place during the last four decades, familial and geographical endogamy still exist at high frequencies, especially in rural areas. The health implications of consanguinity in Tunisian families include an increased risk of the expression of autosomal recessive diseases and particular phenotypic expressions. With new sequencing technologies, the investigation of consanguineous populations provides a unique opportunity to better evaluate the impact of consanguinity on the genome dynamic and on health, in addition to a better understanding of the genetic bases of diseases. © 2014 S. Karger AG, Basel.

  8. Organ donation consanguinity or universality.

    PubMed

    Kishore, R R

    1996-01-01

    1. Neither the "Diseased Persons" nor the "Genetic Relations" provide an answer to "trading" in human body parts. 2. Live human body constitutes a vital source of supply of organs and tissues and the possibilities of optimum utilisation should be explored. 3. There is no scope for dogmatic postures and open-mindedness should be the approach while dealing with the issue of Organ Transplantation. 4. Society owes a duty to save the file of a dying man and in the event of failure to do so, it is absolutely immoral to interfere with his own arrangements by making unrealistic laws. No immorality is involved if an individual disposes of his spare body parts for a valid consideration to a needy person. 5. The scarcity needs to be urgently overcome otherwise unwarranted trade and crime are liable to thrive. 6. Families are not unconnected or antagonistic fragments of humanity. After thousands of years of continuous efforts the individuals on this earth have attained the stage of organic and functional integration. Atomisation of society on the basis of consanguineous proximities amounts to reversing this holistic trend. Organ transplantation is a functional expression of a highly evolved pursuit with inherent and intimate interaction in the form of organic exchange at the individual level, independent of consanguineous inducements or motivations. As such there is absolutely no scope for restricting organ donations by strangers. 7. Commercialisation should be curbed by making the enforcement agencies more efficient and not by depriving a needy person of his genuine requirements. Legislative craftsmanship lies in providing an answer without curtailing the freedom of the people.

  9. Consanguineous marriage and its relevance to obstetric practice.

    PubMed

    de Costa, Caroline M

    2002-08-01

    At the beginning of the twenty-first century, consanguineous marriage is practiced widely in many parts of the world. More than 2 billion people, of various religious and ethnic backgrounds, live in countries where a large proportion of marriages are contracted between blood relatives. The practice is seen as promoting family stability and having significant social and economic advantages. Consanguineous marriage is important genetically-the children of consanguineous unions are more often homozygous for particular alleles than are the offspring of unrelated parents, and therefore, autosomal recessive disorders, which may be lethal or debilitating, are more common in such children. Health-care providers working with communities where consanguineous marriage is common, in particular obstetricians, family physicians, and pediatricians, need to be aware of the possible impact of such marriages on pregnancy outcomes, so the best possible genetic and antenatal care can be provided, sympathetically and nonjudgmentally, and the best possible results obtained.

  10. Impact of 226C>T MSH2 gene mutation on cancer phenotypes in two HNPCC-associated highly-consanguineous families from Kuwait: emphasis on premarital genetic testing.

    PubMed

    Marafie, Makia J; Al-Awadi, Sadiqa; Al-Mosawi, Fatemah; Elshafey, Alaa; Al-Ali, Waleed; Al-Mulla, Fahd

    2009-01-01

    Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC) is one of the commonest cancer susceptibility syndromes. It is characterized by early onset colon cancer and a variety of extracolonic tumours. Germline mutations in the DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS1, and PMS2) are responsible for this disorder. Identifying an affected individual depends on the tumour histopathology, family history that fulfils the Amsterdam and/or Bethesda criteria, tumour immunohistochemistry, microsatellite instability, and finally molecular analysis of an affected member. It is a laborious, time consuming and expensive procedure, which needs the effort of a multi-disciplinary team. However, once the diagnosis is established and germline defect is identified, other high risk pre-symptomatic carriers could be offered intensive surveillance and management as a preventive measure against cancer development. Here, we present two large highly consanguineous HNPCC-families from Kuwait in whom a founder MSH2 mutation was identified. The relationship between this mutation and cancer expressivity in two large consanguineous families harbouring other genetic defects is discussed. Moreover, we shed light on the challenges pertaining to diagnosis, screening, premarital counselling of couples and prenatal diagnosis of offspring with biallelic MSH2 gene mutation.

  11. Association studies in consanguineous populations

    SciTech Connect

    Genin, E.; Clerget-Darpous, F.

    1996-04-01

    To study the genetic determinism of multifactorial diseases in large panmictic populations, a strategy consists in looking for an association with markers closely linked to candidate genes. A distribution of marker genotypes different in patients and controls may indicate that the candidate gene is involved in the disease. In panmictic populations, the power to detect the role of a candidate gene depends on the gametic disequilibrium with the marker locus. In consanguineous populations, we show that it depends on the inbreeding coefficient F as well. Inbreeding increases the power to detect the role of a recessive or quasi-recessive disease-susceptibility factor. The gain in power turns out to be greater for small values of the gametic disequilibrium. Moreover, even in the absence of gametic disequilibrium, the presence of inbreeding may allow to detect the role of a recessive factor. Ignoring inbreeding when it exists may lead to reject falsely a recessive model if the mode of inheritance is inferred on the distribution of genotypes among patients. 5 refs., 6 figs., 1 tab.

  12. Is there a significant trend in prevalence of consanguineous marriage in Tehran? A review of three generations.

    PubMed

    Akrami, Seyed Mohammad; Montazeri, Vahideh; Shomali, Somaieh Rashid; Heshmat, Ramin; Larijani, Bagher

    2009-02-01

    Consanguineous marriage is a common practice in Iran. The present study surveyed the trend in consanguineous marriage across three generations of Iranians. Index cases, consisting of 400 individuals attending the diabetes and osteoporosis clinic in Shariati Hospital, were interviewed. Data on consanguinity status for 1789 marriages within the index cases' families were obtained. Generation 1 consisted of marriages contracted before 1948, Generation 2 consisted of marriages contracted between 1949 and 1978, and Generation 3 consisted of marriages contracted after 1979. Prevalence of consanguineous marriage within these three generations was 8.8%, 16.6% and 19%, respectively, and represented a significant trend (p < 0.001). First cousin marriage was the most common type of consanguinity (69%). Socioeconomic level of families was not significantly related to having a consanguineous marriage. These data suggest that premarital genetic counseling and mass media efforts are needed to increase public awareness about genetic risks associated with consanguineous marriage.

  13. Missouri Small Farm Family Program. Revised.

    ERIC Educational Resources Information Center

    Enlow, George; And Others

    Records maintained by rural extension designees on the Missouri Small Farm Family Program, (initiated in 1972 by the cooperative extension service to help low income farm families learn to use available resources to improve their quality of life) provided data re: family characteristics, farm improvement progress, and improvement in the quality of…

  14. Constitutional Mismatch Repair Deficiency in Israel: High Proportion of Founder Mutations in MMR Genes and Consanguinity.

    PubMed

    Baris, Hagit N; Barnes-Kedar, Inbal; Toledano, Helen; Halpern, Marisa; Hershkovitz, Dov; Lossos, Alexander; Lerer, Israela; Peretz, Tamar; Kariv, Revital; Cohen, Shlomi; Half, Elizabeth E; Magal, Nurit; Drasinover, Valerie; Wimmer, Katharina; Goldberg, Yael; Bercovich, Dani; Levi, Zohar

    2016-03-01

    Heterozygous germline mutations in any of the mismatch repair (MMR) genes, MLH1, MSH2, MSH6, and PMS2, cause Lynch syndrome (LS), an autosomal dominant cancer predisposition syndrome conferring a high risk of colorectal, endometrial, and other cancers in adulthood. Offspring of couples where both spouses have LS have a 1:4 risk of inheriting biallelic MMR gene mutations. These cause constitutional MMR deficiency (CMMRD) syndrome, a severe recessively inherited cancer syndrome with a broad tumor spectrum including mainly hematological malignancies, brain tumors, and colon cancer in childhood and adolescence. Many CMMRD children also present with café au lait spots and axillary freckling mimicking neurofibromatosis type 1. We describe our experience in seven CMMRD families demonstrating the role and importance of founder mutations and consanguinity on its prevalence. Clinical presentations included brain tumors, colon cancer, lymphoma, and small bowel cancer. In children from two nonconsanguineous Ashkenazi Jewish (AJ) families, the common Ashkenazi founder mutations were detected; these were homozygous in one family and compound heterozygous in the other. In four consanguineous families of various ancestries, different homozygous mutations were identified. In a nonconsanguineous Caucasus/AJ family, lack of PMS2 was demonstrated in tumor and normal tissues; however, mutations were not identified. CMMRD is rare, but, especially in areas where founder mutations for LS and consanguinity are common, pediatricians should be aware of it since they are the first to encounter these children. Early diagnosis will enable tailored cancer surveillance in the entire family and a discussion regarding prenatal genetic diagnosis. © 2015 Wiley Periodicals, Inc.

  15. The rate of consanguineous marriages among parents of schizophrenic patients in the Arab Bedouin population in Southern Israel.

    PubMed

    Dobrusin, Michael; Weitzman, Dahlia; Levine, Joseph; Kremer, Ilana; Rietschel, Marcella; Maier, Wolfgang; Belmaker, Robert H

    2009-01-01

    Consanguinity may contribute to the incidence of schizophrenia in offspring despite the usually accepted polygenic model of schizophrenia inheritance. Bedouin Arab families in southern Israel have a high rate of cousin marriages as do families throughout most Arab societies. We studied consanguinity in the parents of schizophrenic patients admitted in a defined catchment area of southern Israel, compared to a control group of parents of all infants born to Bedouin mothers in this catchment area. There was a small but significant increase in the rate of cousin marriages among the parents of schizophrenia patients compared to parents of infant controls. These results are consistent with claims that inbreeding can contribute to the incidence of schizophrenia even as a polygenic illness. However, the absence of a better matched control group limits confidence in the results.

  16. [Frequency of consanguineous unions in the Tlemcen area (West Algeria)].

    PubMed

    Zaoui, Salah; Biémont, Christian

    2002-01-01

    In order to describe consanguineous unions and their effects in a sample of the Algerian population, we interviewed 3,983 couples in a hospital and from urban and rural areas near Tlemcen. We observed that unions between cousins represented 34.0% of the marriages. The frequency of unions between relatives was lower in the urban (30.6%) than in the rural areas (40.5%). This difference can be explained by changing custom and family relationships in urban areas, and is evidenced by social and anthropologic factors and the attitude towards consanguineous unions.

  17. The prevalence of isolated growth hormone deficiency among children of short stature in Jordan and its relationship with consanguinity.

    PubMed

    Zayed, Ayman A; Mustafa Ali, Moaath K; Al-Ani, Mohammad A; Momani, Munther S; Yousef, Al-Motassem F

    2014-12-01

    The prevalence of isolated growth hormone deficiency (IGHD) among short-statured children in Jordan, where consanguineous marriage (CM) is common, is unknown. No studies have investigated the relationship between degrees of consanguinity and IGHD. This study aimed to determine the prevalence of IGHD among short-statured children referred to a university hospital in Jordan and its relationship with different degrees of consanguinity. We conducted a 24-month cross-sectional observational trial at an outpatient tertiary care center in Amman, Jordan. We obtained detailed family histories, medical evaluations and laboratory tests for 94 short-statured children (50 boys and 44 girls aged 6-16 years). Complete and partial GHD were defined as peak GH responses of 5 and 7 μg/l (15 and 21 mIU/l) [IRMA/DiaSorin®], respectively, in both exercise and insulin tolerance tests. GHD was diagnosed in 69·1% of the short children, including 86% (43/50) of the children of consanguineous parents (83·3%, 93·8% and 81·8% of children of first cousins, first cousins once removed and second cousins, respectively) and 50% (20/44) of the children of nonconsanguineous parents (P = 0·039, 0·002 and 0·013, respectively). However, there was no statistically significant difference in the prevalence of small pituitary MRI between GH-deficient children of consanguineous parents and those of nonconsanguineous parents (28·6% vs 13·6%, P = 0·3). The prevalence of IGHD among referred short children in Jordan was exceptionally high and significantly higher in the children of CM. In countries where CM is common, preconception counselling and rigorous surveillance for GHD in short children may be indicated. © 2014 John Wiley & Sons Ltd.

  18. Forgiveness in relation to attachment style and consanguine marriage in Iranian married individuals.

    PubMed

    Shahidi, Shahriar; Zaal, Behnaz; Mazaheri, Mohammad Ali

    2012-04-01

    The aim of this study was to compare forgiveness in secure and insecure Iranian married couples. Whether marriage had occurred within the family (consanguine) or not (non-consanguine) was also considered. 400 married participants completed the Family Forgiveness Scale and the Adult Attachment Questionnaire. Analysis of reported forgiveness within the marital family showed that, although there was no significant difference between secure and insecure participants in overall forgiveness, secure participants rated "reparation" and "resolution" higher, whereas insecure participants rated "realization" and "recognition" higher. Comparing the experience of forgiveness in the family of origin, securely attached couples not only reported significantly more overall forgiveness but reported more "realization" and "resolution" while forgiving. Some interesting sex differences were also found, as individuals in consanguine vs non-consanguine couples differed in mean "recognition" in the forgiveness process.

  19. Consanguinity and reproductive health among Arabs

    PubMed Central

    Tadmouri, Ghazi O; Nair, Pratibha; Obeid, Tasneem; Al Ali, Mahmoud T; Al Khaja, Najib; Hamamy, Hanan A

    2009-01-01

    Consanguineous marriages have been practiced since the early existence of modern humans. Until now consanguinity is widely practiced in several global communities with variable rates depending on religion, culture, and geography. Arab populations have a long tradition of consanguinity due to socio-cultural factors. Many Arab countries display some of the highest rates of consanguineous marriages in the world, and specifically first cousin marriages which may reach 25-30% of all marriages. In some countries like Qatar, Yemen, and UAE, consanguinity rates are increasing in the current generation. Research among Arabs and worldwide has indicated that consanguinity could have an effect on some reproductive health parameters such as postnatal mortality and rates of congenital malformations. The association of consanguinity with other reproductive health parameters, such as fertility and fetal wastage, is controversial. The main impact of consanguinity, however, is an increase in the rate of homozygotes for autosomal recessive genetic disorders. Worldwide, known dominant disorders are more numerous than known recessive disorders. However, data on genetic disorders in Arab populations as extracted from the Catalogue of Transmission Genetics in Arabs (CTGA) database indicate a relative abundance of recessive disorders in the region that is clearly associated with the practice of consanguinity. PMID:19811666

  20. Novel homozygous, heterozygous and hemizygous FRMD7 gene mutations segregated in the same consanguineous family with congenital X-linked nystagmus

    PubMed Central

    Radhakrishna, Uppala; Ratnamala, Uppala; Deutsch, Samuel; Bartoloni, Lucia; Kuracha, Murali R; Singh, Raminder; Banwait, Jasjit; Bastola, Dhundy K; Johar, Kaid; Nath, Swapan K; Antonarakis, Stylianos E

    2012-01-01

    Congenital nystagmus (NYS) is characterized by bilateral, spontaneous, and involuntary movements of the eyeballs that most commonly presents between 2 and 6 months of life. To date, 44 different FRMD7 gene mutations have been found to be etiological factors for the NYS1 locus at Xq26-q27. The aim of this study was to find the FRMD7 gene mutations in a large eleven-generation Indian pedigree with 71 members who are affected by NYS. Mutation analysis of the entire coding region and splice junctions of the FRMD7 gene revealed a novel missense mutation, c.A917G, predicts a substitution of Arg for Gln at codon 305 (Q305R) within exon 10 of FRMD7. The mutation was detected in hemizygous males, and in homozygous and heterozygous states in affected female members of the family. This mutation was not detected in unaffected members of the family or in 100 unrelated control subjects. This mutation was found to be at a highly conserved residue within the FERM-adjacent domain in affected members of the family. Structure prediction and energetic analysis of wild-type FRMD7 compared with mutant (Q305R) revealed that this change in amino acid led to a change in secondary structure predicted to be an energetically unstable protein. The present study represents the first confirmation of FRMD7 gene mutations in a multigenerational Indian family and expands the mutation spectrum for this locus. PMID:22490987

  1. Effects of consanguineous marriage on reproductive behaviour, adverse pregnancy outcomes and offspring mortality in Oman.

    PubMed

    Islam, M Mazharul

    2013-05-01

    The long tradition of high prevalence of consanguineous marriages in Omani society may have ramifications for reproductive behaviour and health of offspring. To examine the relevance of consanguinity to reproductive behaviour, adverse pregnancy outcome and offspring mortality in Oman. The data analysed came from the 2000 Oman National Health Survey. Selected indicators that are related to reproductive behaviour, adverse pregnancy outcome and offspring mortality were considered as explanatory variables. Various statistical methods and tests were used for data analysis. Consanguineous marriage was found to be associated with lower age at first birth, higher preference for larger family size, lower level of husband-wife communication about use of family planning methods and lower rate of contraceptive use. Although bivariate analysis showed elevated fertility and childhood mortality among the women with consanguineous marriage, after controlling for relevant socio-demographic factors in multivariate analysis, fertility, childhood mortality and foetal loss showed no significant association with consanguinity in Oman. Consanguinity plays an important role in determining some of the aspects of reproduction and health of newborns, but did not show any detrimental effects on fertility and offspring mortality. The high level of consanguinity and its relevance to reproduction in Oman need to be considered in its public health strategy in a culturally acceptable manner.

  2. Choice of kin in consanguineous marriages: effects of altruism and ecological factors.

    PubMed

    Denic, Srdjan; Nagelkerke, Nicolaas; Agarwal, Mukesh M

    2010-11-01

    Despite being associated with multiple genetic problems, consanguineous marriages continue to remain extremely prevalent worldwide. Studying the variation of kin preferences in diverse inbred societies may provide some answers to this paradox. To find the reasons for specific kin choice in different geographical areas of the world. We used a set of sociobiological rules (kin altruism, sexuality and inbreeding avoidance) and ecological constraints (e.g. tribal warfare, food availability) that influence human behaviour. The cumulative help that the extended family can provide to a nuclear family was calculated using the coefficient of relatedness between kin in different types of consanguineous families. The maximum potential support for kin markedly varied between different types of consanguineous marriages. Overall, members of consanguineous families received up to two-and-half times more support than members of non-consanguineous families. In various inbred cultures, preference for a specific type of kin was determined by prevailing ecological limitations and sociobiological factors interacting in a complex manner. In different inbred populations, the ideal kin for a consanguineous marriage is the one who can provide the most altruistic support; however, this choice is influenced by biological rules of behaviour and ecological constraints.

  3. Consanguinity in two Uruguayan cities: historical evolution and characteristics (1800--1994).

    PubMed

    Lusiardo, A; Barreto, I; Hidalgo, P C; Bonilla, C; Bertoni, B; Portas, M; Sans, M

    2004-01-01

    Information about consanguinity in Uruguay is scarce and limited to the end of the 20th century. To determine the frequency and characteristics of consanguineous marriages, as well as chronological trends, in two Uruguayan cities over almost two centuries. We analysed 28,393 Roman Catholic Church marriage records and Diocesan consanguinity dispensations belonging to the cities of Melo (Northeast), and Montevideo (South), for the period 1800--1994. 633 (2.23%) marriages were consanguineous. Among them, first cousin marriages were the most common (58.8% of all consanguineous marriages, including double consanguineous), especially those where the bride and groom were related through their maternal side. During the first decades of the 19th century both regions showed low levels of consanguinity. Consanguinity reached its maximum during the mid-1800s and decreased significantly throughout the 20th century. The overall mean coefficients of inbreeding were moderate in both cases, being greater in the Northeast (alpha=0.00165) than in the South (alpha = 0.00089). The low level of consanguinity as well as the structure of consanguineous marriages (distribution by degrees) is similar to that found in other southern South American countries. Temporal trends are similar to those found in industrialized regions in Europe, with maximum inbreeding levels during the middle-late 19th century; however, the clear predominance of first cousin unions, differs from most of the data for European countries. Small differences between the two cities can be related to diverse facts, such as socio-economic conditions, ethnic origin, immigration, and sampling.

  4. Segregation of Incomplete Achromatopsia and Alopecia Due to PDE6H and LPAR6 Variants in a Consanguineous Family from Pakistan

    PubMed Central

    Pedurupillay, Christeen Ramane J.; Landsend, Erlend Christoffer Sommer; Vigeland, Magnus Dehli; Ansar, Muhammad; Frengen, Eirik; Misceo, Doriana; Strømme, Petter

    2016-01-01

    We report on two brothers with visual impairment, and non-syndromic alopecia in the elder proband. The parents were first-degree Pakistani cousins. Whole exome sequencing of the elder brother and parents, followed by Sanger sequencing of all four family members, led to the identification of the variants responsible for the two phenotypes. One variant was a homozygous nonsense variant in the inhibitory subunit of the cone-specific cGMP phosphodiesterase gene, PDE6H:c.35C>G (p.Ser12*). PDE6H is expressed in the cones of the retina, which are involved in perception of color vision. This is the second report of a homozygous PDE6H:c.35C>G variant causing incomplete achromatopsia (OMIM 610024), thus strongly supporting the hypothesis that loss-of-function variants in PDE6H cause this visual deficiency phenotype. The second variant was a homozygous missense substitution in the lysophosphatidic acid receptor 6, LPAR6:c.188A>T (p.Asp63Val). LPAR6 acts as a G-protein-coupled receptor involved in hair growth. Biallelic loss-of-function variants in LPAR6 cause hypotrichosis type 8 (OMIM 278150), with or without woolly hair, a form of non-syndromic alopecia. Biallelic LPAR6:c.188A>T was previously described in five families from Pakistan. PMID:27472364

  5. Dyssegmental dysplasia Silverman-Handmaker type in a consanguineous Druze Lebanese family: long term survival and documentation of the natural history.

    PubMed

    Prabhu, V G; Kozma, C; Leftridge, C A; Helmbrecht, G D; France, M L

    1998-01-13

    We report on a male infant born with clinical and radiographic evidence of a lethal form of dyssegmental dysplasia not comparable to Silverman-Handmaker type, who had a prolonged survival of more than eight months. He had ocular and central nervous system abnormalities which have not been previously described. His course included significant feeding and respiratory difficulties, severe physical and psychomotor retardation, and recurrent fever of unknown etiology believed to be of central origin. The relatively long survival of this infant enabled us to focus on the natural history of this rare syndrome. The infant was born to first cousin parents of Druze Lebanese origin supporting an autosomal recessive mode of inheritance for the condition. This is the first documentation of dyssegmental dysplasia Silverman-Handmaker type in a family of Druze Lebanese ethnicity.

  6. Consanguinity and Neonatal Death: A Nested Case-Control Study

    PubMed Central

    Chaman, Reza; Gholami Taramsari, Mahshid; Khosravi, Ahmad; Amiri, Mohammad; Holakouie Naieni, Kourosh; Yunesian, Masoud

    2014-01-01

    Objective: Although numerous studies have found higher rates of abortion and still births following consanguinity (familial marriages), the question of whether consanguinity significantly increases the risk of neonatal death has inadequately been addressed.This study aims to evaluate familial marriage effects on neonatal death in rural areas in Iran. Materials and methods: In this nested case-control study, 6900 newbornswho were born in rural areas of Kohgiluyeh and Boyerahmad Province (South-West of Iran)were followed till the end of neonatal period, and neonatal death was the outcome of interest. Subsequently 97 cases and 97 controls were selected in study cohort by using risk set sampling model. Crude and adjusted odds ratios (OR) were estimated by usinga conditional logistic regression model. Results: In the final model, prematurity (OR = 5.57), low birthweight (LBW) (OR = 7.68), consanguinity (first cousins) (OR = 5.23), C-section (OR = 7.27), birth rank more than 3 (OR = 6.95) and birthsinterval less than 24 months (OR = 4.65) showed significant statistical association with neonatal mortality (p < 0.05). Conclusion: According to our findings, after adjusting the effects of other significant risk factors, familial marriageto first cousins is considered asan important risk factor for neonatal death. PMID:25530772

  7. Differential impact of consanguineous marriages on autosomal recessive diseases in Tunisia.

    PubMed

    Ben Halim, Nizar; Hsouna, Sana; Lasram, Khaled; Rejeb, Insaf; Walha, Asma; Talmoudi, Faten; Messai, Habib; Sabrine Ben Brick, Ahlem; Ouragini, Houyem; Cherif, Wafa; Nagara, Majdi; Ben Rhouma, Faten; Chouchene, Ibtissem; Ouechtati, Farah; Bouyacoub, Yosra; Ben Rekaya, Mariem; Messaoud, Olfa; Ben Ammar, Slim; El Matri, Leila; Tebib, Neji; Ben Dridi, Marie F; Mokni, Mourad; Amouri, Ahlem; Kefi, Rym; Abdelhak, Sonia

    2016-01-01

    Consanguinity is common in Tunisia. However, little information exists on its impact on recessive disorders. In this study, we evaluate the impact of consanguineous marriages on the occurrence of some specific autosomal recessive disorders and consider how other factors, such as population substructure and mutation frequency, may be of equal importance in disease prevalence. Consanguinity profiles were retrospectively studied among 425 Tunisian patients suffering from autosomal recessive xeroderma pigmentosum, dystrophic epidermolysis bullosa, nonsyndromic retinitis pigmentosa, Gaucher disease, Fanconi anemia, glycogenosis type I, and ichthyosis, and compared to those of a healthy control sample. Consanguinity was observed in 341 cases (64.94%). Consanguinity rates per disease were 75.63, 63.64, 60.64, 61.29, 57.89, 73.33, and 51.28%, respectively. First-cousin marriages were the most common form of consanguinity (48.94%) with the percentages of 55.46, 45.46, 47.87, 48.39, 45.61, 56.66, and 35.90%, respectively. A very high level of geographic endogamy was also observed (93.92%), with the values by disease ranging between 75.86 and 96.64%. We observed an overall excess risk associated to consanguinity of nearly sevenfold which was proportional to the number of affected siblings and the frequency of disease allele in the family. Consanguinity was significantly associated with the first five cited diseases (odds ratio = 24.41, 15.17, 7.5, 5.53, and 5.07, respectively). However, no meaningful effects were reported among the remaining diseases. This study reveals a variation in the excess risk linked to consanguinity according to the type of disorder, suggesting the potential of cryptic population substructure to contribute to disease incidence in populations with complex social structure like Tunisia. It also emphasizes the role of other health and demographic aspects such as mutation frequency and reproductive replacement in diseases etiology. © 2015 Wiley

  8. Consanguineous marriage and reproductive risk: attitudes and understanding of ethnic groups practising consanguinity in Western society

    PubMed Central

    Teeuw, Marieke E; Loukili, Ghariba; Bartels, Edien AC; ten Kate, Leo P; Cornel, Martina C; Henneman, Lidewij

    2014-01-01

    Consanguineous couples should be adequately informed about their increased reproductive risk and possibilities for genetic counselling. Information may only be effective if it meets the needs of the target group. This study aimed to gain more insight into: (1) attitudes of people belonging to ethnic groups in Western society towards consanguinity and their understanding of risk for offspring; and (2) their attitudes regarding reproductive information targeted at consanguineous couples. Dutch Moroccans and Turks were invited to complete an online questionnaire by snowball sampling and by placing a link on two popular Dutch Moroccan/Turkish forum websites between September and October 2011. The questionnaire was completed by 201 individuals who were, on average, neither positive nor negative towards consanguinity. Respondents with a consanguineous partner were more positive, estimated the risk for the offspring lower and were less positive about the provision of risk information to consanguineous couples when compared with respondents without a consanguineous partner. Participants of Turkish origin had a more negative attitude towards consanguinity and estimated the reproductive risk higher than Moroccan participants. More than half of the respondents thought that information should be given before marriage, whereas only 10% thought it should never be provided. The general practitioner was most often mentioned (54%) as the designated professional to inform people. Information about genetic risks related to consanguinity should be offered early, preferably before marriage. The diversity of the target population requires various strategies to disseminate information and reach consanguineous couples with the offer of genetic counselling. PMID:23921534

  9. Consanguineous marriage and reproductive risk: attitudes and understanding of ethnic groups practising consanguinity in Western society.

    PubMed

    Teeuw, Marieke E; Loukili, Ghariba; Bartels, Edien Ac; ten Kate, Leo P; Cornel, Martina C; Henneman, Lidewij

    2014-04-01

    Consanguineous couples should be adequately informed about their increased reproductive risk and possibilities for genetic counselling. Information may only be effective if it meets the needs of the target group. This study aimed to gain more insight into: (1) attitudes of people belonging to ethnic groups in Western society towards consanguinity and their understanding of risk for offspring; and (2) their attitudes regarding reproductive information targeted at consanguineous couples. Dutch Moroccans and Turks were invited to complete an online questionnaire by snowball sampling and by placing a link on two popular Dutch Moroccan/Turkish forum websites between September and October 2011. The questionnaire was completed by 201 individuals who were, on average, neither positive nor negative towards consanguinity. Respondents with a consanguineous partner were more positive, estimated the risk for the offspring lower and were less positive about the provision of risk information to consanguineous couples when compared with respondents without a consanguineous partner. Participants of Turkish origin had a more negative attitude towards consanguinity and estimated the reproductive risk higher than Moroccan participants. More than half of the respondents thought that information should be given before marriage, whereas only 10% thought it should never be provided. The general practitioner was most often mentioned (54%) as the designated professional to inform people. Information about genetic risks related to consanguinity should be offered early, preferably before marriage. The diversity of the target population requires various strategies to disseminate information and reach consanguineous couples with the offer of genetic counselling.

  10. Bleeding disorders in the tribe: result of consanguineous in breeding

    PubMed Central

    2010-01-01

    Objective To determine the frequency and clinical features of bleeding disorders in the tribe as a result of consanguineous marriages. Design Cross Sectional Study Introduction Countries in which consanguinity is a normal practice, these rare autosomal recessive disorders run in close families and tribes. Here we describe a family, living in village Ali Murad Chandio, District Badin, labeled as haemophilia. Patients & Methods Our team visited the village & developed the pedigree of the whole extended family, up to seven generations. Performa was filled by incorporating patients, family history of bleeding, signs & symptoms, and bleeding from any site. From them 144 individuals were screened with CBC, bleeding time, platelet aggregation studies & RiCoF. While for PT, APTT, VWF assay and Factor VIII assay, samples were kept frozen at -70 degrees C until tested. Results The family tree of the seven generations comprises of 533 individuals, 63 subjects died over a period of 20 years and 470 were alive. Out of all those 144 subjects were selected on the basis of the bleeding history. Among them 98(68.1%) were diagnosed to have a bleeding disorder; 44.9% patients were male and 55.1% patients were female. Median age of all the patients was 20.81, range (4 months- 80 yrs). The results of bleeding have shown that majority had gum bleeding, epistaxis and menorrhagia. Most common bleeding disorder was Von Willebrand disease and Platelet functional disorders. Conclusion Consanguineous marriages keep all the beneficial and adversely affecting recessive genes within the family; in homozygous states. These genes express themselves and result in life threatening diseases. Awareness, education & genetic counseling will be needed to prevent the spread of such common occurrence of these bleeding disorders in the community. PMID:20822539

  11. Rubisco small subunit gene family in cassava.

    PubMed

    Yeo, T W; Mak, Y M; Ho, K K

    1999-01-01

    Cassava leaves of two different cultivars, Brazil and Buloh, were used to isolate mRNA. The mRNA isolated was successfully used in the construction of cDNA libraries for each of the cultivars. The cDNA libraries were screened for members of ribulose-1,5-bisphosphate carboxylase/oxygenase small subunit gene family and positive clones were sequenced. A total of seven different SSU genes, of which five were from cultivar Brazil and two were from cultivar Buloh, were isolated. Comparison results show that even though all the sequences are highly similar, they can be classified into three subfamilies. Homology between members of the same subfamily is higher than homology between members from the same cultivar.

  12. Consanguinity Among Parents of Iranian Deaf Children

    PubMed Central

    Ajallouyan, Mohammad; Radfar, Shokofeh; Nouhi, Sima; Tavallaie, Seid Abbas; Amirsalari, Susan; Yousefi, Jaleh; Hasanali Fard, Mahdieh

    2016-01-01

    Background It seems that there is a relationship between consanguinity and profound hearing loss but there is little data about the association of consanguinity and hearing loss in Iran. Objectives The aim of this study is to demonstrate the causes of profound bilateral sensorineural hearing loss among Iranian samples who are candidates for cochlear implantation. Methods This study was retrospective, analytical, and designed to collect information about profound hearing impaired cases referred to the Baqiyatallah Cochlear implantation center using enumeration. A total of 310 children with profound hearing impairments participated in this study. They were aged from 6 months to 4 years old. The study was done between January 2007 and April 2009. Chi-square tests were used to show whether there was any statistical difference between the incidence of marital consanguinity of their parents and the normal population. Results Sixty-five percent of those 310 children had parents who had married with their relatives. Of the 203 (65%) parents that had consanguineous marriages, 132 were first cousins, which includes the children of two brothers (37 [11.8%] patrilateral parallel cousins), the children of two sisters (38 [12.2%] multi-lateral parallel cousins), or the children of a brother and a sister (57 [18.3%] cross cousins). Fifty-four (17.4%) of the parents were second cousins and 17 (5.2%) were beyond second cousins. Also, hearing loss etiology was obvious in 237 (76.3%) of the patients with profound hearing loss but was unknown in 73 (23.7%). Hereditary was identified as the most common cause in 33% of the cases. Conclusions Our data demonstrated a 65% occurrence of consanguineous marriage among the parents of deaf children, which is statistically different from the percentage of consanguineous marriage among Iranian population (38%). This indicates an obvious relationship between severe hearing loss and consanguineous marriage. PMID:28191326

  13. Consanguinity and epilepsy in Oran, Algeria: A case-control study.

    PubMed

    Chentouf, Amina; Talhi, Randa; Dahdouh, Aicha; Benbihi, Latifa; Benilha, Soumia; Oubaiche, Mohand Laid; Chaouch, Malika

    2015-03-01

    The goal of this case-control study was to identify the significance of consanguinity and other risk factors for epilepsy in Oran, Algeria. Unrelated epileptic patients upwards of 16 years, who attended the Neurology Department between October 2013 and March 2014 were included in the study. Controls, matched for age and sex, were selected among non-epileptic patients attending the same department during the same period. The risk factors evaluated were: consanguinity, family history of epilepsy, perinatal complications, infection of the central nervous system, mental retardation, neurological impairment, history of febrile seizures, severe head trauma, cerebrovascular diseases, and addiction. 101 cases and 202 controls participated in the study. Multivariate logistic regression identified five factors significantly associated with epilepsy: first-degree of consanguinity (odds ratio (OR)=2.15), history of epilepsy in first-degree relatives (OR=4.03), antecedent of febrile seizures (OR=5.38), severe head injury (OR=2.94) and mental retardation (OR=9.32). Consanguinity, family history of epilepsy, history of febrile seizures, severe head trauma and mental retardation are risk factors for epilepsy. The implementation of a strategy for prevention and awareness of the impact of consanguineous marriages as well as genetic counseling for couples with a family history of epilepsy are needed. Copyright © 2015 Elsevier B.V. All rights reserved.

  14. Consanguineous marriage in PR China: a study in rural Man (Manchu) communities.

    PubMed

    Wang, W; Qian, Cong; Bittles, A H

    2002-01-01

    Although there is a long history of consanguineous marriage in China, information on its prevalence is very limited. The Man (Qing) dynasty ruled China for over 250 years, but no consanguinity studies have been reported on this important population. The objective of the present investigation was to determine the present-day level of consanguineous marriage in the Man community, and to compare the data with existing consanguinity information on other Chinese populations. The study was conducted in a group of 11 rural Man communities in the north-eastern Chinese province of Liaoning. Household-based interviews were conducted by local staff on 513 couples, 418 of whom were Man with another 95 Man-Han inter-ethnic marriages. Basic pedigrees were constructed to determine the biological relationship between each set of spouses. Thirty of the 418 couples were in a consanguineous union, with a mean coefficient of inbreeding alpha = 0.0012. The small population sizes of the study may have contributed to the spatial variation in the patterns of inbreeding. Across generations there was a reduction in consanguineous marriages and an increase in inter-ethnic unions, which paralleled changes in civil marriage regulations.

  15. Consanguinity and disorders of sex development.

    PubMed

    Bashamboo, Anu; McElreavey, Ken

    2014-01-01

    Disorders of sex development (DSD) are defined as 'congenital conditions in which the development of chromosomal, gonadal, or anatomical sex is atypical' [Lee et al., Pediatrics 2006;118:e488-e500]. Studies conducted in Western countries, with low rates of consanguinity, show that truly ambiguous genitalia have an estimated incidence of 1:5,000 births. There are indications that the prevalence of DSD is higher in endogamous communities. The incidence of ambiguous genitalia in Saudi Arabia has been estimated at 1:2,500 live births; whilst in Egypt, it has been estimated at 1:3,000 live births. This may be due in part to an increase in disorders of androgen synthesis associated with 46,XX DSD. There is clearly a need for further studies to address the frequency of DSD in communities with high levels of consanguinity. This will be challenging, as an accurate diagnosis is difficult and expensive even in specialized centres. In developing countries with high levels of consanguinity, these limitations can be compounded by cultural, social and religious factors. Overall there is an indication that consanguinity may lead to an increase in incidences of both 46,XY and 46,XX DSD, and a co-ordinated study of populations with higher incidences of consanguinity/endogamy is needed to resolve this. © 2014 S. Karger AG, Basel

  16. Consanguineous marriage in Oman: understanding the community awareness about congenital effects of and attitude towards consanguineous marriage.

    PubMed

    Mazharul Islam, M

    2017-05-01

    Although consanguinity is widely practiced in Oman, the attitude of community towards consanguinity and the awareness of its health consequences to offspring remain largely unexplored. To analyse the levels and trends of consanguineous marriage and examine community awareness about congenital anomaly associated with consanguinity and attitude towards consanguinity in Oman. The data come from a nationally representative survey on Omani adults of age 18 years and above, irrespective of their marital status. Data were analysed using both descriptive and multivariate statistical techniques. The survey results indicate a very high rate (49%) of consanguineous marriage in Oman. There is a declining trend in consanguinity which may be attributed to decline in first cousin marriage. Omani adults have moderately high knowledge (69%) about health consequences of consanguineous marriage. There is a high positive attitude towards consanguineous marriage (75%) which appeared as a significant predictor of current practice of consanguineous marriage in Oman. The positive attitude of the Omani community towards consanguinity outweighs the negative health consequences of consanguinity, and the practice is likely to remain high in the near future. Strong educational and motivational programmes are needed to bring further changes in attitude towards consanguinity and, thus, reduce the burden of congenital anomalies associated with consanguinity in Oman.

  17. Consanguinity, endogamy and inborn errors of metabolism in Oman: a cross-sectional study.

    PubMed

    Al-Thihli, Khalid; Al-Murshedi, Fathiya; Al-Hashmi, Nadia; Al-Mamari, Watfa; Islam, M Mazharul; Al-Yahyaee, Said A

    2014-01-01

    The Sultanate of Oman, like many other Arab countries, has relatively high rates of consanguinity. Reports suggest that the incidence of inborn errors of metabolism (IEM) is also high in Oman. This retrospective cross-sectional study was designed to evaluate the number of patients with IEM being followed at the only two tertiary centers in Oman treating such patients, and to calculate the consanguinity rates among these families. The electronic medical records of all patients were reviewed for demographic and clinical characteristics. A total of 285 patients with IEM were being followed at the 2 centers involved; 162 (56.8%) were male and 123 (43.2%) were female. The history of consanguinity was documented or available for 241 patients: 229 patients (95%) were born to consanguineous parents related as second cousins or closer. First-cousin marriages were reported in 191 families (79.3%), while 31 patients (12.9%) were born to second cousins. The parents of 5 patients (2%) were related as double first cousins, and 2 patients (1%) were born to first cousins once removed. The average coefficient of inbreeding (F) in our study was 0.081. Seventeen patients (6%) had associated comorbid conditions other than IEM. Our study highlights the clinical burden of IEM in Oman and emphasizes the high consanguinity rates among the parents of affected patients. © 2014 S. Karger AG, Basel

  18. Tuberous breast and predisposition to breast deformity in consanguineous.

    PubMed

    Dessy, Luca Andrea; De Santo, Liliana; Onesti, Maria Giuseppina; Fallico, Nefer; Mazzocchi, Marco

    2017-05-30

    Tuberous breast deformity is a pathologic condition of the breast consisting of a constricting ring at the breast base, reduction in the volume of the breast parenchyma, and herniation of breast tissue through the nipple-areola complex with areola enlargement. This pathology is generally congenital and has an unknown etiopathogenesis. We report the first observation of tuberous breast deformity in consanguineous. This report suggests the potential role of a genetic base in the development of this deformity. Between May 2008 and March 2011, we observed six female patients from two different families, aged between 18 and 55 years, affected by tuberous breast deformity. The breast deformity was characterized by breast asymmetry in all six cases. Four patients underwent surgery to correct the deformity. Standardized objective measurements of breast and chest were taken. A Visual Analog Scale was used to evaluate patients' and physicians' satisfaction. The first three patients were consanguineous; two were first cousins, and the third was second cousin with one of the above. The other three patients were also from the same family: two sisters and their mother. According to Von Heimburg's classification, the patients presented different degrees of breast deformity. In all operated cases, a good esthetic result with a high satisfaction (average visual analog scale score 9) was achieved. The results remained stable over time and no revisions were needed after the 1-year follow-up. The possibility of a parental consanguinity for breast deformities such tuberous breast has never been described in the literature. This report suggests the possible genetic role in the development of tuberous breast deformity. Further studies and genetic tests are required to prove this hypothesis. © 2017 Wiley Periodicals, Inc.

  19. KIN AND NON-KIN MARRIAGES AND FAMILY STRUCTURE IN A RICH TRIBAL SOCIETY.

    PubMed

    Bakoush, Omran; Bredan, Amin; Denic, Srdjan

    2016-11-01

    Human consanguinity is often attributed to poverty, lack of education and social insecurity. Nevertheless, kin unions continue to be arranged in socioeconomically transformed societies. This study examined the structure of families and marriages in the rich tribal society of the United Arab Emirates, which has had a high gross domestic product for the last two generations and currently has one of the highest in the world. The respondents were 217 national medical students whose families are proportionally distributed to the population of the country emirates. The rate of parental consanguinity (defined as a union of any two cousins) was 36%. The social status and mean size of consanguineous and non-consanguineous families were not significantly different. In non-consanguineous families, polygamy was more common and the number of half-siblings per family was higher. The extended families were on average 7% larger among non-consanguineous families. In contrast, for the extended families of the participants' grandparents, non-consanguineous families were smaller than their consanguineous counterparts. Participants from consanguineous families indicated that marriage of either a son or daughter was more difficult to arrange than did participants from non-consanguineous families. Though consanguineous parents had their offspring marry consanguineously more often than non-consanguineous parents, the numbers of married offspring in the two groups of families were not different. Consanguineous parents have more difficulty than non-consanguineous parents in finding spouses for themselves and for their offspring, and they arranged kin marriages for their children more often.

  20. Axial mesodermal dysplasia complex: a new case with parental consanguinity.

    PubMed

    Mota, C R; Azevedo, M; Rocha, G; Manuela, F; Coelho, R; Lima, M R

    2000-01-01

    A female is described with axial mesodermal dysplasia complex (AMDC) born to a consanguineous couple. This is thought to be the first description of a patient with AMDC born to consanguineous parents.

  1. A review of consanguinity in Ireland--estimation of frequency and approaches to mitigate risks.

    PubMed

    Barrett, P

    2016-02-01

    Over half of marriages are consanguineous in some countries, and about 10 % of children worldwide have consanguineous parents. Perceived benefits of consanguineous marriage (CM) include preservation of tradition, stronger family ties, financial advantages, and bride protection. Potential harms include autosomal recessive disorders, complex congenital malformations, stillbirths, postnatal mortality. There have been no population-based data published on frequency of CM in Ireland since 1970. International prevalence figures and published estimates of CM were applied to 2011 Irish Census data to calculate the frequency of CM in at-risk groups. Searches of the published and grey literature were conducted to review evidence-based approaches to mitigate risks of CM and apply findings to the Irish context. The estimated number of consanguineous couples has grown in subpopulations in Ireland in the past decade, particularly among Pakistanis (>967 couples), Nigerians (418-794 couples) and Indians (54-2099 couples). There are up to 3000 consanguineous couples in the Traveller community. Evidence for approaches to mitigate associated risks supports a three-stranded approach: family-centred genetics services, training and education of healthcare professionals (HCPs), community education programmes. Consanguineous couples desire accurate information for reproductive decisions, but may avoid hospital-based services due to language barriers, poor understanding, stigma. Uptake of genetic counselling and carrier testing is higher if a family-centred approach is provided, ideally through home visits in the couple's preferred language. Targeted education programmes enhance community awareness and have led to declines in CM elsewhere. Education of HCPs is necessary to clarify referral pathways, as many have exaggerated impressions of the genetic risks.

  2. The influence of the wahlund effect on the consanguinity hypothesis: consequences for recessive disease incidence in a socially structured pakistani population.

    PubMed

    Overall, Andrew D J

    2009-01-01

    Standard population genetic theory predicts that the relative risk of inheriting recessive disorders between consanguineous and non-consanguineous populations can be manyfold. However, it is rarely considered that consanguineous populations might be composites of socially defined endogamous and genetically differentiated subpopulations. A recent study of a British Pakistani population found evidence to suggest that extended families (biraderi) could contribute significantly to excessive homozygosity over that contributed by consanguinity. This study sets out to illustrate the potential of cryptic population substructure (the Wahlund effect) to contribute to recessive disease incidence in populations with complex social structure. Population parameter estimates were drawn from a recent study of the British Pakistani population along with allele frequency estimates of nine recessive inborn errors of metabolism. The relative contribution of consanguinity and biraderi endogamy to recessive disease incidence was predicted. Population substructure of the magnitude estimated from studies of biraderi endogamy are sufficient to significantly contribute to the incidence of recessive disorders within consanguineous populations. Because non-consanguineous couples have a higher risk of sharing the same recessive mutation in a substructured population relative to a non-substructured population, the health benefits of avoiding consanguinity in these situations is likely to be less pronounced than the standard consanguinity hypothesis predicts. Copyright 2008 S. Karger AG, Basel.

  3. A Small Library in Family Planning.

    ERIC Educational Resources Information Center

    Planned Parenthood Federation of America, Inc., New York, NY.

    This annotated listing of books is intended as a reference for anyone seeking an authoritative introduction to population and family planning information, as a world, family, or individual concern. For each entry, the International Standard Book Number (ISBN) is provided if available. The number preceding each reference represents the…

  4. Importance of Genetic Studies in Consanguineous Populations for the Characterization of Novel Human Gene Functions

    PubMed Central

    Shihab, Hashem A.; Rodriguez, Santiago; Gaunt, Tom R.; Day, Ian N.M.

    2016-01-01

    Summary Consanguineous offspring have elevated levels of homozygosity. Autozygous stretches within their genome are likely to harbour loss of function (LoF) mutations which will lead to complete inactivation or dysfunction of genes. Studying consanguineous offspring with clinical phenotypes has been very useful for identifying disease causal mutations. However, at present, most of the genes in the human genome have no disorder associated with them or have unknown function. This is presumably mostly due to the fact that homozygous LoF variants are not observed in outbred populations which are the main focus of large sequencing projects. However, another reason may be that many genes in the genome—even when completely “knocked out,” do not cause a distinct or defined phenotype. Here, we discuss the benefits and implications of studying consanguineous populations, as opposed to the traditional approach of analysing a subset of consanguineous families or individuals with disease. We suggest that studying consanguineous populations “as a whole” can speed up the characterisation of novel gene functions as well as indicating nonessential genes and/or regions in the human genome. We also suggest designing a single nucleotide variant (SNV) array to make the process more efficient. PMID:27000383

  5. Consanguinity and its sociodemographic differentials in Bhimber District, Azad Jammu and Kashmir, Pakistan.

    PubMed

    Jabeen, Nazish; Malik, Sajid

    2014-06-01

    Kashmiri population in the northeast of Pakistan has strong historical, cultural and linguistic affinities with the neighbouring populations of upper Punjab and Potohar region of Pakistan. However, the study of consanguineous unions, which are customarily practised in many populations of Pakistan, revealed marked differences between the Kashmiris and other populations of northern Pakistan with respect to the distribution of marriage types and inbreeding coefficient (F). The current descriptive epidemiological study carried out in Bhimber district of Mirpur division, Azad Jammu and Kashmir, Pakistan, demonstrated that consanguineous marriages were 62% of the total marriages (F=0.0348). First-cousin unions were the predominant type of marriages and constituted 50.13% of total marital unions. The estimates of inbreeding coefficient were higher in the literate subjects, and consanguinity was witnessed to be rising with increasing literacy level. Additionally, consanguinity was observed to be associated with ethnicity, family structure, language, and marriage arrangements. Based upon these data, a distinct sociobiological structure, with increased stratification and higher genomic homozygosity, is expected for this Kashmiri population. In this communication, we present detailed distribution of the types of marital unions and the incidences of consanguinity and inbreeding coefficient (F) across various sociodemographic strata of Bhimber/Mirpuri population. The results of this study would have implication not only for other endogamous populations of Pakistan but also for the sizeable Kashmiri community immigrated to Europe.

  6. Profiling β Thalassemia Mutations in Consanguinity and Nonconsanguinity for Prenatal Screening and Awareness Programme

    PubMed Central

    Kumar, Ravindra; Arya, Vandana; Agarwal, Sarita

    2015-01-01

    Mutation spectrum varies significantly in different parts and different ethnic groups of India. Social factors such as preference to marry within the community and among 1st degree relatives (consanguinity) play an important role in impeding the gene pool of the disease within the community and so in society by and large. The present paper discusses the role of consanguinity in profiling of beta thalassemia mutation, and thus the approach for prenatal screening and prevention based awareness programme. Clinically diagnosed 516 cases of beta thalassemia were screened at molecular level. A detailed clinical Proforma was recorded with the information of origin of the family, ethnicity, and consanguinity. The present study reports that subjects originating from Uttar Pradesh, Uttarakhand, Bihar, and Jharkhand have c.92+5G>C and c.124_127delTTCT mutation as the commonest mutation compared to the subjects hailing from Madhya Pradesh and Chhattisgarh and Nepal where sickle mutation was found more common. In 40 consanguineous unions more common and specific beta mutations with higher rate of homozygosity have been reported. This consanguinity-based data helps not only in deciding target oriented prenatal diagnostic strategies but also in objective based awareness programmes in prevention of thalassemia major birth. PMID:26576156

  7. [Scattered papules in three Togolese children from a consanguineous marrige: epidermodysplasia verruciformis].

    PubMed

    Saka, B; Mouhari-Touré, A; Kombaté, K; Pitché, P; Tchangaï-Walla, K

    2009-06-01

    Epidermodysplasia verruciformis (EV) is a rare condition characterized by diffuse flat wart-like lesions. It is an autosomal recessive genodermatosis associated with susceptibility to infection by specific human papillomavirus genotypes and a high risk of skin cancer. In this report we describe three cases of EV after a consanguineous marriage in a family with no history of EV.

  8. Attitude of Saudi Arabian adults towards consanguineous marriage

    PubMed Central

    Alharbi, Omar A.; Al-Shaia, Walaa A.; Al-Hamam, Abdulaziz A.; Al-Marzoug, Hala M.; Ahmed, Anwar E.; Bagha, Muhammed

    2015-01-01

    Background: Research on the attitudes of Saudi adults towards consanguinity is scarce. The study aimed to explore the attitudes towards consanguinity and its associations with socio-demographic characteristics in a sample of Saudi adults. Methods: A cross-sectional study was conducted using a self-administered questionnaire. A total of 386 outpatient waiting-area attendees at King Abdul-Aziz Medical City-Riyadh were included. Participants were asked about their socio-demographic characteristics, attitude towards consanguinity and the reasons behind this. Results: The positive attitude towards consanguinity among the study respondents was 48.1% with 95% confidence interval (42.91–53.33%). Social and traditional culture (59.9%) were found to be the predominant reasons for favoring consanguinity in Saudi Arabia. Evidence against a positive attitude towards consanguinity was noted in respondents who received medical information about consanguinity versus those who had not received medical information (42.3% vs. 57%, p-value = 0.008). According to the multivariate logistic model, the odds of a positive attitude towards consanguinity were 2 times higher for males (adjusted odds ratio [aOR]: 2.2; 95% CI: 1.147, 4.290) and 4.1 times higher in respondents in consanguineous marriages (aOR: 4.1; 95% CI: 2.350, 7.156). The odds of a positive attitude towards consanguinity were 50% less in respondents who received health information on consanguinity compared to those who had not received health information about consanguinity (aOR: 0.50; 95% CI: 0.253, 0.863). Conclusion: One in every two Saudi adults favors consanguinity however, Saudi men and women differ in their attitudes towards consanguinity. Receiving health information on consanguinity was associated with a negative attitude towards this practice. PMID:26835408

  9. [Analysis of clinical phenotype and mode of inheritance in retinitis pigmentosa patients with consanguineous marriage].

    PubMed

    Rong, Wei-ning; Sheng, Xun-lun; Liu, Ya-ni

    2012-10-01

    To analyse the mode of inheritance and clinical characteristics of retinitis pigmentosa (RP) patients with consanguineous marriage. RP patients were recruited for this study in Ningxia Eye Hospital from September 2009 to July 2011. All patients received complete ophthalmic examination. The mode of inheritance were determined based on family history and marriage history. Clinical features were characterized by complete ophthalmic examinations including visual acuity, macular OCT, visual field and electroretinogram (ERG). A total of 143 individuals with RP (33 families) were recruited. Based on analysis of family history and marriage history, 20 RP families (23 patients) had consanguineous marriage history accounted for 60.6% RP families (16.1% RP patients). There were 4 patients (from 4 families) diagnosed as Usher syndrome. In 20 RP families with consanguineous marriage history, 7 families (35.0%) were Hui ethnicity and 13 families (65%) were Han ethnicity. The marriages of 15 families were between first cousins and 3 families were between second cousins, only 2 families were between half cousins matrimony. Of 23 RP patients, 12 were males and 11 were females. The average age of onset was 11.4 ± 6.8 years and the average age of recruitment was (32.0 ± 13.5) years. The best-corrected visual acuity was less than 0.6 in 78.2% patients. According to the features of the fundus, 13 patients were classical retinitis pigmentosa and 10 patients were retinitis pigmentosa sine pigmento. Visual field examination showed that all patients had varying degrees of peripheral visual field defect. Retinal neuroepithelial layer of macular and peripheral retina became thinner and retinal photoreceptors were disappeared. The average thickness of macular fovea was (186.1 ± 78.7) µm on right eyes and (187.4 ± 76.3) µm on left eyes. The incidence of RP with consanguineous marriages was high in Ningxia Region. The mode of inheritance of RP patients with consanguinity is autosomal

  10. Consanguinity-related hyperdontia: An orthopantomographic study.

    PubMed

    Shokry, Shereen M; Alenazy, Mohammed S

    2013-11-01

    The aim of this retrospective study was to describe the distribution of the non-syndromal supernumerary teeth (NSST) in a population of patients who attended the clinics of Riyadh Colleges of Dentistry and Pharmacy (RCsDP), Riyadh, Saudi Arabia. The study reviewed 1521 panoramic radiographs of Saudi and non-Saudi subjects who attended RCsDP clinic from November 2009 to November 2010. The data were analyzed using the Statistical Package for Social Sciences, utilizing Chi-square. Eighteen (1.2%) patients were found to have NSST, comprising twelve males (66.7%), and six females (33.3%). The most common supernumerary teeth (ST) were the pre-molars six cases (33.3%), followed by the mesiodens, five cases (27.8%). The canines and distomolars three cases (16.6%) each respectively, while the least were the lateral incisors and paramolars of the two cases (11.1%) each. Consanguinity appeared to have a role in the development of hyperdontia in Saudi population because 13 cases (72.2%) out of 18 cases had consanguineous parents, while all patients having consanguineous parents had eumorphic ST.

  11. Turkish women show preference for small families.

    PubMed

    1995-01-01

    A brief summary is provided of results from the 1993 Turkish Demographic and Health Survey on women's family size preferences. Over 66% of married women 15-49 years old reported a desire to stop childbearing, and 14% desired a delay of at least 2 years in future childbearing. The ideal family size was reported as 2.4 children per woman, while the total fertility rate was 2.7 children per woman. 33% of births in the 5 years before the survey were unwanted or mistimed. 63% of married women used family planning. 33% used modern methods. 19% used the IUD, 7% used the condom, and 5% used the pill. The most widely used method was withdrawal (26%). The abortion rate was 18 per 100 pregnancies. 67% were performed by private physicians, and 27% were performed in government hospitals. 58% of women who had had an abortion reported their reason as a desire to stop childbearing. Post abortion, 27% were using withdrawal and 39% used no method at all. Only 32% were using modern contraception post abortion. Maternal health has improved to the point where 63% of mothers received prenatal care, and 76% were assisted at delivery by medical personnel. Infant mortality declined by 35% to 53 deaths per 1000 births. Under-5 mortality declined from 97 in 1983 to 61 in 1993. About 59% of children 12-23 months old were fully immunized. Almost 20% of children by age 5 years had chronic malnutrition, particularly in rural areas and among children with mothers with no education.

  12. The influence of past endogamy and consanguinity on genetic disorders in northern Sweden.

    PubMed

    Bittles, A H; Egerbladh, I

    2005-09-01

    It has been widely believed that consanguineous marriage was infrequent in northern Europe. As part of ongoing studies into the population structure of northern Sweden, the Demographic DataBase of Umeå University has undertaken digitization of the parish record books of the Swedish Lutheran Church, which date back to the late 17th century. To examine the prevalence and patterns of consanguineous marriage, information from the DataBase was abstracted for the Skellefteå region during the period 1720-1899 and extended family pedigrees constructed. Of the 14,639 marriages recorded, 3,043 (20.8%) were between couples related as sixth cousins or closer. Following changes in the Swedish civil law in 1844 that removed the requirement of royal dispensation for first cousin unions, a significant increase in first cousin marriages occurred during the next two generations, even though the total population of the region grew significantly. There was also strong evidence that consanguineous marriages were favoured within particular families. The findings of the study are consistent with the patterns of single gene disorders reported in specific communities in the region, and they suggest that founder effect, drift and consanguinity all were important influences on population genetic structure in previous generations.

  13. IFT27, encoding a small GTPase component of IFT particles, is mutated in a consanguineous family with Bardet-Biedl syndrome.

    PubMed

    Aldahmesh, Mohammed A; Li, Yuanyuan; Alhashem, Amal; Anazi, Shams; Alkuraya, Hisham; Hashem, Mais; Awaji, Ali A; Sogaty, Sameera; Alkharashi, Abdullah; Alzahrani, Saeed; Al Hazzaa, Selwa A; Xiong, Yong; Kong, Shanshan; Sun, Zhaoxia; Alkuraya, Fowzan S

    2014-06-15

    Bardet-Biedl syndrome (BBS) is an autosomal recessive ciliopathy with multisystem involvement. So far, 18 BBS genes have been identified and the majority of them are essential for the function of BBSome, a protein complex involved in transporting membrane proteins into and from cilia. Yet defects in the identified genes cannot account for all the BBS cases. The genetic heterogeneity of this disease poses significant challenge to the identification of additional BBS genes. In this study, we coupled human genetics with functional validation in zebrafish and identified IFT27 as a novel BBS gene (BBS19). This is the first time an intraflagellar transport (IFT) gene is implicated in the pathogenesis of BBS, highlighting the genetic complexity of this disease.

  14. Spectra of small Koronis family members

    NASA Astrophysics Data System (ADS)

    Thomas, C.; Rivkin, A.; Trilling, D.; Moskovitz, N.

    2014-07-01

    The space-weathering process and its implications for the relationships between S- and Q-type asteroids and ordinary chondrite meteorites are long-standing problems in asteroid science. Although the visible and near-infrared spectra of S- and Q-type objects qualitatively show the same absorption features and quantitatively show evidence of the same minerals, the S types display increased spectral slopes and muted absorption features compared to the Q types. This spectral mismatch is consistent with the effects of the space weathering process. Binzel et al. provided the missing link between Q- and S-type bodies in near-Earth space by showing a reddening of spectral slope in objects from 0.1 to 5 km that corresponded to the transition from Q- to S-type spectra. This result implied that size, and therefore age, is related to the relationship between Q- and S-type. The existence of Q-type objects in the main belt was not confirmed until Mothe-Diniz and Nesvorny (2008) found them in young S-type clusters. To investigate the trend from Q to S in the main belt, we examined space weathering within the old main-belt Koronis family using a spectrophotometric survey (Rivkin et al. 2011, Thomas et al. 2011). Rivkin et al. (2011) identified several potential Q-type objects within the Koronis family. Our Q-type candidates were identified using broad-band spectrophotometry and could not be taxonomically classified on that basis alone. We obtained follow-up visible and near-infrared spectral observations of our potential Q-type objects, (26970) Elias, (45610) 2000 DJ_{48}, and (37411) 2001 XF_{152}, using Gemini and Magellan. We will present the results of these spectral follow-up observations. Observations of (26970) Elias demonstrate that the object is more consistent with the average Q-type spectrum than the average S-type spectrum.

  15. Meckel Gruber syndrome: occurrence in non-consanguineous marriages.

    PubMed

    de Silva, M V C; Senanayake, H; Siriwardana, K D V P

    2004-03-01

    Meckel Gruber syndrome is an uncommon, lethal, autosomal recessive disorder, associated consistently with polycystic kidneys, posterior encephalocoele and polydactly. We report three cases in non-consanguineous marriages, suggesting that the single gene defect occurs more commonly in non-consanguineous marriages than mutant genes associated with other autosomal recessive disorders that are usually related with consanguineous marriages. The usefulness of prenatal diagnosis is discussed.

  16. Is consanguineous marriage religiously encouraged? Islamic and Iranian considerations.

    PubMed

    Akrami, Seyed Mohammad; Osati, Zahra

    2007-03-01

    Consanguineous marriage has had considerable attention as a causative factor in the prevalence of genetic disorders. Iran, with its majority Muslim population, has a high rate of consanguineous marriage. In Iranian tradition, first cousin marriage is an acceptable and appreciated custom. However, there seems to be no encouragement of consanguineous marriage in the Islamic context; it is merely mentioned as a traditional and common custom. This paper may help medical professionals providing premarital genetic counselling, who are regularly asked about consanguineous marriage, especially in Islamic communities. Increased public awareness via the mass media would seem to be a priority.

  17. Consanguinity and other marriage market effects of a wealth shock in Bangladesh.

    PubMed

    Mobarak, Ahmed Mushfiq; Kuhn, Randall; Peters, Christina

    2013-10-01

    This paper uses a wealth shock from the construction of a flood protection embankment in rural Bangladesh coupled with data on the universe of all 52,000 marriage decisions between 1982 and 1996 to examine changes in marital prospects for households protected by the embankment relative to unprotected households living on the other side of the river. We use difference-in-difference specifications to document that brides from protected households commanded larger dowries, married wealthier households, and became less likely to marry biological relatives. Financial liquidity-constrained households appear to use within-family marriage (in which one can promise ex-post payments) as a form of credit to meet up-front dowry demands, but the resultant wealth shock for households protected by the embankment relaxed this need to marry consanguineously. Our results shed light on the socioeconomic roots of consanguinity, which carries health risks for offspring but can also carry substantial benefits for the families involved.

  18. Consanguinity trends and correlates in the Palestinian Territories.

    PubMed

    Assaf, Shireen; Khawaja, Marwan

    2009-01-01

    Secondary analysis of the trends and correlates of consanguinity in the Palestinian Territories was conducted using data from two separate surveys in 1995 and 2004. The analysis was conducted on ever-married women aged 15-54 who were asked about their relation to their husband in both surveys. A total of 16,197 women in 1995 and 4971 women in 2004 were successfully interviewed. Consanguinity was found to be widely practised in the Palestinian Territories with rates of total consanguinity reaching 45% of all marriages in 2004. Analysis was conducted with the data from the two surveys combined and this indicated that consanguinity was significantly decreasing with time after controlling for other variables. Age of the women, their age at marriage, region and locality type they lived in and their standard of living were all found to be significant predictors of consanguinity. The education level of the women was not found to be significant. After controlling for the survey year, women's labour force status was also found to be a non-significant predictor of consanguinity. Although consanguinity was found to be significantly decreasing slowly with time after controlling for other variables, the future trends of consanguinity are not known due to the unstable political situation in the territories, which could have a direct effect on marriage patterns.

  19. The Implications of Parental Consanguinity on the Care of Neonates.

    PubMed

    Ng, Diana

    2016-08-01

    Approximately 6% of births worldwide, 7.9 million children, are born with a serious genetic congenital abnormality each year. A factor thought to increase the prevalence of birth defects is parental consanguinity, which is a social custom practiced in at least 20% of the world's population. The purpose of this article is to explore the relationship between consanguinity and congenital defects. This article also aims to enhance neonatal healthcare practitioners' comprehension of its implications for practice and research. A review of literature was compiled from a search of the online databases Cumulative Index of Nursing and Allied Health (CINAHL), PubMed, EBSCO MegaFILE, and Google Scholar. Literature pertinent to this topic primarily consists of research studies that examine the inbreeding depression phenomenon through comparison of the prevalence of birth defects among the offspring of consanguineous and nonconsanguineous couples. Current studies indicate that the progeny of consanguineous couples are at an increased risk of congenital defects compared with those of nonconsanguineous couples. Consanguinity is one risk factor among many that can lead to a major birth defect. Relationships between consanguineous populations and neonatal healthcare practitioners such as registered nurses, advanced practice nurses, and physicians could significantly alter neonatal health outcomes. Specific recommendations such as genetic counseling and therapeutic communication are discussed. Further studies need to investigate the connection between consanguinity and birth defects while controlling for nongenetic variables. Moreover, a focus on consanguineous communities in the United States would prove beneficial.

  20. Training and HRD Strategies in Family and Non-Family Owned Small Businesses: A Comparative Approach.

    ERIC Educational Resources Information Center

    Matlay, Harry

    2002-01-01

    A survey of 6,000 British small businesses, 600 interviews, and 120 case studies found that 70-80% were family owned; most favored informal management styles. In family-owned businesses, training of nonfamily employees was considered less crucial; investments in the latter were related to long-term business strategies and potential succession.…

  1. Endogamy, consanguinity and community disease profiles.

    PubMed

    Bittles, A H

    2005-01-01

    Considerable attention is paid to the role of consanguineous marriage as a causative factor in the prevalence of genetic disorders. At the same time, the potential influence of community endogamy on overall levels of homozygosity and disease profiles remains largely under-investigated. With the ongoing global epidemiological transition from infectious to non-communicable disease, the impact of genetic disorders will become increasingly important and a thorough understanding of the determinants of human population-genetic structure will be all the more necessary. In particular, the genetic components of adult-onset diseases will become more obvious and assume greater significance. Similarly, refinements of study design to incorporate intercommunity genetic variation appear to be an essential prerequisite in pharmacogenetic research if the concept of individualized treatments is to achieve reality, with equivalent subject-control comparison difficulties also predicted in forensic genetics. Copyright 2005 S. Karger AG, Basel.

  2. Genetic Counseling and Screening of Consanguineous Couples and Their Offspring: Recommendations of the National Society of Genetic Counselors.

    PubMed

    Bennett, Robin L; Motulsky, Arno G; Bittles, Alan; Hudgins, Louanne; Uhrich, Stefanie; Doyle, Debra Lochner; Silvey, Kerry; Scott, C Ronald; Cheng, Edith; McGillivray, Barbara; Steiner, Robert D; Olson, Debra

    2002-04-01

    The objective of this document is to provide recommendations for genetic counseling and screening for consanguineous couples (related as second cousins or closer) and their offspring with the goals of1. providing preconception reproductive options2. improving pregnancy outcome and identifying reproductive choices3. reducing morbidity and mortality in the 1st years of life, and4. respecting psychosocial and multicultural issues.The recommendations are the opinions of a multicenter working group (the Consanguinity Working Group (CWG)) with expertise in genetic counseling, medical genetics, biochemical genetics, genetic epidemiology, pediatrics, perinatology, and public health genetics, which was convened by the National Society of Genetic Counselors (NSGC). The consensus of the CWG and NSGC reviewers is that beyond a thorough medical family history with follow-up of significant findings, no additional preconception screening is recommended for consanguineous couples. Consanguineous couples should be offered similar genetic screening as suggested for any couple of their ethnic group. During pregnancy, consanguineous couples should be offered maternal-fetal serum marker screening and high-resolution fetal ultrasonography. Newborns should be screened for impaired hearing and detection of treatable inborn errors of metabolism. These recommendations should not be construed as dictating an exclusive course of management, nor does use of such recommendations guarantee a particular outcome. The professional judgment of a health care provider, familiar with the facts and circumstances of a specific case, will always supersede these recommendations.

  3. Consanguineous marriages in the province of Antalya, Turkey.

    PubMed

    Alper, O M; Erengin, H; Manguoğlu, A E; Bilgen, T; Cetin, Z; Dedeoğlu, N; Lüleci, G

    2004-01-01

    To assess the trends in the frequency and the medical effects of consanguinity in the south coast of Turkish population using local and national data in the last 11 years. This cross-sectional study was carried out in Manavgat province, which is a major tourism center on the Mediterranean coast of Turkey. The authors studied consanguineous marriages in rural and urban population in the Mediterranean coast, Manavgat province, Turkey, via a 1500 random survey sample of married couples. There has been a significant increase in the incidence of consanguineous marriages in rural areas (40.7%) since 1989 in the southern population of Turkey. The results showed that the most frequent type of marriage was between the first cousins. It is found that there is no statistically significant difference between the consanguineous and non-consanguineous marriages in the different age groups. The results were discussed on the basis of educational status, reasons for having consanguineous marriages and the general medical effects as well as with the relation of congenital malformations. The custom of consanguineous unions in the Mediterranean population of Turkey is still extremely high, and preventive measures should be done to decrease its frequency and associated complications.

  4. Familial risk of small intestinal carcinoid and adenocarcinoma.

    PubMed

    Kharazmi, Elham; Pukkala, Eero; Sundquist, Kristina; Hemminki, Kari

    2013-08-01

    Small intestinal cancer (SIC) is rare, and its etiology is poorly understood. We compared clusters of families with SICs of different histologic subtypes. By using the nationwide family cancer data sets of Sweden and Finland, we identified a cohort of 9964 first-degree relatives of 1799 patients with SIC, diagnosed from 1961 through 2009. Data were collected from time periods as long as 47 years (mean, 35.4 y), and cancer incidence was determined. Standardized incidence ratios (SIRs) were calculated and stratified by sex, age, time period, and cancer type, using the incidence rates for the entire national population as the reference. Among the 1799 SIC cases, 1.1% had a sibling with SIC, so the SIR was 11.8 (95% confidence interval [CI], 7.2-18.2); 1.1% had a parent or child with SIC (SIR, 3.5; 95% CI, 2.0-5.6). The SIR of concordant carcinoid histology of SIC among siblings was 28.4 (95% CI, 14.7-49.6; n = 12) and in parent-child pairs was 9.9 (95% CI, 5.4-16.6; n = 14). The familial risk of concordant histologic subtypes increased for siblings diagnosed with adenocarcinoma, but only 2 familial cases were identified. In family members of patients with SIC of the adenocarcinoma subtype, risks of colorectal and bladder cancer were modestly but significantly increased compared with the general population. Family members of patients with SIC of the carcinoid subtype had an increased risk for kidney cancer and polycythemia vera. Based on data from our population-based study, first-degree relatives of patients with small intestinal carcinoid tumors have developed these tumors with high incidence. Because of the rareness of this tumor, the absolute risk remains moderate even within families. Gastroenterologists could inform patients with small intestinal carcinoids about the familial risk and encourage counseling for their first-degree relatives. Studies are needed to identify genetic factors that affect susceptibility to SIC. Copyright © 2013 AGA Institute. Published

  5. Prevalence of consanguineous marriages in South Sinai, Egypt.

    PubMed

    Yamamah, G; Abdel-Raouf, E; Talaat, A; Saad-Hussein, A; Hamamy, H; Meguid, N A

    2013-01-01

    A total of 3961 married couples from six major geographical areas representing the South Sinai governorates in Egypt were studied to assess the rate of consanguineous marriage. The population of six selected areas (St Catherines, Nuweiba, Abu Rudeis, Ras Sudr, El Tor and Abu Zenima) were subdivided into Bedouin, urban and mixed populations. A questionnaire-based interview was conducted showing that the consanguinity rate in this region is 37.5%, with the highest rate recorded in Abu Rudeis (52.3%) and lowest rate in Nuweiba (24.1%). Consanguinity was significantly higher among the Bedouin population compared with the urban population in Abu Rudeis, Ras Sudr, El Tor and Abu Zenima, while in St Catherines and Nuweiba there was no statistically significant difference. Among consanguineous couples, 5%, 60% and 35% were double first cousins, first cousins and second cousins respectively. The mean inbreeding coefficient α of the studied population was 0.01845.

  6. Posttranslational lipid modification of Rho family small GTPases.

    PubMed

    Mitin, Natalia; Roberts, Patrick J; Chenette, Emily J; Der, Channing J

    2012-01-01

    The Rho family comprises a major branch of the Ras superfamily of small GTPases. A majority of Rho GTPases are synthesized as inactive, cytosolic proteins. They then undergo posttranslational modification by isoprenoid or fatty acid lipids, and together with additional carboxyl-terminal sequences target Rho GTPases to specific membrane and subcellular compartments essential for function. We summarize the use of biochemical and cellular assays and pharmacologic inhibitors instrumental for the study of the role of posttranslational lipid modifications and processing in Rho GTPase biology.

  7. Ras Family Small GTPase-mediated Neuroprotective Signaling in Stroke

    PubMed Central

    Shi, Geng-Xian; Andres, Douglas A.; Cai, Weikang

    2012-01-01

    Selective neuronal cell death is one of the major causes of neuronal damage following stroke, and cerebral cells naturally mobilize diverse survival signaling pathways to protect against ischemia. Importantly, therapeutic strategies designed to improve endogenous anti-apoptotic signaling appear to hold great promise in stroke treatment. While a variety of complex mechanisms have been implicated in the pathogenesis of stroke, the overall mechanisms governing the balance between cell survival and death are not well-defined. Ras family small GTPases are activated following ischemic insults, and in turn, serve as intrinsic switches to regulate neuronal survival and regeneration. Their ability to integrate diverse intracellular signal transduction pathways makes them critical regulators and potential therapeutic targets for neuronal recovery after stroke. This article highlights the contribution of Ras family GTPases to neuroprotective signaling cascades, including mitogen-activated protein kinase (MAPK) family protein kinase- and AKT/PKB-dependent signaling pathways as well as the regulation of cAMP response element binding (CREB), Forkhead box O (FoxO) and hypoxia-inducible factor 1(HIF1) transcription factors, in stroke. PMID:21521171

  8. Characterization of EHT 1864, a novel small molecule inhibitor of Rac family small GTPases.

    PubMed

    Onesto, Cercina; Shutes, Adam; Picard, Virginie; Schweighoffer, Fabien; Der, Channing J

    2008-01-01

    There is now considerable experimental evidence that aberrant activation of Rho family small GTPases promotes uncontrolled proliferation, invasion, and metastatic properties of human cancer cells. Therefore, there is considerable interest in the development of small molecule inhibitors of Rho GTPase function. However, to date, most efforts have focused on inhibitors that block Rho GTPase function indirectly, either by targeting enzymes involved in post-translational processing or downstream protein kinase effectors. We have reported the identification and characterization of the EHT 1864 small molecule as an inhibitor of Rac family small GTPases, placing Rac1 in an inert and inactive state and then impairing Rac1-mediated functions in vivo. Our work suggests that EHT 1864 selectively inhibits Rac1 downstream signaling and cellular transformation by a novel mechanism involving guanine nucleotide displacement. This chapter provides the details for some of the biochemical and biological methods used to characterize the mode of action of EHT 1864 on Rac1 and its impact on Rac1-dependent cellular functions.

  9. Effects of consanguinity on pre-reproductive mortality: does demographic transition matter?

    PubMed

    Alfonso-Sánchez, Miguel A; Peña, José A

    2005-01-01

    The aim of this study was to investigate whether there is an increase on premature deaths due to genetically determined factors at the beginning of a demographic transition. We also analyzed the effects of parental consanguinity on offspring mortality from an epidemiological viewpoint, using parish records for family reconstitution in a Basque population (1800-1990). Among the offspring of unrelated parents, 13.1% died before their first year of life (infant mortality), and 22.8% died before the age of 16 (pre-reproductive mortality). Significant increases in both infant (23.6%) and pre-reproductive (38.5%) deaths were found among the progeny of first cousins or closer relatives, 1C (F > or = 0.0625). The corresponding relative risks of mortality were 1.79 (95% confidence limits: 1.37-2.28) and 1.68 (1.38-2.01), respectively. Estimates of the population attributable risks indicate that 4% of pre-reproductive mortality is ascribable to consanguineous unions, although kinships other than 1C produced only slight increases in offspring mortality. Evidence on the relationship between the demographic transition and the increase in premature deaths due to genetic factors was obtained through a principal component analysis (95.1% of variance accounted for). During the initial stages of the demographic transition, the population experienced substantial elevations in mean family size, natural increase of the population, frequency of close consanguineous matings (1C), and death rate due to congenital anomalies and perinatal diseases. These findings are of interest for the health services of many developing societies in Asia, Africa, and Latin America, which are nowadays immersed in the demographic transition process.

  10. Consanguinity and prereproductive mortality in the Utah Mormon population.

    PubMed

    Jorde, L B

    2001-01-01

    To test the effects of parental consanguinity on mortality among offspring, inbreeding coefficients were estimated for 303,675 members of the Utah Mormon population who were born between 1847 and 1945. Although consanguinity has been relatively rare in this population, the large sample size permitted the identification of more than 3,500 inbred offspring. Among the offspring of unrelated parents, 13.2% died before the age of 16. Significant elevations in prereproductive mortality were seen among the offspring of first-cousin marriages (22%) and among the offspring of closer unions (32%). The cor- responding relative risks are 1.70 (95% confidence limits = 1.52, 1.91) and 2.41 (95% confidence limits = 1.59, 3.41), respectively. Other categories of relationship did not produce significant elevations in offspring mortality. Similar results were obtained when a case-control approach was used to remove the effects of socioeconomic variation. Consistent with many other studies of populations with low consanguinity rates, this population experienced a relatively high absolute increase in mortality among the offspring of first-cousin marriages (9%). Preliminary evidence is offered for the hypothesis that mortality differentials are larger in populations with low inbreeding and low mortality because nongenetic causes of death do not obscure the effects of consanguinity. Copyright 2001 S. Karger AG, Basel

  11. Impact of consanguineous marriages in GJB2-related hearing loss in the Iranian population: a report of a novel variant.

    PubMed

    Mahdieh, Nejat; Rabbani, Bahareh; Shirkavand, Atefeh; Bagherian, Hamideh; Movahed, Zahra Shahab; Fouladi, Paanti; Rahiminejad, Faezeh; Masoudifard, Masoumeh; Akbari, Mohammad Taghi; Zeinali, Sirous

    2011-01-01

    Mutations in GJB2 and GJB6 genes are the main causes of autosomal recessive nonsyndromic hearing loss (ARNSHL) in many populations. Here, we investigated GJB2 and GJB6 mutations in 114 patients from 77 affected ARNSHL families including 54 consanguineous marriages and 23 nonrelative marriages in the Iranian population. Clinical studies and genetic counseling were performed for all families. GJB2 and GJB6 genes were directly sequenced. Three known GJB6 large deletions [del(GJB6-D13S1830), del(GJB6-D13S1854), and a 920 kb deletion] were also checked by quantification of a common deleted region within the GJB6 gene. The frequency of consanguinity was 70.13% among the studied families. Biallelic GJB2 mutations were 16.67% in consanguineous marriages and 4.35% in nonrelative marriages. Mutations found were 35delG, delE120, R127H, M163V, W24X, V37I, G12D, V84A, 313-326del14, and E110K. The latter was a novel variant. Neither point mutation nor a large deletion in the GJB6 gene was found in the population. Mean frequency of GJB2 mutations was 17.92%. GJB2 mutations (and not GJB6 mutations) are the major causes of hearing loss in Iran. The role of consanguineous marriages is also highlighted in occurrence of GJB2-related hearing loss. We suggest that other genes may be involved in the population.

  12. Recessive versus imprinted disorder: consanguinity can impede establishing the diagnosis of autosomal dominant pseudohypoparathyroidism type Ib

    PubMed Central

    Turan, Serap; Akin, Leyla; Akcay, Teoman; Adal, Erdal; Sarikaya, Sevil; Bastepe, Murat; Jüppner, Harald

    2010-01-01

    Hypocalcemia and hyperphosphatemia with low/normal parathyroid hormone (PTH) levels can be observed in hypoparathyroidism (HP), a disorder that may follow an autosomal dominant (AD) or autosomal recessive (AR) mode of inheritance. Similar biochemical changes are also observed in pseudohypoparathyroidism (PHP) type Ia and Ib, but affected patients usually show elevated PTH levels indicative of hormonal resistance. Features of Albright’s hereditary osteodystrophy (AHO) are typically not observed in patients affected by familial forms of PHP-Ib, which are most frequently caused by maternally inherited, heterozygous microdeletions within STX16 and are associated with isolated loss of methylation at GNAS exon A/B. We established the molecular defect in two children of consanguineous Turkish parents, who presented with hypocalcemia, hyperphosphatemia, and low 25-OH vitamin D levels, but initially normal or only mildly elevated PTH levels, i.e. findings that do not readily exclude HP. After normalizing serum magnesium levels, hypocalcemia and hyperphosphatemia persisted, and PTH levels increased, suggesting PTH-resistance rather than PTH-deficiency. Because of the absence of AHO and parental consanguinity, an AR form of PHP-Ib appeared plausible, which had previously been suggested for sporadic cases. However, loss of GNAS methylation was restricted to exon A/B, which led to the identification of the 3-kb STX16 microdeletion. The same mutation was also detected in the healthy mother, who did not show any GNAS methylation abnormality, indicating that her deletion resides on the paternal allele. Our findings emphasize the importance of considering a parentally imprinted, autosomal dominant disorder even if consanguinity suggests an autosomal recessive mode of inheritance. PMID:20538864

  13. Family Portrait of the Small Inner Satellites of Jupiter

    NASA Technical Reports Server (NTRS)

    1997-01-01

    These images, taken by Galileo's solid state imaging system between November 1996 and June 1997, provide the first ever 'family portrait' of the four small, irregularly shaped moons that orbit Jupiter in the zone between the planet's ring and the larger Galilean satellites. The moons are shown in their correct relative sizes, with north approximately up in all cases. From left to right, arranged in order of increasing distance from Jupiter, are Metis (longest dimension is approximately 60 kilometers or 37 miles across), Adrastea (20 kilometers or 12 miles across), Amalthea (247 kilometers or 154 miles across), and Thebe (116 kilometers or 72 miles across). While Amalthea, the largest of these four tiny moons, was imaged by NASA's two Voyager spacecraft in 1979 with a resolution comparable to what is shown here, the new Galileo observations represent the first time that Metis, Adrastea, and Thebe have been seen as more than points of light.

    The Jet Propulsion Laboratory, Pasadena, CA manages the Galileo mission for NASA's Office of Space Science, Washington, DC. JPL is an operating division of California Institute of Technology (Caltech).

    This image and other images and data received from Galileo are posted on the World Wide Web, on the Galileo mission home page at URL http://www.jpl.nasa.gov/ galileo.

  14. Family Portrait of the Small Inner Satellites of Jupiter

    NASA Technical Reports Server (NTRS)

    1997-01-01

    These images, taken by Galileo's solid state imaging system between November 1996 and June 1997, provide the first ever 'family portrait' of the four small, irregularly shaped moons that orbit Jupiter in the zone between the planet's ring and the larger Galilean satellites. The moons are shown in their correct relative sizes, with north approximately up in all cases. From left to right, arranged in order of increasing distance from Jupiter, are Metis (longest dimension is approximately 60 kilometers or 37 miles across), Adrastea (20 kilometers or 12 miles across), Amalthea (247 kilometers or 154 miles across), and Thebe (116 kilometers or 72 miles across). While Amalthea, the largest of these four tiny moons, was imaged by NASA's two Voyager spacecraft in 1979 with a resolution comparable to what is shown here, the new Galileo observations represent the first time that Metis, Adrastea, and Thebe have been seen as more than points of light.

    The Jet Propulsion Laboratory, Pasadena, CA manages the Galileo mission for NASA's Office of Space Science, Washington, DC. JPL is an operating division of California Institute of Technology (Caltech).

    This image and other images and data received from Galileo are posted on the World Wide Web, on the Galileo mission home page at URL http://www.jpl.nasa.gov/ galileo.

  15. Reproductive wastage and developmental disorders in relation to consanguinity in south India.

    PubMed

    Asha Bai, P V; John, T J; Subramaniam, V R

    1981-09-01

    The effect of consanguinity on fertility, reproductive loss and developmental disorders were studied in 156 consanguineous marriages in comparison with 221 non-consanguineous marriages. Although fertility was greater (P less than 0.05) in consanguineous than in non-consanguineous marriages, the number of living children were approximately equal in both groups, on account of increased child mortality in the former (P less than 0.05). The frequencies of abortion and stillbirth were (also) approximately equal in both groups. Developmental anomalies were significantly more frequent (P less than 0.001) among the offspring of consanguineous parents. These results indicate the continued presence of deleterious genes in this population, in spite of the practice of consanguinity over many generations.

  16. Consanguinity and genetic diseases in North Africa and immigrants to Europe.

    PubMed

    Anwar, Wagida A; Khyatti, Meriem; Hemminki, Kari

    2014-08-01

    Endemic diseases are caused by environmental and genetic factors. While in this special issue several chapters deal with environmental factors, including infections, the present focus is on genetic causes of disease clustering due to inbreeding and recessive disease mechanisms. Consanguinity is implying sharing of genetic heritage because of marriage between close relatives originating from a common ancestor. With limited natural selection, recessive genes may become more frequent in an inbred compared with an outbred population. Consanguinity is common in North Africa (NA), and the estimates range from 40 to 49% of all marriages in Tunisia and 29-33% in Morocco. As a consequence, recessive disorders are common in the NA region, and we give some examples. Thalassaemia and sickle cell disease/anaemia constitute the most common inherited recessive disorders globally and they are common in NA, but with immigration they have spread to Europe and to other parts of the world. Another example is familial Mediterranean fever, which is common in the Eastern Mediterranean area. With immigrantion from that area to Sweden, it has become the most common hereditary autoinflammatory disease in that country, and there is no evidence that any native Swede would have been diagnosed with this disease. The examples discussed in this chapter show that the historic movement of populations and current immigration are influencing the concept of 'endemic' disease.

  17. First steps in exploring prospective exome sequencing of consanguineous couples.

    PubMed

    Teeuw, Marieke; Waisfisz, Quinten; Zwijnenburg, Petra J G; Sistermans, Erik A; Weiss, Marjan M; Henneman, Lidewij; ten Kate, Leo P; Cornel, Martina C; Meijers-Heijboer, Hanne

    2014-01-01

    Consanguinity is one of the most frequent risk factors for congenital disorders. In theory, prospective exome sequencing of consanguineous couples could identify couples who both are carriers of autosomal recessive diseases, and empower such couples to make informed reproductive decisions. To investigate this, we sent blood samples to our laboratory of four pairs of consanguineous parents having one or more children affected by an autosomal recessive disorder, without revealing any diagnostic information. The study was restricted to find identical, previously described, or evidently pathogenic mutations in both parents of each couple, in over 400 genes known to result in severe autosomal recessive disorders. Out of the six autosomal recessive disorders known to the four couples studied, two were correctly identified. Carrier status of one not previously known autosomal recessive disorder was discovered. As expected, given the pipeline used, large deletions, mutations in genes not present in the gene list, mutations outside the exons and consensus splice sites, and mutations that were not evidently pathogenic and previously not reported, were not identified. The restriction to detecting only couples with identical mutations diminishes the risk of revealing unsolicited findings and shortens the time needed for analysis, but also results in missing couples with different mutations in the same gene. In addition to the proposed pipeline, couples should be offered testing for carrier status of frequent disorders that can present themselves by large deletions, non-exonic mutations or compound heterozygous mutations (e.g. thalassemia, spinal muscular atrophy, cystic fibrosis). Even though sensitivity is reduced, offering exome sequencing prospectively will increase reproductive options for consanguineous couples.

  18. Consanguinity and late fertility: spatial analysis reveals positive association patterns.

    PubMed

    Lisa, Antonella; Astolfi, Paola; Zei, Gianna; Tentoni, Stefania

    2015-01-01

    The role of consanguinity on human complex traits is an important and controversial issue. In this work we focused on the Sardinian population and examined the effect of consanguineous unions on late female fertility. During the last century the island has been characterized by a high incidence of marriages between relatives, favoured by socio economic conditions and geographical isolation, and by high fertility despite a widespread tendency to delay reproduction. Through spatial analysis techniques, we explored the geographical heterogeneity of consanguinity and late fertility, and identified in Central-Eastern Sardinia a common area with an excess of both traits, where the traits are positively associated. We found that their association did not significantly affect women's fertility in the area, despite the expected negative role of both traits. Intriguingly, this critical zone corresponds well to areas reported by previous studies as being peculiar for a high frequency of centenarians and for lower risk in pregnancy outcome. The proposed approach can be generally exploited to identify target populations on which socioeconomic, biodemographic and genetic data can be collected at the individual level, and deeper analyses carried out to disentangle the determinants of complex biological traits and to investigate their association.

  19. CONSANGUINITY AND INBREEDING COEFFICIENT IN TRIBAL PASHTUNS INHABITING THE TURBULENT AND WAR-AFFECTED TERRITORY OF BAJAUR AGENCY, NORTH-WEST PAKISTAN.

    PubMed

    Ahmad, Bashir; Rehman, Atta Ur; Malik, Sajid

    2016-01-01

    The north-western populations of Pakistan in the Federally Administered Tribal Areas (FATA) adjoining the Pakistan-Afghanistan border are an amalgamation of native and migrated Pashtun tribes. These tribal populations are in transition due to war conditions and geo-political turmoil on both sides of the border since the Soviet invasion in 1979. Bio-demographic and epidemiological data for these tribes are scarce. A prospective cross-sectional sample of 967 males was selected from a representative Pashtun population of Bajaur Agency, and information obtained on bio-demographic variables and marital union types. Analysis of these data revealed that consanguinity was 22.34% and the inbreeding coefficient F was calculated to be 0.0134. The inbreeding coefficient was observed to be higher in subjects who were illiterate, had unskilled jobs and who belonged to younger age categories, extended families and the Tarkalani tribe. Further analyses with respect to temporal variables like subject's age, year of marriage and age at marriage revealed that after a transition in marital union types in the early 80s, there has been a declining trend in the rate of consanguineous unions. Further, consanguineous unions in the parental generation were only 5%, but parental marriage types were predictors of subjects' marital union types. The data further establish that, contrary to a general notion about a high consanguinity rate in Pakistan, consanguineous unions are not common in Bajaur Agency and first cousin marriage is not the preferred type. Furthermore, this research shows that there is a great regional variation in the pattern of consanguinity in Pakistan that needs to be documented in order to draw a more comprehensive picture of the inbreeding coefficient in the country.

  20. Assessing the Local Need for Family and Child Care Services: A Small Area Utilization Analysis.

    ERIC Educational Resources Information Center

    Percy, Andrew; Carr-Hill, Roy; Dixon, Paul; Jamison, James Q.

    2000-01-01

    Describes study of administrative data from Northern Ireland on the costs of family and child care services, using small area utilization modeling, to derive a new set of needs indicators that could be used within the family and child care capitation funding formula. Argues that small area utilization modeling produces a fairer and more equitable…

  1. Hurler disease (mucopolysaccharidosis type IH): clinical features and consanguinity in Tunisian population

    PubMed Central

    2011-01-01

    Mucopolysaccharidosis type I (MPS I) was a group of rare autosomal recessive disorder caused by the deficiency of the lysosomal enzyme, alpha -L -iduronidase, and the resulting accumulation of undergraded dematan sulfate and heparan sulfate. MPS I patients have a wide range of clinical presentations, that makes it difficult to predict patient phenotype which is needed for genetic counseling and also impedes the selection and evaluation of patients undergoing therapy bone marrow transplantation. Aim of the study consanguinity rates have been determined among 14 families with mucopolysaccharidosis type I, seen in the pediatric departments of different geographic areas of Tunisia (Central and Southern areas) for the period August 2004 - August 2011 in order to investigate the relation between consanguinity and this disorder. Patients and methods Clinical and molecular analyses confirmed the diagnosis for MPS type I in the studied families. Results Most of the Tunisian MPS I patients have been identified at the homozygous status: p.P533R mutation (7 homozygous and one double heterozygous p.L578Q/p.P533R patients; 41.66% of all the investigated MPSI patients), p.F177S (1 homozygous patient; 5.55%), p.L530fs (1 patient; 5.55%), p.Y581X (2 patients; 11.11%), p.F602X (3 patients; 16.66%), p.R628X (1 patient; 5.55%). Another mutation: p.L578Q has been identified at the heterozygous status in the only double heterozygous p.L578Q/p.P533R case. Part of the mutations was the result of a founder effect. These described points are the consequences of the high rate of consanguinity. Conclusion The high frequency of p.P533R mutation could be explained by the high degree of inbreeding. This is due to the richness of the genetic background of the studied population. A multidisciplinary approach is essential to develop adequate preventive program adapted to the social, cultural, and economic context. PMID:22074387

  2. The practice of consanguineous marriage in Oman: prevalence, trends and determinants.

    PubMed

    Islam, M Mazharul

    2012-09-01

    The practice of consanguineous marriage has been the culturally preferred form of marriage in most Arab and the Middle Eastern countries, including Oman, but due to a paucity of population-based data in the past there is a dearth of information about its form and dynamics in Oman. Recent national-level surveys allow this gap to be filled. This paper examines the prevalence, trends and determinants of consanguineous marriages in Oman using data from the 2000 Oman National Health Survey. The results indicate a very high prevalence of consanguineous marriage in Oman, as more than half (52%) of marriages are consanguineous. First cousin unions are the most common type of consanguineous unions, constituting 39% of all marriages and 75% of all consanguineous marriages. The study observed various patterns of consanguinity, some of them common with other Arab nations, and some unique in nature. Women's age at marriage, employment, place of childhood residence and geographical region appear to be significant determinants of consanguineous marriages. Consanguineous marriage shows a strong association with marital stability, early age at marriage and early-age childbearing. There has been no appreciable change in the prevalence of consanguineous unions in Oman over the last four decades despite massive socioeconomic development and modernization. However, recent marriage cohorts show slight declining trends. The results suggest that consanguinity is likely to remain stable in the future or decline at a slow rate. Specific health education and genetic counselling should be followed in line with WHO recommendations to minimize the negative health consequences of consanguinity for child health.

  3. The Family Farm in California. Final Report of the Small Farm Viability Project.

    ERIC Educational Resources Information Center

    California State Office of Economic Development, Sacramento. Community Services Administration.

    Most of California's farms are relatively small, family run operations, and their future has been called into question by current agricultural trends. The Small Farm Viability Planning Project was initiated to identify obstacles to small farm economic viability and make recommendations to the state on policies and actions that might reduce these…

  4. Effect of consanguinity on Argentinean Angus beef DNA traceability.

    PubMed

    Baldo, A; Rogberg-Muñoz, A; Prando, A; Mello Cesar, A S; Lirón, J P; Sorarrain, N; Ramelli, P; Posik, D M; Pofcher, E; Ripoli, M V; Beretta, E; Peral-García, P; Vaca, R; Mariani, P; Giovambattista, G

    2010-08-01

    Since the 1990s several authors have envisaged the use of DNA to certify meat origin. Two major parameters must be assessed before a DNA based traceability protocol can be implemented in the food chain: (i) the information content of a DNA marker set in a specific livestock breed or group of breeds; (ii) the minimum number of DNA markers needed to obtain a statistically acceptable match probability. The objective of the present work was to establish the effect of different levels of inbreeding in the matching efficiency, and the minimum number of microsatellite markers needed, in a DNA based meat traceability program, starting from an 11-microsatellite marker panel. Samples were obtained from beef production farms in South America, where animals are typically bred under pasture-based extensive conditions. Three groups of animals with different consanguinity rates were sampled. Exclusion power (Q) was higher than 0.999998 and match probability lower than 3.01E-08, for the whole set of markers within each group. Both values were affected by consanguinity. To reach a two mismatch criteria exclusion power (Q(2)) of 99.99, six markers were needed in unrelated animals whereas seven markers were needed in related animals. To reach Q(2)=99.9999, 8 and 10 microsatellite markers, respectively, were needed. In general, one or two more microsatellite markers were needed to identify consanguineous animals. This study proved the DNA marker set used to be suitable for the identification of the meat from all slaughtered animals in Argentina, per week, month, and year. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

  5. Promoting Population Stabilization: Incentives for Small Families. Worldwatch Paper 54.

    ERIC Educational Resources Information Center

    Jacobsen, Judith

    A wide variety of incentive and disincentive programs are presented in an effort to stabilize the population and prevent bankruptcy of physical, economic, and social resources, particularly in countries like India and China. Following an introduction, the document discusses several programs, including (1) the use of small one-time payments for…

  6. Diagnosis of Bardet-Biedl Syndrome in Consecutive Pregnancies Affected with Echogenic Kidneys and Polydactyly in a Consanguineous Couple

    PubMed Central

    Baker, Tieneka M.; Sturm, Erica L.; Turner, Clesson E.; Petersen, Scott M.

    2013-01-01

    Bardet-Biedl syndrome (BBS) is an autosomal recessive ciliopathic human genetic disorder with variable expression that is difficult to diagnose in pregnancy without known risk factors. Homozygosity testing has been shown to be a useful tool in identifying BBS mutations and candidate genes in affected individuals. We present the first case of prenatal diagnosis of BBS in consecutive pregnancies aided by homozygosity testing via SNP microarray analysis. This case demonstrates a novel approach to the evaluation of recurrent echogenic kidneys in consanguineous couple with no significant family history. PMID:23533844

  7. Small families mean better health for mothers and kids.

    PubMed

    Mugumya, E

    1994-01-01

    The practice of family planning (FP) has been used since time immemorial to solve community, individual, and familial problems. There are Biblical references to incest being used to ensure the conception of children and to coitus interruptus being used to prevent conception. Pastoralists used cessation of breastfeeding of male calves to promote the conception and birth of more desirable female calves. The condom has ancient precursors made of animal intestines, and the IUD has a prototype in the stone commonly inserted in the uterus of a camel during long journeys to prevent conception. The issues of effectiveness, safety, and convenience that led to these ancient activities also inform the development and use of modern contraception. FP incorporates fertility control, both treatment for infertility and contraception; abortion is regarded as an indicator of a need for FP, not as part of FP. FP is justified on the grounds of human rights, because it allows an individual to choose whether or not to have a child; on the grounds of health, because maternal age and parity affect the health of the mother and child; on socioeconomic grounds, because overpopulation creates drains on already decreasing resources and because birth to unwed mothers creates difficulties for the children and for society; and on the grounds of improving the status of women because unwanted pregnancy causes women to abandon educational and employment opportunities. The maternal and child health and FP services in Uganda provide immunization, nutrition, prenatal and postpartum care, young child clinic services, school health education, and FP services.

  8. Consanguinity profile in the Gaza Strip of Palestine: large-scale community-based study.

    PubMed

    Sirdah, Mahmoud M

    2014-02-01

    Consanguineous marriages which have been practiced throughout history continue to be practiced within different ethnic, religious and social groups to varying degrees with highest prevalences in North Africa, Middle East and central and south Asia. In the Gaza Strip of Palestine, little is known about the consanguinity profile, so the present large-scale study aims to explore the consanguinity profile of two generations using data from the β-thalassemia premarital screening program. Sociodemographic data analysis included 156,635 (141,200 males and 15,435 females) persons and their parents, representing 141,200 couples who were referred to the Thalassemia and Hemophilia Center for premarital testing. In addition, the consanguinity characteristics of parents of 217 transfusion-dependent β-thalassemic non-sibling patients were analyzed. Results revealed a significant decrease in the overall prevalence of consanguineous (first- and second-cousin) marriages between the previous (fathers') generation (45.2%) and the current (groom/bride) generation (39.9%). Among the five governorates of the Gaza Strip, records of Gaza Governorate revealed the lowest occurrence (36.9% current generation and 42.1% previous generation) of consanguineous marriages, as compared to all others. Consanguineous marriages are significantly higher in semi-urban areas (41.6%) than in urban areas (39.1%) in the current generation (previous generation, 46.4% vs 44.7%, respectively). Compound consanguinity (two generation) and a single level of consanguinity were seen in 20.7% and 43.7%, respectively, of the cases. The average age of those with first-cousin marriages is significantly lower (22.4±4.4 years) than those with second-cousin marriages (24.3±6.1 years) and the non-consanguineous (26.5±8.2 years). The rate of consanguineous marriages among never married people (42.2%) is significantly much higher than the rate of people with multiple marriages (18.1%). About 74.7% of the non

  9. Consanguineous marriages in the population of Sheikhupura (Punjab), Pakistan.

    PubMed

    Shami, S A; Iqbal, I

    1983-01-01

    This study was based on 1007 couples from the Sheikhupura population. The proportions of various parental relationships were: 0.3784 1st cousins, 0.0318 1st cousins once removed, 0.0784 double 2nd cousins, 0.1033 bradari distant relations, 0.3416 bradari, and 0.0665 unrelated parents. Mean paternal ages in unrelated couples are significantly higher than in 1st cousins, double 2nd cousins, and bradari relations. The differences in paternal and maternal ages are significantly higher in unrelated relations as compared to 1st cousins and double 2nd cousins. Procounced effects of consanguinity on parental deaths and neonatal deaths were observed in 1st cousin marriages compared to other relationships. Juvenile and infant deaths show comparatively less effects of consanguinity in 1st cousin marriages. Mean coefficient of inbreeding calculated for this population was 0.0271. Lethal gene equivalents calculated were 1.5424. The added risk of affected children in 1st cousins over that of unrelated parents was 4.82%. The results suggest that the deleterious genes show their effects more in the prenatal than in the postnatal period.

  10. Consanguinity and pregnancy outcomes in a multi-ethnic, metropolitan European population.

    PubMed

    Becker, Rolf; Keller, Thomas; Wegner, Rolf-Dieter; Neitzel, Heidemarie; Stumm, Markus; Knoll, Ute; Stärk, Markus; Fangerau, Heiner; Bittles, Alan

    2015-01-01

    The aim of the present study was to assess the risk of major anomalies in the offspring of consanguineous couples, including data on the prenatal situation. Over 20 years (1993-2012), 35,391 fetuses were examined by prenatal sonography. In 675 cases (1.9%), parents were consanguineous, with 307 couples (45.5%) related as first cousins, 368 couples (54.5%) beyond first cousins. Detailed information was retrieved on 31,710 (89.6%) fetuses, (consanguineous 568: 1.8%). Overall prevalence of major anomalies among fetuses with non-consanguineous parents was 2.9% (consanguineous, 10.9%; first cousins, 12.4%; beyond first cousins, 6.5%). Adjusting the overall numbers for cases having been referred because of a previous index case, the prevalences were 2.8% (non-consanguineous) and 6.1% (consanguineous) (first cousin, 8.5%; beyond first cousin, 3.9%). Further adjustment for differential rates of trisomic pregnancies indicated 2.0%/5.9% congenital anomalies (non-consanguineous/consanguineous groups), that is, a consanguinity-associated excess of 3.9%, 6.1% in first cousin progeny and 1.9% beyond first cousin. The prevalence of major fetal anomalies associated with consanguinity is higher than in evaluations based only on postnatal life. It is important that this information is made available in genetic counselling programmes, especially in multi-ethnic and multi-religious communities, to enable couples to make informed decisions. © 2014 John Wiley & Sons, Ltd.

  11. A novel family of small proteins that affect plant development

    SciTech Connect

    John Charles Walker

    2011-04-29

    The DVL genes represent a new group of plant proteins that influence plant growth and development. Overexpression of DVL1, and other members of the DVL family, causes striking phenotypic changes. The DVL proteins share sequence homology in their C-terminal half. Point mutations in the C-terminal domain show it is necessary and deletion studies demonstrate the C-terminal domain is sufficient to confer the overexpression phenotypes. The phenotypes observed, and the conservation of the protein sequence in the plant kingdom, does suggest the DVL proteins have a role in modulating plant growth and development. Our working hypothesis is the DVL proteins function as regulators of cellular signaling pathways that control growth and development.

  12. Fertility Related Attitudes of Minority Mothers with Large and Small Families.

    ERIC Educational Resources Information Center

    Linn, Margaret W.; And Others

    The relationship between certain attitudes and the levels of fertility in five cultural groups was explored in this study. The group studied were blacks, Cubans, American Indians, migrant Chicanos, and white Protestants. Mothers, aged 35-45, with one or two children (small family) or five children (large family) were compared. Attitudes measured…

  13. Out of Sight, Out of Mind: Homeless Children and Families in Small-Town America.

    ERIC Educational Resources Information Center

    Vissing, Yvonne M.

    Homelessness in small towns and rural areas is on the rise, and a substantial portion of the rural homeless consists of families with children. This book draws on interviews and case studies of over 300 homeless children and their families, primarily in New Hampshire, and on supporting statistics to provide individual and sociological perspectives…

  14. Out of Sight, Out of Mind: Homeless Children and Families in Small-Town America.

    ERIC Educational Resources Information Center

    Vissing, Yvonne M.

    Homelessness in small towns and rural areas is on the rise, and a substantial portion of the rural homeless consists of families with children. This book draws on interviews and case studies of over 300 homeless children and their families, primarily in New Hampshire, and on supporting statistics to provide individual and sociological perspectives…

  15. Unexpected genetic heterogeneity in a large consanguineous Brazilian pedigree presenting deafness.

    PubMed

    Lezirovitz, Karina; Pardono, Eliete; de Mello Auricchio, Maria T B; de Carvalho E Silva, Fernando L; Lopes, Juliana J; Abreu-Silva, Ronaldo S; Romanos, Jihane; Batissoco, Ana C; Mingroni-Netto, Regina C

    2008-01-01

    Nonsyndromic autosomal recessive deafness accounts for 80% of hereditary deafness. To date, 52 loci responsible for autosomal recessive deafness have been mapped and 24 genes identified. Here, we report a large inbred Brazilian pedigree with 26 subjects affected by prelingual deafness. Given the extensive consanguinity found in this pedigree, the most probable pattern of inheritance is autosomal recessive. However, our linkage and mutational analysis revealed, instead of an expected homozygous mutation in a single gene, two different mutant alleles and a possible third undetected mutant allele in the MYO15A gene (DFNB3 locus), as well as evidence for other causes for deafness in the same pedigree. Among the 26 affected subjects, 15 were homozygous for the novel c.10573delA mutation in the MYO15A gene, 5 were compound heterozygous for the mutation c.10573delA and the novel deletion c.9957_9960delTGAC and one inherited only a single c.10573delA mutant allele, while the other one could not be identified. Given the extensive consanguinity of the pedigree, there might be at least one more deafness locus segregating to explain the condition in some of the subjects whose deafness is not clearly associated with MYO15A mutations, although overlooked environmental causes could not be ruled out. Our findings illustrate a high level of etiological heterogeneity for deafness in the family and highlight some of the pitfalls of genetic analysis of large genes in extended pedigrees, when homozygosity for a single mutant allele is expected.

  16. Do consanguineous parents of a child affected by an autosomal recessive disease have more DNA identical-by-descent than similarly-related parents with healthy offspring? Design of a case-control study

    PubMed Central

    2010-01-01

    Background The offspring of consanguineous relations have an increased risk of congenital/genetic disorders and early mortality. Consanguineous couples and their offspring account for approximately 10% of the global population. The increased risk for congenital/genetic disorders is most marked for autosomal recessive disorders and depends on the degree of relatedness of the parents. For children of first cousins the increased risk is 2-4%. For individual couples, however, the extra risk can vary from zero to 25% or higher, with only a minority of these couples having an increased risk of at least 25%. It is currently not possible to differentiate between high-and low-risk couples. The quantity of DNA identical-by-descent between couples with the same degree of relatedness shows a remarkable variation. Here we hypothesize that consanguineous partners with children affected by an autosomal recessive disease have more DNA identical-by-descent than similarly-related partners who have only healthy children. The aim of the study is thus to establish whether the amount of DNA identical-by-descent in consanguineous parents of children with an autosomal recessive disease is indeed different from its proportion in consanguineous parents who have healthy children only. Methods/Design This project is designed as a case-control study. Cases are defined as consanguineous couples with one or more children with an autosomal recessive disorder and controls as consanguineous couples with at least three healthy children and no affected child. We aim to include 100 case couples and 100 control couples. Control couples are matched by restricting the search to the same family, clan or ethnic origin as the case couple. Genome-wide SNP arrays will be used to test our hypothesis. Discussion This study contains a new approach to risk assessment in consanguineous couples. There is no previous study on the amount of DNA identical-by-descent in consanguineous parents of affected children

  17. Orissa women want small families - but the system fails them.

    PubMed

    Jena, M

    1998-01-01

    A 1996 survey conducted in Orissa by the British Council for the British Overseas Development Administration (ODA) on opportunities and barriers to contraceptive uptake found that while women are aware of the health and financial benefits of child spacing, attitudinal and economic obstacles interfere with their ability to act upon that awareness. 3360 women and 840 men from 28 urban and periurban neighborhoods of 14 towns in 8 districts were sampled in the survey. The survey also found that men and women held similar desires with regard to birth spacing patterns; more than 50% wanted to have no additional children and 63% wanted to wait at least 2 years between births. However, despite the considerable observed interest in birth spacing and birth limiting, 78.4% of the women who expressed the desire to use modern methods of contraception were not doing so. While some couples in Orissa practice traditional methods of family planning, the current extent of such use is inadequate. Furthermore, while women in Orissa are overwhelmingly relegated the responsibility for contracepting, and the age at marriage remains approximately 22 years, most women are ignorant about contraceptive methods and their side effects.

  18. Water striders (family Gerridae): mercury sentinels in small freshwater ecosystems.

    PubMed

    Jardine, Timothy D; Al, Tom A; MacQuarrie, Kerry T B; Ritchie, Charles D; Arp, Paul A; Maprani, Antu; Cunjak, Richard A

    2005-03-01

    To circumvent some of the previous limitations associated with contaminant-monitoring programs, we tested the suitability of the water strider (Hemiptera: Gerridae) as a mercury sentinel by comparing total mercury concentrations in water striders and brook trout (Salvelinus fontinalis) from a variety of stream sites in New Brunswick, Canada. There was a strong association between the two variables across sites (r(2)=0.81, P<0.001) in systems where both atmospheric deposition and a point source (an abandoned gold mine) were likely contributing to ambient mercury levels. In a small stream draining the gold mine tailings pile, water striders had mercury concentrations an order of magnitude higher than those from reference locations. Temporal variation at three southern New Brunswick stream sites was non-significant. These results suggest that water strider mercury levels accurately quantify food chain entry of the element. The use of sentinel species holds great potential for expanding contaminant-monitoring programs.

  19. Genetic studies of the members of small, dynamical asteroid families

    NASA Astrophysics Data System (ADS)

    Kelley, Michael Shawn

    1999-10-01

    Analyses of spectrophotometric data of asteroids 9 Metis and 113 Amalthea have revealed a probable genetic (compositional) link between these two objects. The nearly identical composition of the silicate components of these two asteroids is consistent with their derivation from a single parent body. Based on the present compositional and morphological interpretations of 9 Metis and 113 Amalthea, and using plausible (chondritic) starting compositions for the parent body, the original parent asteroid is estimated to have been between approximately 300 and 600 kilometers in diameter. Thus Metis and Amalthea are the largest survivors of a highly-evolved, genetic asteroid family from which 86-96% of the original mass has been lost. New data in the wavelength region of approximately 0.4-2.5 μm have been obtained for asteroid 434 Hungaria. This is the most complete visible to near- infrared spectrum to date for this object. The near- infrared portion of the spectrum is smooth, featureless, and agrees well with previous visible region data. Hungaria's relatively high albedo of 46 percent and lack of intense spectral absorption features strictly limits the suite of possible mineral analogs for this asteroid. Based on spectral, meteoritic and petrologic considerations the silicate composition of the surface of Hungaria is mostly likely made up of iron-free enstatite. However, new visible region data appear to exhibit weak, broad spectral absorption features near 0.5, 0.6, and 1 μm. While the features near 0.5 and 1 μm are unreliable and inconsistent, the weak feature near 0.6 μm appears to be real and may help to constrain the composition of Hungaria. Most minerals which exhibit a similar absorption feature, and are commonly found in meteorites, have a much lower albedo. The dark chondritic inclusions in the Cumberland Falls aubrite exhibit a similar feature near 0.6 μm, and this meteorite provides a possible spectral and compositional analog for Hungaria.

  20. The prevalence and correlates of consanguineous marriages in Yemen: similarities and contrasts with other Arab countries.

    PubMed

    Jurdi, Rozzet; Saxena, Prem C

    2003-01-01

    Using data on 9762 women from the 1997 Yemen Demographic and Maternal and Child Health Survey, this paper examines the prevalence and socioeconomic correlates of consanguineous marriages in Yemen. The results indicate that 40% of marriages are consanguineous, over 85% of which are between first cousins. The prevalence of consanguineous marriages appears to have increased over time, particularly for the last marriage cohort. As for socioeconomic correlates, the study confirms the inverse association between consanguineous marriages and women's education and occupation, age at marriage and economic status. However, no statistically significant difference in the prevalence of consanguinity has been found by place of residence and geographical region. Somewhat unexpected results have been obtained by husband's background characteristics, with higher educated men and those working in the modern sector of the economy being more likely to be married to cousins.

  1. Domestic violence and consanguineous marriages - perspective from Rawalpindi, Pakistan.

    PubMed

    Shaikh, M Ali; Kayani, A; Shaikh, I Ali

    2014-01-09

    Domestic violence is globally endemic and adversely impacts the health and economic well-being of women and society. This study used the standardized and validated assessment instrument "Woman Abuse Screening Tool" to study the prevalence of various forms of domestic violence among married women. The relationship between domestic violence and consanguineous marriage was studied using the chi-squared test. Cumulatively, 1010 married women were interviewed. Emotional abuse was the most commonly reported abuse, reported by 721 (71.4%) women as either often or sometimes, followed by sexual abuse and physical abuse, reported by 527 (52.2%) and 511 (50.6%) respectively. Being married to one's cousin did not protect married women from being abused either emotionally or physically by their husbands; thsi was statistically significant. There is a need for better understanding of the magnitude and scale of domestic violence in Pakistan by using standardized assessment tools for meaningful comparisons across different parts of the country over time.

  2. Genomic Runs of Homozygosity Record Population History and Consanguinity

    PubMed Central

    Kirin, Mirna; McQuillan, Ruth; Franklin, Christopher S.; Campbell, Harry; McKeigue, Paul M.; Wilson, James F.

    2010-01-01

    The human genome is characterised by many runs of homozygous genotypes, where identical haplotypes were inherited from each parent. The length of each run is determined partly by the number of generations since the common ancestor: offspring of cousin marriages have long runs of homozygosity (ROH), while the numerous shorter tracts relate to shared ancestry tens and hundreds of generations ago. Human populations have experienced a wide range of demographic histories and hold diverse cultural attitudes to consanguinity. In a global population dataset, genome-wide analysis of long and shorter ROH allows categorisation of the mainly indigenous populations sampled here into four major groups in which the majority of the population are inferred to have: (a) recent parental relatedness (south and west Asians); (b) shared parental ancestry arising hundreds to thousands of years ago through long term isolation and restricted effective population size (Ne), but little recent inbreeding (Oceanians); (c) both ancient and recent parental relatedness (Native Americans); and (d) only the background level of shared ancestry relating to continental Ne (predominantly urban Europeans and East Asians; lowest of all in sub-Saharan African agriculturalists), and the occasional cryptically inbred individual. Moreover, individuals can be positioned along axes representing this demographic historic space. Long runs of homozygosity are therefore a globally widespread and under-appreciated characteristic of our genomes, which record past consanguinity and population isolation and provide a distinctive record of the demographic history of an individual's ancestors. Individual ROH measures will also allow quantification of the disease risk arising from polygenic recessive effects. PMID:21085596

  3. Genomic runs of homozygosity record population history and consanguinity.

    PubMed

    Kirin, Mirna; McQuillan, Ruth; Franklin, Christopher S; Campbell, Harry; McKeigue, Paul M; Wilson, James F

    2010-11-15

    The human genome is characterised by many runs of homozygous genotypes, where identical haplotypes were inherited from each parent. The length of each run is determined partly by the number of generations since the common ancestor: offspring of cousin marriages have long runs of homozygosity (ROH), while the numerous shorter tracts relate to shared ancestry tens and hundreds of generations ago. Human populations have experienced a wide range of demographic histories and hold diverse cultural attitudes to consanguinity. In a global population dataset, genome-wide analysis of long and shorter ROH allows categorisation of the mainly indigenous populations sampled here into four major groups in which the majority of the population are inferred to have: (a) recent parental relatedness (south and west Asians); (b) shared parental ancestry arising hundreds to thousands of years ago through long term isolation and restricted effective population size (N(e)), but little recent inbreeding (Oceanians); (c) both ancient and recent parental relatedness (Native Americans); and (d) only the background level of shared ancestry relating to continental N(e) (predominantly urban Europeans and East Asians; lowest of all in sub-Saharan African agriculturalists), and the occasional cryptically inbred individual. Moreover, individuals can be positioned along axes representing this demographic historic space. Long runs of homozygosity are therefore a globally widespread and under-appreciated characteristic of our genomes, which record past consanguinity and population isolation and provide a distinctive record of the demographic history of an individual's ancestors. Individual ROH measures will also allow quantification of the disease risk arising from polygenic recessive effects.

  4. Oculocutaneous albinism and consanguineous marriage among Spanish Gitanos or Calé--a study of 83 cases.

    PubMed

    Gamella, Juan F; Carrasco-Muñoz, Elisa Martín; Núñez Negrillo, Ana María

    2013-09-01

    This paper studies 83 cases of oculocutaneous albinism (OCA) in family networks of Gitanos in southeastern Spain, and analyzes their sustained inbreeding patterns and complex genealogical relationships. It is based in the family and genealogy reconstitution of the Gitano population of 22 contiguous localities using ethnographic and historical demography methods. The study found a prevalence of OCA among Gitanos in the area of about 1: 1,200. Most of the cases belong to three extended kin networks in which consanguineous marriages have been common for generations. In these networks there are other cases of visual and auditive congenital anomalies, and other birth defects such as brachydactily, polydactily, neurological defects, Potter Sequence, etc. In 61 OCA cases it was possible to trace inbreeding links with a depth of three to nine generations. For these cases the estimated alpha (average of the inbreeding coefficient, F) is 0.0222. Relationships between the parents of people affected are of three types: close, as between first or second cousins; distant, as between third or fourth cousins, and non-existent, as in mixed marriages. In most cases, however, persons with albinism are linked by multiple consanguineous links. Albinism seems to be a visible example of a high prevalence of birth defects in this minority, associated with founder effects, sustained inbreeding and high fertility rates. These conditions derive from Gitano's marriage preferences and pronatalist strategies. In turn, these strategies have to be related to the exclusion, persecution and segregation that Spanish Gypsies have suffered for centuries.

  5. [Phenotype and genotype analysis for a consanguineous pedigree with combined coagulation factor VII and X deficiency].

    PubMed

    Jin, Yanhui; Wang, Mingshan; Wang, Yingyu; Yang, Xiaoli; Yang, Lihong; Xie, Yaosheng; Xie, Haixiao; Zhu, Liqing; Yu, Fangyou

    2014-02-01

    To identify potential mutations and explore the molecular mechanism underlying combined inherited coagulation factors VII(FVII) and X(FX) deficiency for a family featuring consanguineous marriage between maternal cousins. Prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, FVII activity (FVII:C), FX activity (FX:C), FVII antigen (FVII:Ag), FX antigen (FX:Ag) and other coagulant parameters of the proband and 5 family members were measured. Potential mutations in exons, exon-intron boundaries and 5', 3' untranslated sequences of F7 and F10 genes were screened by polymerase chain reaction and direct sequencing. Suspected mutations were confirmed by sequencing the opposite strand. PT and APTT of the proband were obviously prolonged to become 76.4 s and 60.2 s, respectively. FVII:C, FVII:Ag,FX:C and FX:Ag of the proband were obviously reduced to become 4%, 6%, 6% and 33%, respectively. Both PT and APTT of her grandmother, father, mother and daughter were slightly prolonged, which have measured 16.4 s, 15.8 s,16.9 s, 16.5 s, and 44.0 s, 42.1 s, 41.1 s, 43.5 s, respectively. And their FVII:C (34%, 39%, 31%, 40%, respectively), FX:C (50%, 58%, 47%, 42%, respectively) and FX:Ag (51%, 54%, 58%, 47%, respectively) were slightly reduced, while FVII:Ag was in the normal range. The coagulant parameters of her younger brother were within normal range. Two homozygous mutations, g.11267C to T in exon 8 of F7 gene, which resulted in an Arg277Cys substitution, and g.28139G to T in exon 8 of F10 gene which led to a Val384Phe substitution, were identified in the proband. The proband's grandmother, parents and daughter were heterozygous for both Arg277Cys and Val384Phe mutationss. Wild-type alleles of both F7 and F10 genes were also found in the younger brother. A homozygous Arg277Cys mutation and a Val384Phe mutation have been respectively identified in the F7 and F10 genes, which can explain the low levels of FVII and FX in this family. The former has been

  6. Bombay blood group: Is prevalence decreasing with urbanization and the decreasing rate of consanguineous marriage.

    PubMed

    Mallick, Sujata; Kotasthane, Dhananjay S; Chowdhury, Puskar S; Sarkar, Sonali

    2015-01-01

    Bombay blood group although rare is found to be more prevalent in the Western and Southern states of India, believed to be associated with consanguineous marriage. To estimate the prevalence of the Bombay blood group (Oh) in the urban population of Puducherry. To find the effect of urbanization on consanguineous marriage and to establish whether consanguinity plays a part in the prevalence of Oh group. To compare Oh group prevalence with that of other neighboring states, where population is not predominantly urban. This is a descriptive study in a tertiary care hospital in Puducherry, over a period of 6 years. All blood samples showing 'O' group were tested with anti-H lectin. Specialized tests like Adsorption Elution Technique, inhibition assay for determination of secretor status were performed on Oh positive cases. Any history of consanguineous marriage was recorded. All variables were categorical variable and percentage and proportions were calculated manually. Analysis of the results of 35,497 study subjects showed that the most common group was 'O' group constituting 14,164 (39.90%) of subjects. Only three "Oh" that is, Bombay phenotype (0.008%) were detected. Consanguinity was observed in two cases (66.66%). This study shows the prevalence of Bombay blood group representing the urban population of Puducherry, to be high (0.008%) and associated with consanguineous marriage (66.66%). Thus, consanguinity is still an important risk factor present, even in an urban population in Southern India.

  7. Consanguineous marriage and differentials in age at marriage, contraceptive use and fertility in Pakistan.

    PubMed

    Hussain, R; Bittles, A H

    1999-01-01

    Fertility rates in Pakistan have remained consistently high over the past three decades. While numerous studies have examined sociodemographic determinants, the role of biological factors, and particularly consanguinity, has received little attention, even though marriage between close biological relatives continues to be the norm in Pakistan. Reproductive behaviour among women in consanguineous (first cousin) and non-consanguineous unions was compared, using data from a 1995 study of multi-ethnic communities in Karachi and the 1990-91 Pakistan Demographic & Health Survey (PDHS). The results show that, although female age at first marriage has been gradually rising in both study samples, women in consanguineous unions married at younger ages and were less likely to use modern contraceptive methods. In the Karachi sample, women in first cousin unions experienced a higher mean number of pregnancies and also reported a higher mean number of children ever born (CEB). However, their mean number of surviving children did not differ from those born to women in non-consanguineous unions, implying higher prenatal and/or postnatal losses in couples related as first cousins. On the other hand, the PDHS showed both lower CEB values for women in consanguineous marriages and a lower number of surviving children. Given the continuing popularity of consanguineous marriage, these findings have important implications for future fertility reduction in Pakistan.

  8. Gene-Targeted Next Generation Sequencing Identifies PNPLA1 Mutations in Patients with a Phenotypic Spectrum of Autosomal Recessive Congenital Ichthyosis: The Impact of Consanguinity.

    PubMed

    Vahidnezhad, Hassan; Youssefian, Leila; Saeidian, Amir Hossein; Zeinali, Sirous; Mansouri, Parvin; Sotoudeh, Soheila; Barzegar, Mohammadreza; Mohammadi-Asl, Javad; Karamzadeh, Razieh; Abiri, Maryam; McCormick, Kevin; Fortina, Paolo; Uitto, Jouni

    2017-03-01

    Autosomal recessive congenital ichthyosis is a heterogeneous group of disorders associated with mutations in at least nine distinct genes. To ascertain the molecular basis of ichthyosis patients in Iran, a country of approximately 80 million people with a high prevalence of customary consanguineous marriages, we have developed a gene-targeted next generation sequencing array consisting of 38 genes reported in association with ichthyosis phenotypes. In a subset of nine extended consanguineous families, we found homozygous missense mutations in the PNPLA1 gene, six of them being distinct and, to our knowledge, previously unpublished. This gene encodes an enzyme with lipid hydrolase activity, important for development and maintenance of the barrier function of the epidermis. These six mutations, as well as four previously published mutations, reside exclusively within the patatin-like subdomain of PNPLA1 containing the catalytic site. The mutations clustered around the active center of the enzyme or resided at the surface of the protein possibly involved in the protein-protein interactions. Clinical features of the patients showed considerable intra- and interfamilial heterogeneity. Knowledge of the specific mutations allows identification of heterozygous carriers, assisting in genetic counseling, prenatal testing, and preimplantation genetic diagnosis in extended families at risk of recurrence of this disorder, the incidence of which is significantly increased in consanguineous marriages. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  9. Small Families

    MedlinePlus

    ... Each child receives more parental attention and educational advantages, which generally raise her self-esteem. Children in ... they expect of them. Maintain your own adult social life as a couple (or as an individual, ...

  10. Gender, Work-Family Linkages, and Economic Success among Small Business Owners.

    ERIC Educational Resources Information Center

    Loscocco, Karyn A.; Leicht, Kevin T.

    1993-01-01

    Investigated work-family connections and economic success among women and men small business owners. Analyses of data from 3-year panel survey of 99 women and 312 men showed considerable gender similarity in processes through which business and individual characteristics affect personal earnings, although women were disadvantaged in some…

  11. Female-Headed Families: An Ecological Model of Residential Concentration in a Small City.

    ERIC Educational Resources Information Center

    And Others; Roncek, Dennis W.

    1980-01-01

    Proposed an ecological model to explain the concentration of female-headed families in a small city. Data for city blocks provided patterns of concentration. Of the physical variables, only historical development of the city and market decisions by nonresidential consumers were important predictors of concentration; spatial concentration was not…

  12. Gender, Work-Family Linkages, and Economic Success among Small Business Owners.

    ERIC Educational Resources Information Center

    Loscocco, Karyn A.; Leicht, Kevin T.

    1993-01-01

    Investigated work-family connections and economic success among women and men small business owners. Analyses of data from 3-year panel survey of 99 women and 312 men showed considerable gender similarity in processes through which business and individual characteristics affect personal earnings, although women were disadvantaged in some…

  13. Isonymy, consanguinity and repeated pairs of surnames in Aromun populations.

    PubMed

    Schmidt, H D; Efremovska, L; Handziski, Z

    2001-09-01

    The Aromuns represent a small and almost unknown people that live scattered over the Balkan Peninsula. Due to their language, that is very similar to classical Latin, they are in a special position. The Aromuns settled only in more recent times. Until now they lived as shepherds, as caravan guides and merchants and lead a semi-nomadic life. We are currently carrying out studies to determine the genetic structure of this population. To facilitate the interpretation of these data, we are also trying to obtain other important parameters that pertain to migration processes and the genealogical structure of this populations. The data arise from three areas in Albania, the Republic of Macedonia and Romania. The inbreeding coefficient and the proportion of repeated pairs of surnames was calculated through the use of genealogies and the isonymy method. The difference between these three populations are due primarily to confounding by selection of mates and family composition.

  14. Reduced small world brain connectivity in probands with a family history of epilepsy.

    PubMed

    Bharath, R D; Chaitanya, G; Panda, R; Raghavendra, K; Sinha, S; Sahoo, A; Gohel, S; Biswal, B B; Satishchandra, P

    2016-12-01

    The role of inheritance in ascertaining susceptibility to epilepsy is well established, although the pathogenetic mechanisms are still not very clear. Interviewing for a positive family history is a popular epidemiological tool in the understanding of this susceptibility. Our aim was to visualize and localize network abnormalities that could be associated with a positive family history in a group of patients with hot water epilepsy (HWE) using resting-state functional magnetic resonance imaging (rsfMRI). Graph theory analysis of rsfMRI (clustering coefficient γ; path length λ; small worldness σ) in probands with a positive family history of epilepsy (FHE+, 25) were compared with probands without FHE (FHE-, 33). Whether a closer biological relationship was associated with a higher likelihood of network abnormalities was also ascertained. A positive family history of epilepsy had decreased γ, increased λ and decreased σ in bilateral temporofrontal regions compared to FHE- (false discovery rate corrected P ≤ 0.0062). These changes were more pronounced in probands having first degree relatives and siblings with epilepsy. Probands with multiple types of epilepsy in the family showed decreased σ in comparison to only HWE in the family. Graph theory analysis of the rsfMRI can be used to understand the neurobiology of diseases like genetic susceptibility in HWE. Reduced small worldness, proportional to the degree of relationship, is consistent with the current understanding that disease severity is higher in closer biological relations. © 2016 EAN.

  15. Modernization or cultural maintenance: the practice of consanguineous marriage in Iran.

    PubMed

    Jalal Abbasi-Shavazi, Mohammad; McDonald, Peter; Hosseini-Chavoshi, Meimanat

    2008-11-01

    Consanguineous marriage has been the culturally preferred form of marriage in Iran. This paper examines the extent to which education, urbanization and changes in modes of economic production have affected the incidence of consanguineous marriage and attitudes towards consanguineous marriages. The 2002 Iran Fertility Transition Survey conducted in the four provinces of Gilan, Sistan and Baluchistan, Yazd and West Azarbaijan provides information on the degree of relationship of marriage partners from around 6550 ever-married women aged 15-49. Attitudinal data were also obtained. Overall, the level of marriage to biological relatives ranged from 23% in Gilan to 78% in Sistan and Baluchistan. The paper finds that the practice of marriage to biological relatives has remained surprisingly resilient in the face of modernizing influences and that ethnicity, province and area of residence remain important determinants. On the other hand, attitudes have shifted towards marriage with a non-relative. Anthropological research would illuminate the processes of consanguineous marriage in Iran.

  16. Consanguinity and endogamy in the Netherlands: demographic and medical genetic aspects.

    PubMed

    Ten Kate, Leo P; Teeuw, Marieke E; Henneman, Lidewij; Cornel, Martina C

    2014-01-01

    This paper reviews what is currently known about the presence of consanguinity and endogamy in the Netherlands, in the past and today, and concludes with a discussion of medical genetic aspects. First geographic characteristics, the demographic history, the genetic make-up of the native population, legal aspects and the public opinion are reviewed. Then data on the prevalence of consanguinity in the native population are presented for marriages since 1840, followed by data on consanguineous marriages among immigrants from countries with a tradition of close-kin marriages. It is estimated that approximately 1% of at-risk consanguineous couples are referred to clinical genetic centres for prospective genetic counselling in the Netherlands. This picture will change dramatically if and when next-generation sequencing is introduced to identify couples at ≥ 25% risk prospectively. © 2014 S. Karger AG, Basel.

  17. [Oral mucosa analog allografts in non-consanguineous rats].

    PubMed

    González, Luis; Padrón, Karla; Salmen, Siham; Jerez, Elsy; Dávila, Lorena; Solórzano, Eduvigis

    2017-01-24

    Although there are therapeutic options for the treatment of oral mucosa defects, the need for functional, anatomical and aesthetically similar substitutes persists, as well as for solutions to reduce autologous grafts morbidity. To determine clinical and histological compatibility of equivalent oral mucosa allografts generated through tissue engineering in non-consanguineous rats. We used a sample of oral mucosa from Sprague Dawley rats to obtain a fibroblast culture and a keratinocytes and fibroblasts co-culture. In both cases, we used a commercial collagen membrane as "scaffold". After ten weeks of culture, we grafted the resulting membranes into four Wistar rats. The first phase of the study was the development of the oral mucosa equivalents generated by tissue engineering. Then, we implanted them in immunocompetent Wistar rats, and finallywe evaluated the clinical and histological features of the allografts. In vivo evaluation of mucosal substitutes showed a correct integration of artificial oral mucosa in immunocompetent hosts, with an increase in periodontal biotype and the creation of a zone with increased keratinization. Histologically, the tissue was similar to the control oral mucosa sample with no inflammatory reaction nor clinical or histological rejection signs. The equivalent oral mucosa allografts generated by tissue engineering showed clinical and histological compatibility.

  18. Patterns of relating between physicians and medical assistants in small family medicine offices.

    PubMed

    Elder, Nancy C; Jacobson, C Jeffrey; Bolon, Shannon K; Fixler, Joseph; Pallerla, Harini; Busick, Christina; Gerrety, Erica; Kinney, Dee; Regan, Saundra; Pugnale, Michael

    2014-01-01

    The clinician-colleague relationship is a cornerstone of relationship-centered care (RCC); in small family medicine offices, the clinician-medical assistant (MA) relationship is especially important. We sought to better understand the relationship between MA roles and the clinician-MA relationship within the RCC framework. We conducted an ethnographic study of 5 small family medicine offices (having <5 clinicians) in the Cincinnati Area Research and Improvement Group (CARInG) Network using interviews, surveys, and observations. We interviewed 19 MAs and supervisors and 11 clinicians (9 family physicians and 2 nurse practitioners) and observed 15 MAs in practice. Qualitative analysis used the editing style. MAs' roles in small family medicine offices were determined by MA career motivations and clinician-MA relationships. MA career motivations comprised interest in health care, easy training/workload, and customer service orientation. Clinician-MA relationships were influenced by how MAs and clinicians respond to their perceptions of MA clinical competence (illustrated predominantly by comparing MAs with nurses) and organizational structure. We propose a model, trust and verify, to describe the structure of the clinician-MA relationship. This model is informed by clinicians' roles in hiring and managing MAs and the social familiarity of MAs and clinicians. Within the RCC framework, these findings can be seen as previously undefined constraints and freedoms in what is known as the Complex Responsive Process of Relating between clinicians and MAs. Improved understanding of clinician-MA relationships will allow a better appreciation of how clinicians and MAs function in family medicine teams. Our findings may assist small offices undergoing practice transformation and guide future research to improve the education, training, and use of MAs in the family medicine setting.

  19. A Quick Test on Rotation Period Clustering for the Small Members of the Koronis Family

    NASA Astrophysics Data System (ADS)

    Chang, Chan-Kao; Lin, Hsing-Wen; Ip, Wing-Huen

    2016-01-01

    Rotation period clustering in prograde/retrograde rotators might be the preliminary indication of the Slivan state in the Koronis family as a result of the Yarkovsky-O’Keefe-Radzievskii-Paddack effect. We follow the general scenario of dispersion in the semimajor axis of the asteroid family members to separate prograde and retrograde rotators in the Koronis family. From the available rotation periods obtained from PTF/iPTF, we were unable to find the rotation period clustering of objects with H ≳ 12 mag in the Koronis family. This could be the result of the intermittent collisional process of small asteroids (D ≲ 20 km) which leads to astray Yarkovsky drifting. Measurement of the pole orientations of our sample will verify our preliminary result and validate our method.

  20. Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity.

    PubMed

    Saleheen, Danish; Natarajan, Pradeep; Armean, Irina M; Zhao, Wei; Rasheed, Asif; Khetarpal, Sumeet A; Won, Hong-Hee; Karczewski, Konrad J; O'Donnell-Luria, Anne H; Samocha, Kaitlin E; Weisburd, Benjamin; Gupta, Namrata; Zaidi, Mozzam; Samuel, Maria; Imran, Atif; Abbas, Shahid; Majeed, Faisal; Ishaq, Madiha; Akhtar, Saba; Trindade, Kevin; Mucksavage, Megan; Qamar, Nadeem; Zaman, Khan Shah; Yaqoob, Zia; Saghir, Tahir; Rizvi, Syed Nadeem Hasan; Memon, Anis; Hayyat Mallick, Nadeem; Ishaq, Mohammad; Rasheed, Syed Zahed; Memon, Fazal-Ur-Rehman; Mahmood, Khalid; Ahmed, Naveeduddin; Do, Ron; Krauss, Ronald M; MacArthur, Daniel G; Gabriel, Stacey; Lander, Eric S; Daly, Mark J; Frossard, Philippe; Danesh, John; Rader, Daniel J; Kathiresan, Sekar

    2017-04-12

    A major goal of biomedicine is to understand the function of every gene in the human genome. Loss-of-function mutations can disrupt both copies of a given gene in humans and phenotypic analysis of such 'human knockouts' can provide insight into gene function. Consanguineous unions are more likely to result in offspring carrying homozygous loss-of-function mutations. In Pakistan, consanguinity rates are notably high. Here we sequence the protein-coding regions of 10,503 adult participants in the Pakistan Risk of Myocardial Infarction Study (PROMIS), designed to understand the determinants of cardiometabolic diseases in individuals from South Asia. We identified individuals carrying homozygous predicted loss-of-function (pLoF) mutations, and performed phenotypic analysis involving more than 200 biochemical and disease traits. We enumerated 49,138 rare (<1% minor allele frequency) pLoF mutations. These pLoF mutations are estimated to knock out 1,317 genes, each in at least one participant. Homozygosity for pLoF mutations at PLA2G7 was associated with absent enzymatic activity of soluble lipoprotein-associated phospholipase A2; at CYP2F1, with higher plasma interleukin-8 concentrations; at TREH, with lower concentrations of apoB-containing lipoprotein subfractions; at either A3GALT2 or NRG4, with markedly reduced plasma insulin C-peptide concentrations; and at SLC9A3R1, with mediators of calcium and phosphate signalling. Heterozygous deficiency of APOC3 has been shown to protect against coronary heart disease; we identified APOC3 homozygous pLoF carriers in our cohort. We recruited these human knockouts and challenged them with an oral fat load. Compared with family members lacking the mutation, individuals with APOC3 knocked out displayed marked blunting of the usual post-prandial rise in plasma triglycerides. Overall, these observations provide a roadmap for a 'human knockout project', a systematic effort to understand the phenotypic consequences of complete

  1. Classic Kaposi’s sarcoma in three unrelated Turkish children born to consanguineous kindreds

    PubMed Central

    Sahin, Gürses; Palanduz, Ayse; Aydogan, Gonul; Cassar, Olivier; Ertem, A Ulya; Telhan, Leyla; Canpolat, Nur; Jouanguy, Emmanuelle; Picard, Capucine; Gessain, Antoine; Abel, Laurent; Casanova, Jean-Laurent; Plancoulaine, Sabine

    2010-01-01

    Infection by human herpes virus 8 (HHV-8) in childhood is common in the Mediterranean basin; however, classic Kaposi’s sarcoma (KS) is exceedingly rare in children not infected with HIV and not receiving immunosuppression, with only 30 cases reported since 1960. We recently reported two children with autosomal and X-linked recessive primary immunodeficiencies underlying KS in a context of multiple clinical manifestations. These reports suggested that classic KS in otherwise healthy children might also result from inborn errors of immunity more specific to HHV-8. In this paper, we describe three unrelated Turkish children with classic KS born to first-cousin parents. The first patient, a girl, developed KS at two years of age with disseminated cutaneous and mucosal lesions. The clinical course progressed rapidly and the patient died within three months, despite treatment with vincristine. The other two children developed a milder form of KS at the age of nine years, with multiple cutaneous lesions. A boy treated with interferon alpha therapy for 12 months is now in full remission at age 14, two years after treatment. The second girl is currently stabilized with etoposide, which was begun four months ago. None of the three children had any relevant familial history or other clinical features. The occurrence of classic KS in three unrelated Turkish children, each born to consanguineous parents, strongly suggests that autosomal recessive predisposition may drive the rare occurrence of HHV-8-associated classic KS in children. PMID:20156905

  2. Health problems, complex life, and consanguinity among ethnic minority Muslim women in Nepal.

    PubMed

    Bhatta, Dharma Nand; Haque, Anwarul

    2015-01-01

    Marriage between blood relatives is common among Muslim ethnic minority population in Nepal. Albeit, the adverse effects of such a consanguineous marriage on health are controversial. To determine the prevalence, characteristics and health outcomes related to consanguineous marriage. A cross-sectional survey was carried out using a cluster sampling technique to select the respondents. A total of 400 women aged 15-49 years were interviewed from September 2011 to February 2012. A structured questionnaire was administered through face-to-face meetings. Adjusted odds ratios (AOR) were estimated by a stepwise likelihood ratio method with binary logistic regression. The overall prevalence of consanguinity was 36.7%. The median age at marriage and age at first childbirth was 15 and 18 years, respectively. The association of being in a consanguineous marriage among women whose husband's education level were secondary or higher was 3.35 (95% CI 1.56, 7.12) times greater than among those whose husbands were unable to read and write. Woman who have consanguineous marriage were less likely to have (AOR 0.46, 95% CI 0.26, 0.82) used contraceptive than those who have non-consanguineous marriage. Women who have consanguineous marriage were more (AOR 1.80; 95% CI 0.90, 3.61) likely to have birth defect in their children than those who have non-consanguineous marriage. The association of having a history of death after live birth among women who experienced emotional violence was 2.60 (95% CI 1.36, 5.00) and physical violence 2.15 (95% CI 1.16, 3.93) times greater than among those who did not experience violence. Several factors like husband's education and dowry practices are associated with consanguineous marriage. Further, these factors including consanguineous marriage and marital violence are also accountable for negative health consequences. Thus, multicomponent interventions are needed in order to improve the health condition of Nepalese Muslim community in rural area.

  3. Spectrum of malformations of the hindbrain (cerebellum, pons, and medulla) in a cohort of children with high rate of parental consanguinity.

    PubMed

    Sztriha, László; Johansen, Johan G

    2005-06-01

    We review 25 patients with a spectrum of hindbrain (cerebellum, pons, and medulla) malformations from a cohort of children with high parental consanguinity rate. Twenty-three of the 25 patients were born to consanguineous parents. The patients were classified in four groups. Eleven patients of 6 families had malformation of the hindbrain and midbrain with molar tooth sign (10 patients of 5 families with typical Joubert syndrome), 5 patients showed severe supratentorial anomalies in addition to the hindbrain malformations, 5 patients had pontocerebellar or cerebellar hypoplasia with anterior horn cell disease in the spinal cord (spinal muscular atrophy), and 4 patients showed malformations affecting predominantly the hindbrain without substantial involvement of other systems. A locus for Joubert syndrome was previously identified on chromosome 9q34.3 in two families, and a second locus on chromosome 11p12-q13.3 in another family. A third Joubert syndrome locus has been mapped at 6q23 and a mutation in the AHI1 gene at this site has been found recently in a further family from this cohort. Delineation of homogeneous subgroups of patients with hindbrain malformations and molecular genetic analysis of these groups may lead to identification of further loci, genes and mutations responsible for the malformations.

  4. Small bowel obstruction in patients with familial adenomatous polyposis related desmoid disease.

    PubMed

    Xhaja, X; Church, J

    2013-12-01

    Intra-abdominal desmoid disease is one of the most common extra-intestinal manifestations of familial adenomatous polyposis. Small bowel obstruction occurs frequently in affected patients and is notoriously difficult to treat. The aim of this study was to review the management and outcome of desmoid-related small bowel obstruction. This was a retrospective, descriptive study of patients with familial adenomatous polyposis and intra-abdominal desmoid disease who developed small bowel obstruction. Demographic data and data concerning the presentation, diagnosis and treatment of the bowel obstructions were abstracted from the polyposis database or patients' records. Patients with obstruction unrelated to desmoid disease were excluded. There were 47 patients (30 women and 17 men). Median age at first bowel obstruction was 24.2 (interquartile range 19.2-34.2) years. The median time from index surgery to first bowel obstruction was 4.1 (interquartile range 1.5-9.0) years. Twenty-two patients had a colectomy and ileorectal anastomosis and 21 a proctocolectomy and ileoanal pouch. Obstruction was treated medically in 29% of cases and surgically in 69%. Thirteen patients had total parental nutrition. Thirty (63.8%) had a second episode of small bowel obstruction at a mean of 5.3 years after the first, 50% of which were treated medically. Eighteen (37.5%) patients had more than two episodes of bowel obstruction. There were 118 operations, including lysis of adhesions (29), small bowel resection (14), bypass (12), ileostomy (12), desmoid excision (9) and stricturoplasty (2). Desmoid-related small bowel obstruction in familial adenomatous polyposis patients requires multiple surgical strategies to restore a patent gastrointestinal tract. WHAT DOES THIS PAPER ADD TO THE LITERATURE?: This is the only series in the literature specifically addressing small bowel obstruction in patients with familial adenomatous polyposis and intra-abdominal desmoid disease. The data show that small

  5. Discovery and characterization of small molecule inhibitors of the BET family bromodomains.

    PubMed

    Chung, Chun-Wa; Coste, Herve; White, Julia H; Mirguet, Olivier; Wilde, Jonathan; Gosmini, Romain L; Delves, Chris; Magny, Sylvie M; Woodward, Robert; Hughes, Stephen A; Boursier, Eric V; Flynn, Helen; Bouillot, Anne M; Bamborough, Paul; Brusq, Jean-Marie G; Gellibert, Francoise J; Jones, Emma J; Riou, Alizon M; Homes, Paul; Martin, Sandrine L; Uings, Iain J; Toum, Jerome; Clement, Catherine A; Boullay, Anne-Benedicte; Grimley, Rachel L; Blandel, Florence M; Prinjha, Rab K; Lee, Kevin; Kirilovsky, Jorge; Nicodeme, Edwige

    2011-06-09

    Epigenetic mechanisms of gene regulation have a profound role in normal development and disease processes. An integral part of this mechanism occurs through lysine acetylation of histone tails which are recognized by bromodomains. While the biological and structural characterization of many bromodomain containing proteins has advanced considerably, the therapeutic tractability of this protein family is only now becoming understood. This paper describes the discovery and molecular characterization of potent (nM) small molecule inhibitors that disrupt the function of the BET family of bromodomains (Brd2, Brd3, and Brd4). By using a combination of phenotypic screening, chemoproteomics, and biophysical studies, we have discovered that the protein-protein interactions between bromodomains and acetylated histones can be antagonized by selective small molecules that bind at the acetylated lysine recognition pocket. X-ray crystal structures of compounds bound into bromodomains of Brd2 and Brd4 elucidate the molecular interactions of binding and explain the precisely defined stereochemistry required for activity.

  6. Bombay blood group: Is prevalence decreasing with urbanization and the decreasing rate of consanguineous marriage

    PubMed Central

    Mallick, Sujata; Kotasthane, Dhananjay S.; Chowdhury, Puskar S.; Sarkar, Sonali

    2015-01-01

    Context: Bombay blood group although rare is found to be more prevalent in the Western and Southern states of India, believed to be associated with consanguineous marriage. Aims: To estimate the prevalence of the Bombay blood group (Oh) in the urban population of Puducherry. To find the effect of urbanization on consanguineous marriage and to establish whether consanguinity plays a part in the prevalence of Oh group. To compare Oh group prevalence with that of other neighboring states, where population is not predominantly urban. Settings and Design: This is a descriptive study in a tertiary care hospital in Puducherry, over a period of 6 years. Materials and Methods: All blood samples showing ‘O’ group were tested with anti-H lectin. Specialized tests like Adsorption Elution Technique, inhibition assay for determination of secretor status were performed on Oh positive cases. Any history of consanguineous marriage was recorded. Statistical Analysis Used: All variables were categorical variable and percentage and proportions were calculated manually. Results: Analysis of the results of 35,497 study subjects showed that the most common group was ‘O’ group constituting 14,164 (39.90%) of subjects. Only three “Oh” that is, Bombay phenotype (0.008%) were detected. Consanguinity was observed in two cases (66.66%). Conclusions: This study shows the prevalence of Bombay blood group representing the urban population of Puducherry, to be high (0.008%) and associated with consanguineous marriage (66.66%). Thus, consanguinity is still an important risk factor present, even in an urban population in Southern India. PMID:26420929

  7. Inbreeding in Gredos mountain range (Spain): contribution of multiple consanguinity and intervalley variation.

    PubMed

    Fuster, V; Jiménez, A M; Colantonio, S E

    2001-04-01

    The present paper examines consanguineous marriages occurring between 1874 and 1975 in three valleys (Tormes, Alberche, and Tiétar) in the Sierra de Gredos mountain range, Avila province, Spain. Information was obtained from parish registers of 42 localities, corresponding to a total of 41,696 weddings. Consanguineous marriages were defined as those up to the third degree of consanguinity (second cousins). From 1874 to 1975 the percentage of related mates was 4.45% and the inbreeding coefficient was 0.0011868 (for 1874 to 1917 corresponding figures up to the fourth degree were 16.44% and 0.00 19085, respectively). In order to ascertain the characteristics and evolution of mating patterns in Gredos, the contribution of each degree of kinship was analyzed as a whole and then for each valley separately. Regarding total consanguineous marriages in Gredos, there is a low frequency of uncle-niece matings (0.21%) and a first-second cousin mating ratio (C22/C33) of 0.23 (up to the third degree of consanguinity). Before 1918 multiple matings (i.e., those involving more than a single relationship) accounted for 19.16% of consanguineous marriages (up to the fourth degree). The observed frequencies of multiple consanguineous marriages was, on average, about twice that expected at random, and the proportion of such marriages to total inbreeding was 34.65%. The temporal change of the Gredos inbreeding pattern was characterized by a recent decrease; the highest inbreeding levels correspond to the period from 1915 to 1944. Finally, intervalley differences (maximum inbreeding coefficient in the Tormes, minimum in the Tiétar) are interpreted considering the geography, population size, and population mobility for each valley

  8. Investigation of current university research concerning energy conversion and conservation in small single-family dwellings

    NASA Technical Reports Server (NTRS)

    Grossman, G. R.; Roberts, A. S., Jr.

    1975-01-01

    An investigation was made of university research concerning energy conversion and conservation techniques which may be applied in small single-family residences. Information was accumulated through published papers, progress reports, telephone conversations, and personal interviews. A synopsis of each pertinent investigation is given. Finally, a discussion of the synopses is presented and recommendations are made concerning the applicability of concepts for the design and construction of NASA-Langley Research Center's proposed Technology Utilization House in Hampton, Virginia.

  9. A community-based study of mucopolysaccharidosis type VI in Brazil: the influence of founder effect, endogamy and consanguinity.

    PubMed

    Costa-Motta, Fabiana Moura; Bender, Fernanda; Acosta, Angelina; Abé-Sandes, Kiyoko; Machado, Taísa; Bomfim, Thaís; Boa Sorte, Tatiana; da Silva, Danniel; Bittles, Alan; Giugliani, Roberto; Leistner-Segal, Sandra

    2014-01-01

    Mucopolysaccharidosis type VI (MPS VI - Maroteaux-Lamy syndrome) is a globally rare lysosomal storage disease caused by a deficiency of arylsulfatase B. However, in Monte Santo, a poor and isolated rural region in Northeast Brazil with large family sizes and high rates of community endogamy and parental consanguinity (α = 0.00483), 9 living and 4 now deceased individuals in 11 kindreds have been diagnosed with MPS VI, all with the same p.H178L missense founder mutation. A further 33 deceased persons have been identified by family members as exhibiting the disease phenotype. Detailed pedigrees were constructed for the 13 genomically confirmed MPS VI patients, with blood samples collected from 236 unaffected family members to determine the prevalence of the p.H178L mutation. A total of 98 (20.8%) mutant alleles and 374 (79.2%) normal alleles were identified, with 41.5% of the individuals heterozygous for the p.H178L mutation and 58.5% homozygous for the normal allele. A significant number of other family members with a 50 or 25% chance of being heterozygous for the p.H178L mutation were unavailable for testing. The data indicate a compelling case for community-based neonatal screening in conjunction with further initiatives among MPS VI family members to promote genetic education and genetic counselling. © 2014 S. Karger AG, Basel

  10. Challenges in the care for consanguineous couples: an exploratory interview study among general practitioners and midwives

    PubMed Central

    2012-01-01

    Background It is often suggested that an effort must be made to increase awareness among consanguineous couples of their reproductive risk, and to refer them for genetic counseling if needed. Primary care professionals are considered most appropriate for addressing the subject and identifying couples at risk during consultations in their practice. This Dutch study aims to explore the experiences, attitudes and beliefs of such professionals regarding their care for consanguineous couples. Methods Sixteen semi-structured interviews were conducted with midwives and general practitioners. Results Although most primary care professionals considered it their task to inform couples about the risks of consanguinity, during consultations the topic was generally only briefly touched upon and quickly abandoned. Important reasons for this were professionals’ beliefs about religious and social values of couples, their low perception of the couples’ reproductive risk and expected limited feasibility of referral. Feelings of embarrassment regarding addressing consanguinity did not seem to play a significant role. Conclusions Primary care professional beliefs about their clients’ religious and social values, their attitudes toward the risk, and perceived limited options for referral seem to conflict with the professional norm to address the topic of consanguinity. PMID:23102514

  11. A positive association between consanguinity and fertility in communities of Paraíba, Northeast Brazil.

    PubMed

    Weller, Mathias; Santos, Silvana

    2013-01-01

    Consanguinity of human populations can but does not have to be associated with increased fertility. A recent study involving communities of Northeast Brazil revealed increased levels of endogamy. Data from 20 451 interviewed couples and their 74 289 children were analysed. The present study aimed to compare fertility between consanguineous and unrelated couples of these communities. Consanguineous and unrelated couples of the 39 communities had an average of 4.3 (SD = 0.9) and 3.5 (SD = 0.8) children (p < 0.0001), respectively. Average offspring number of consanguineous couples varied from 3.9 (SD = 1.1) to 5.6 (SD = 3.4) for couples related at the level of third cousins and double first cousin/uncle-niece, respectively (p < 0.005). The correlation coefficient between Human Development Index and fertility was -0.38 (p = 0.0179) and -0.23 (p = 0.17) for unrelated and related couples, respectively. Results indicated an overall positive association between consanguinity and fertility. Fertility tended to be increased, for closely related couples, compared to those related more distantly.

  12. Challenges in the care for consanguineous couples: an exploratory interview study among general practitioners and midwives.

    PubMed

    Teeuw, Marieke E; Hagelaar, Anouk; ten Kate, Leo P; Cornel, Martina C; Henneman, Lidewij

    2012-10-26

    It is often suggested that an effort must be made to increase awareness among consanguineous couples of their reproductive risk, and to refer them for genetic counseling if needed. Primary care professionals are considered most appropriate for addressing the subject and identifying couples at risk during consultations in their practice. This Dutch study aims to explore the experiences, attitudes and beliefs of such professionals regarding their care for consanguineous couples. Sixteen semi-structured interviews were conducted with midwives and general practitioners. Although most primary care professionals considered it their task to inform couples about the risks of consanguinity, during consultations the topic was generally only briefly touched upon and quickly abandoned. Important reasons for this were professionals' beliefs about religious and social values of couples, their low perception of the couples' reproductive risk and expected limited feasibility of referral. Feelings of embarrassment regarding addressing consanguinity did not seem to play a significant role. Primary care professional beliefs about their clients' religious and social values, their attitudes toward the risk, and perceived limited options for referral seem to conflict with the professional norm to address the topic of consanguinity.

  13. Specificity and mechanism of action of EHT 1864, a novel small molecule inhibitor of Rac family small GTPases.

    PubMed

    Shutes, Adam; Onesto, Cercina; Picard, Virginie; Leblond, Bertrand; Schweighoffer, Fabien; Der, Channing J

    2007-12-07

    There is now considerable experimental evidence that aberrant activation of Rho family small GTPases promotes the uncontrolled proliferation, invasion, and metastatic properties of human cancer cells. Therefore, there is considerable interest in the development of small molecule inhibitors of Rho GTPase function. However, to date, most efforts have focused on inhibitors that indirectly block Rho GTPase function, by targeting either enzymes involved in post-translational processing or downstream protein kinase effectors. We recently determined that the EHT 1864 small molecule can inhibit Rac function in vivo. In this study, we evaluated the biological and biochemical specificities and biochemical mechanism of action of EHT 1864. We determined that EHT 1864 specifically inhibited Rac1-dependent platelet-derived growth factor-induced lamellipodia formation. Furthermore, our biochemical analyses with recombinant Rac proteins found that EHT 1864 possesses high affinity binding to Rac1, as well as the related Rac1b, Rac2, and Rac3 isoforms, and this association promoted the loss of bound nucleotide, inhibiting both guanine nucleotide association and Tiam1 Rac guanine nucleotide exchange factor-stimulated exchange factor activity in vitro. EHT 1864 therefore places Rac in an inert and inactive state, preventing its engagement with downstream effectors. Finally, we evaluated the ability of EHT 1864 to block Rac-dependent growth transformation, and we determined that EHT 1864 potently blocked transformation caused by constitutively activated Rac1, as well as Rac-dependent transformation caused by Tiam1 or Ras. Taken together, our results suggest that EHT 1864 selectively inhibits Rac downstream signaling and transformation by a novel mechanism involving guanine nucleotide displacement.

  14. The effect of reproductive compensation on recessive disorders within consanguineous human populations.

    PubMed

    Overall, A D J; Ahmad, M; Nichols, R A

    2002-06-01

    We investigate the effects of consanguinity and population substructure on genetic health using the UK Asian population as an example. We review and expand upon previous treatments dealing with the deleterious effects of consanguinity on recessive disorders and consider how other factors, such as population substructure, may be of equal importance. For illustration, we quantify the relative risks of recessive lethal disorders by presenting some simple calculations that demonstrate the effect 'reproductive compensation' has on the maintenance of recessive alleles. The results show how reproductive compensation can effectively counteract the purging of deleterious alleles within consanguineous populations. Whereas inbreeding does not elevate the equilibrium frequency of affected individuals, reproductive compensation does. We suggest this effect must be built into interpretations of the incidence of genetic disease within populations such as the UK Asians. Information of this nature will benefit health care workers who inform such communities.

  15. An empirical analysis of the effects of consanguineous marriages on economic development.

    PubMed

    Bildirici, Melike; Kökdener, Meltem; Ersin, Oezgür ömer

    2010-01-01

    In this study, development experiences toward economic development are investigated to provide an alternative analysis of economic development, human capital, and genetic inheritance in the light of consanguineous marriages. The countries analyzed in the study are discussed in accordance with consanguineous marriage practices and classified by their per capita gross domestic product (GDP) growth. A broad range of countries are analyzed in the study. Arab countries that experienced high rates of growth in their gross national income during the twentieth century but failed to fulfill adequate development measures as reflected in the growth in national income, countries undergoing transition from tight government regulation to free market democracy, and African nations that have experienced complications in the process of development show important differences in the process of economic development. It is shown that the countries that have reached high average development within the context of per capita GDP have overcome problems integral to consanguineous marriage.

  16. Fetus with two identical reciprocal translocations: description of a rare complication of consanguinity.

    PubMed

    Martinet, Danielle; Vial, Yvan; Thonney, Francine; Beckmann, Jacques S; Meagher-Villemure, Kathleen; Unger, Sheila

    2006-04-01

    We report on a 24-week fetus with multiple organ anomalies secondary to biparental inheritance of an apparently balanced t(17;20) reciprocal translocation. The pregnancy was terminated following the discovery by ultrasound of an abnormal heart and micrognathia. At autopsy, the following anomalies were found: Pierre-Robin sequence, hypoplasia of the right ventricle with muscular hypertrophy, and endocardial fibroelastosis, hypoplastic lungs, dysplastic left kidney, bilateral pelvicalyceal dilatation, central nervous system periventricular heterotopias and right sided club foot. Given the endocardial fibroelastosis and cleft palate, Eastman-Bixler syndrome (Facio-cardio-renal) is a possible diagnosis. The parents were first cousins and each had an identical t(17;20)(q21.1;p11.21) translocation. The fetal karyotype was 46,XX,t(17;20)(q21.1;p11.21)mat,t(17;20)(q21.1;p11.21)pat. While there are a few reports of consanguineous families where both the mother and father had the same reciprocal translocation and offspring with unbalanced karyotypes, we were unable to find any reports of a fetus/child with double identical reciprocal translocations. We propose that although the fetus had an apparently balanced karyotype, inheriting only the translocated chromosomes led to the unmasking of a recessive syndrome. It seems most likely that a gene (or genes) was disrupted by the breaks but the parents might also be heterozygous carriers of a recessive gene mutation since the fetus must be homozygous by descent for many loci on both chromosomes 17 and 20 (as well as on other chromosomal segments). It was not possible to totally exclude segmental uniparental disomy as a cause of the anomalies as no recombinations were detected for chromosome 17. However, there is no evidence to suggest that chromosome 17 is imprinted and UPD 20 was excluded thus making an imprinting error unlikely. Copyright 2006 Wiley-Liss, Inc.

  17. Campanulaceae: a family with small seeds that require light for germination.

    PubMed

    Koutsovoulou, Katerina; Daws, Matthew I; Thanos, Costas A

    2014-01-01

    The Campanulaceae is a large cosmopolitan family, but is understudied in terms of germination, and seed biology in general. Small seed mass (usually in the range 10-200 µg) is a noteworthy trait of the family, and having small seeds is commonly associated with a light requirement. Thus, the purpose of this study was to investigate the effect of light on germination in 131 taxa of the Campanulaceae family, from all five continents of its distribution. For all taxa, seed germination was tested in light (8 or 12 h photoperiod) and continuous darkness under constant and alternating temperatures. For four taxa, the effect of light on germination was examined over a wide range of temperatures on a thermogradient plate, and the possible substitution of the light requirement by gibberellic acid and nitrate was examined in ten taxa. For all 131 taxa, seed germination was higher in light than in darkness for every temperature tested. Across species, the light requirement decreased significantly with increasing seed mass. For larger seeded species, germination in the dark reached higher levels under alternating than under constant temperatures. Gibberellic acid promoted germination in darkness whereas nitrates partially substituted for a light requirement only in species showing some dark germination. A light requirement for germination, observed in virtually all taxa examined, constitutes a collective characteristic of the family. It is postulated that smaller seeded taxa might germinate only on the soil surface or at shallow depths, while larger seeded species might additionally germinate when buried in the soil if cued to do so by fluctuating temperatures.

  18. The Rho family of small GTPases is involved in epithelial cystogenesis and tubulogenesis.

    PubMed

    Rogers, Katherine K; Jou, Tzuu-Shuh; Guo, Wei; Lipschutz, Joshua H

    2003-05-01

    Epithelial cyst and tubule formation represent critical processes for the development of many mammalian organs and involve transient, highly choreographed changes in cell polarity. The Rho family of small GTPases, whose prototypes are RhoA, Rac1, and Cdc42, regulate many biologic processes, including cell polarization and morphogenesis. The exocyst is a conserved eight-subunit protein complex involved in the biogenesis of polarity; in yeast, it is a downstream effector for several Rho family proteins, and, in mammals, plays a central role in cystogenesis and tubulogenesis. Inducible cell lines expressing mutant forms of RhoA, Rac1, and Cdc42 and an in vitro model of cystogenesis and tubulogenesis were used to examine the effects of Rho family proteins on cyst and tubule formation. A series of pulse-chase assays, using basolateral, apical, and secretory proteins, were performed to examine the synthesis and membrane trafficking profile of the various Rho family mutant proteins. We show that expression of mutant RhoA, Rac1, and Cdc42 proteins all result in abnormal cyst and tubule formation. Furthermore, with respect to cystogenesis and tubulogenesis, the phenotypic effects of expressing each mutant Rho family protein are different. Specifically, cyst and, therefore, tubule formation is completely inhibited in the presence of constitutively active RhoA and tubulogenesis is inhibited in the presence of dominant negative Rac1. Reversal of cyst polarity is seen in the presence of dominant negative RhoA, dominant negative Rac1, and both dominant negative and constitutively active Cdc42. The series of synthesis and delivery assays, using basolateral, apical, and secretory proteins, revealed that Rho family mutant proteins display an exocyst-like trafficking profile. The differential effects suggest that RhoA, Rac1, and Cdc42 all act to control cyst and tubule formation and may act in concert to control these higher-order processes. The exocyst-like membrane trafficking

  19. A family of small cyclic amphipathic peptides (SCAmpPs) genes in citrus.

    PubMed

    Belknap, William R; McCue, Kent F; Harden, Leslie A; Vensel, William H; Bausher, Michael G; Stover, Ed

    2015-04-16

    Citrus represents a crop of global importance both in economic impact and significance to nutrition. Citrus production worldwide is threatened by the disease Huanglongbing (HLB), caused by the phloem-limited pathogen Candidatus Liberibacter spp.. As a source of stable HLB-resistance has yet to be identified, there is considerable interest in characterization of novel disease-associated citrus genes. A gene family of Small Cyclic Amphipathic Peptides (SCAmpPs) in citrus is described. The citrus genomes contain 100-150 SCAmpPs genes, approximately 50 of which are represented in the citrus EST database. These genes encode small ~50 residue precursor proteins that are post-translationally processed, releasing 5-10 residue cyclic peptides. The structures of the SCAmpPs genes are highly conserved, with the small coding domains interrupted by a single intron and relatively extended untranslated regions. Some family members are very highly transcribed in specific citrus tissues, as determined by representation in tissue-specific cDNA libraries. Comparison of the ESTs of related SCAmpPs revealed an unexpected evolutionary profile, consistent with targeted mutagenesis of the predicted cyclic peptide domain. The SCAmpPs genes are displayed in clusters on the citrus chromosomes, with apparent association with receptor leucine-rich repeat protein arrays. This study focused on three SCAmpPs family members with high constitutive expression in citrus phloem. Unexpectedly high sequence conservation was observed in the promoter region of two phloem-expressed SCAmpPs that encode very distinct predicted cyclic products. The processed cyclic product of one of these phloem SCAmpPs was characterized by LC-MS-MS analysis of phloem tissue, revealing properties consistent with a K(+) ionophore. The SCAmpPs amino acid composition, protein structure, expression patterns, evolutionary profile and chromosomal distribution are consistent with designation as ribosomally synthesized defense

  20. Small Science: Infants and Toddlers Experiencing Science in Everyday Family Life

    NASA Astrophysics Data System (ADS)

    Sikder, Shukla; Fleer, Marilyn

    2014-09-01

    Vygotsky (1987) stated that the restructured form of everyday concepts learned at home and in the community interact with scientific concepts introduced in formal school settings, leading to a higher level of scientific thinking for school-aged children. But, what does this mean for the scientific learning of infants and toddlers? What kinds of science learning are afforded at home during this early period of life? The study reported in this paper sought to investigate the scientific development of infants-toddlers (10 to 36 months) growing up in Bangladeshi families living in Australia and Singapore. Four families were studied over 2 years. Digital video observations were made of everyday family life and analysed using Vygotsky's theoretical framework of everyday concepts and scientific concepts (51 h of digital observations). While there are many possibilities for developing scientific concepts in infants-toddlers' everyday life, our study found four categories of what we have called small science: multiple possibilities for science; discrete science; embedded science and counter intuitive science. The findings of this study contribute to the almost non-existent literature into infants and toddlers' scientific development and advance new understandings of early childhood science education.

  1. Small Science: Infants and Toddlers Experiencing Science in Everyday Family Life

    NASA Astrophysics Data System (ADS)

    Sikder, Shukla; Fleer, Marilyn

    2015-06-01

    Vygotsky (1987) stated that the restructured form of everyday concepts learned at home and in the community interact with scientific concepts introduced in formal school settings, leading to a higher level of scientific thinking for school-aged children. But, what does this mean for the scientific learning of infants and toddlers? What kinds of science learning are afforded at home during this early period of life? The study reported in this paper sought to investigate the scientific development of infants-toddlers (10 to 36 months) growing up in Bangladeshi families living in Australia and Singapore. Four families were studied over 2 years. Digital video observations were made of everyday family life and analysed using Vygotsky's theoretical framework of everyday concepts and scientific concepts (51 h of digital observations). While there are many possibilities for developing scientific concepts in infants-toddlers' everyday life, our study found four categories of what we have called small science: multiple possibilities for science; discrete science; embedded science and counter intuitive science. The findings of this study contribute to the almost non-existent literature into infants and toddlers' scientific development and advance new understandings of early childhood science education.

  2. A family of small coiled-coil-forming proteins functioning at the late endosome in yeast.

    PubMed

    Kranz, A; Kinner, A; Kölling, R

    2001-03-01

    The multispanning membrane protein Ste6, a member of the ABC-transporter family, is transported to the yeast vacuole for degradation. To identify functions involved in the intracellular trafficking of polytopic membrane proteins, we looked for functions that block Ste6 transport to the vacuole upon overproduction. In our screen, we identified several known vacuolar protein sorting (VPS) genes (SNF7/VPS32, VPS4, and VPS35) and a previously uncharacterized open reading frame, which we named MOS10 (more of Ste6). Sequence analysis showed that Mos10 is a member of a small family of coiled-coil-forming proteins, which includes Snf7 and Vps20. Deletion mutants of all three genes stabilize Ste6 and show a "class E vps phenotype." Maturation of the vacuolar hydrolase carboxypeptidase Y was affected in the mutants and the endocytic tracer FM4-64 and Ste6 accumulated in a dot or ring-like structure next to the vacuole. Differential centrifugation experiments demonstrated that about half of the hydrophilic proteins Mos10 and Vps20 was membrane associated. The intracellular distribution was further analyzed for Mos10. On sucrose gradients, membrane-associated Mos10 cofractionated with the endosomal t-SNARE Pep12, pointing to an endosomal localization of Mos10. The growth phenotypes of the mutants suggest that the "Snf7-family" members are involved in a cargo-specific event.

  3. The evolution and expression of the snaR family of small non-coding RNAs

    PubMed Central

    Parrott, Andrew M.; Tsai, Michael; Batchu, Priyanka; Ryan, Karen; Ozer, Harvey L.; Tian, Bin; Mathews, Michael B.

    2011-01-01

    We recently identified the snaR family of small non-coding RNAs that associate in vivo with the nuclear factor 90 (NF90/ILF3) protein. The major human species, snaR-A, is an RNA polymerase III transcript with restricted tissue distribution and orthologs in chimpanzee but not rhesus macaque or mouse. We report their expression in human tissues and their evolution in primates. snaR genes are exclusively in African Great Apes and some are unique to humans. Two novel families of snaR-related genetic elements were found in primates: CAS (catarrhine ancestor of snaR), limited to Old World Monkeys and apes; and ASR (Alu/snaR-related), present in all monkeys and apes. ASR and CAS appear to have spread by retrotransposition, whereas most snaR genes have spread by segmental duplication. snaR-A and snaR-G2 are differentially expressed in discrete regions of the human brain and other tissues, notably including testis. snaR-A is up-regulated in transformed and immortalized human cells, and is stably bound to ribosomes in HeLa cells. We infer that snaR evolved from the left monomer of the primate-specific Alu SINE family via ASR and CAS in conjunction with major primate speciation events, and suggest that snaRs participate in tissue- and species-specific regulation of cell growth and translation. PMID:20935053

  4. A Small Family of Chloroplast Atypical Thioredoxins1[C][W][OA

    PubMed Central

    Dangoor, Inbal; Peled-Zehavi, Hadas; Levitan, Alexander; Pasand, Ohad; Danon, Avihai

    2009-01-01

    The reduction and the formation of regulatory disulfide bonds serve as a key signaling element in chloroplasts. Members of the thioredoxin (Trx) superfamily of oxidoreductases play a major role in these processes. We have characterized a small family of plant-specific Trxs in Arabidopsis (Arabidopsis thaliana) that are rich in cysteine and histidine residues and are typified by a variable noncanonical redox active site. We found that the redox midpoint potential of three selected family members is significantly less reducing than that of the classic Trxs. Assays of subcellular localization demonstrated that all proteins are localized to the chloroplast. Selected members showed high activity, contingent on a dithiol electron donor, toward the chloroplast 2-cysteine peroxiredoxin A and poor activity toward the chloroplast NADP-malate dehydrogenase. The expression profile of the family members suggests that they have distinct roles. The intermediate redox midpoint potential value of the atypical Trxs might imply adaptability to function in modulating the redox state of chloroplast proteins with regulatory disulfides. PMID:19109414

  5. How a Small Family Run Business Adopted Critical Reflection Action Learning Using Hand Drawn Images to Initiate Organisational Change

    ERIC Educational Resources Information Center

    Shepherd, Gary

    2016-01-01

    In this account of practice I would like to share my experiences of facilitating a Critical Reflection Action Learning (CRAL) set with a small family run business, struggling to make change and expand their services due to the problems they encountered in separating their business lives from their family lives. The account I present here is based…

  6. How a Small Family Run Business Adopted Critical Reflection Action Learning Using Hand Drawn Images to Initiate Organisational Change

    ERIC Educational Resources Information Center

    Shepherd, Gary

    2016-01-01

    In this account of practice I would like to share my experiences of facilitating a Critical Reflection Action Learning (CRAL) set with a small family run business, struggling to make change and expand their services due to the problems they encountered in separating their business lives from their family lives. The account I present here is based…

  7. GASA4, One of the 14-Member Arabidopsis GASA Family of Small Polypeptides, Regulates Flowering and Seed Development

    USDA-ARS?s Scientific Manuscript database

    Members of the plant-specific gibberellic acid-stimulated Arabidopsis (GASA) gene family play roles in hormone response, defense and development. We have identified six new Arabidopsis GASA genes, bringing the total number of family members to 14. Here we show that these genes all encode small polyp...

  8. Parental consanguinity as a cause for increased incidence of births defects in a study of 238,942 consecutive births.

    PubMed

    Stoll, C; Alembik, Y; Roth, M P; Dott, B

    1999-01-01

    The risk for birth defects in the offspring of first-cousin matings has been estimated to increase sharply compared to non consanguineous marriages. As a general decline in the frequency of consanguineous marriages was observed in this century, one wonders whether consanguinity is still a factor in the appearance of birth defects in developed countries. Based on our registry of congenital anomalies we tried to answer to this question. In the population studied in North-Eastern France a consanguineous mating was known in 1.21% of the cases with congenital anomalies, vs. 0.27% in controls, (p < 0.001). The frequency of the malformations recorded paralleled the degree of consanguinity: out of 89 malformed children, 51 were seen in first-cousins mating (10.3 times more frequent than in offspring of non consanguineous couples), 17 in second-cousins marriages and 18 in more distant relatives mating. Three were uncle-niece marriage. Excluding known mendelian conditions these numbers were 73, 36, 17 and 17 respectively and the corresponding relative risk were 3.68, 3.01, 3.41 and 4.89 respectively. Therefore there is a negative dose-response effect between level of inbreeding and risk of congenital malformations. Consanguineous mothers were more often pregnant than non consanguineous mothers (p < 0.01) and they had more stillbirths than non consanguineous mothers. These results show that consanguinity is still a factor of birth defects and they must be taken into account for genetic counseling of inbred marriages, in developed countries.

  9. Effect of consanguinity on birth weight for gestational age in a developing country.

    PubMed

    Mumtaz, Ghina; Tamim, Hala; Kanaan, Mona; Khawaja, Marwan; Khogali, Mustafa; Wakim, Gerard; Yunis, Khalid A

    2007-04-01

    Consanguinity, the marriage between relatives, has been associated with adverse child health outcomes because it increases homozygosity of recessive alleles. The objective of this study was to assess the effect of consanguinity on the birth weight of newborns in Greater Beirut, Lebanon. Cross-sectional data were collected on 10,289 consecutive liveborn singleton newborns admitted to eight hospitals belonging to the National Collaborative Perinatal Neonatal Network during the years 2000 and 2001. Birth weight was modeled by use of the fetal growth ratio, defined as the ratio of the observed birth weight to the median birth weight for gestational age. A mixed-effect multiple linear regression model was used to predict the net effect of first- and second-cousin marriage on the birth weight for gestational age, accounting for within-hospital clustering of data. After controlling for medical and sociodemographic covariates, the authors found a statistically significant negative association between consanguinity and birth weight at each gestational age. No significant difference was observed in the decrease in birth weight between the first- and second-cousin marriages. Overall, consanguinity was associated with a decrease in birth weight for gestational age by 1.8% (beta = -0.018, 95% confidence interval: -0.027, -0.008). The largest effects on fetal growth were seen with lower parity and smoking during pregnancy.

  10. The Effect of Consanguineous Marriage on Reading Disability in the Arab Community

    ERIC Educational Resources Information Center

    Abu-Rabia, Salim; Maroun, Lateefeh

    2005-01-01

    The present study examined the effect of consanguineous marriage in the Arab community on reading disabilities of offspring. It examined whether the rate of reading disabilities was higher among offspring of first-cousin parents than offspring of unrelated parents; and whether reading-disabled children of first-cousin parents were more disabled in…

  11. Cleft lip and cone-rod dystrophy in a consanguineous sibship.

    PubMed

    Ausems, M G; Wittebol-Post, D; Hennekam, R C

    1996-10-01

    Three siblings from a consanguineous marriage were found to have a cleft lip. Two of them developed a progressive retinopathy which was identified as a cone-rod dystrophy. It is suggested that this association may represent a hitherto unreported entity with an autosomal recessive pattern of inheritance, although chance co-occurrence cannot be excluded.

  12. National impacts of the Weatherization Assistance Program in single-family and small multifamily dwellings

    SciTech Connect

    Brown, M.A.; Berry, L.G.; Balzer, R.A.; Faby, E.

    1993-05-01

    Since 1976, the US Department of Energy (DOE) has operated one of the largest energy conservation programs in the nation -- the low-income Weatherization Assistance Program. The program strives to increase the energy efficiency of dwellings occupied by low-income persons in order to reduce their energy consumption, lower their fuel bills, increase the comfort of their homes, and safeguard their health. It targets vulnerable groups including the elderly, people with disabilities, and families with children. The most recent national evaluation of the impacts of the Program was completed in 1984 based on energy consumption data for households weatherized in 1981. DOE Program regulations and operations have changed substantially since then: new funding sources, management principles, diagnostic procedures, and weatherization technologies have been incorporated. Many of these new features have been studied in isolation or at a local level; however, no recent evaluation has assessed their combined, nationwide impacts to date or their potential for the future. In 1990, DOE initiated such an evaluation. This evaluation is comprised of three ``impact`` studies (the Single-Family Study, High-Density Multifamily Study, and Fuel-Oil Study) and two ``policy`` studies. Altogether, these five studies will provide a comprehensive national assessment of the Weatherization Assistance Program as it existed in the 1989 Program Year (PY 1989). This report presents the results of the first phase of the Single-Family Study. It evaluates the energy savings and cost effectiveness of the Program as it has been applied to the largest portion of its client base -- low-income households that occupy single-family dwellings, mobile homes, and small (2- to 4-unit) multifamily dwellings. It is based upon a representative national sample that covers the full range of conditions under which the program was implemented in PY 1989.

  13. The Overlap of Small Molecule and Protein Binding Sites within Families of Protein Structures

    PubMed Central

    Davis, Fred P.; Sali, Andrej

    2010-01-01

    Protein–protein interactions are challenging targets for modulation by small molecules. Here, we propose an approach that harnesses the increasing structural coverage of protein complexes to identify small molecules that may target protein interactions. Specifically, we identify ligand and protein binding sites that overlap upon alignment of homologous proteins. Of the 2,619 protein structure families observed to bind proteins, 1,028 also bind small molecules (250–1000 Da), and 197 exhibit a statistically significant (p<0.01) overlap between ligand and protein binding positions. These “bi-functional positions”, which bind both ligands and proteins, are particularly enriched in tyrosine and tryptophan residues, similar to “energetic hotspots” described previously, and are significantly less conserved than mono-functional and solvent exposed positions. Homology transfer identifies ligands whose binding sites overlap at least 20% of the protein interface for 35% of domain–domain and 45% of domain–peptide mediated interactions. The analysis recovered known small-molecule modulators of protein interactions as well as predicted new interaction targets based on the sequence similarity of ligand binding sites. We illustrate the predictive utility of the method by suggesting structural mechanisms for the effects of sanglifehrin A on HIV virion production, bepridil on the cellular entry of anthrax edema factor, and fusicoccin on vertebrate developmental pathways. The results, available at http://pibase.janelia.org, represent a comprehensive collection of structurally characterized modulators of protein interactions, and suggest that homologous structures are a useful resource for the rational design of interaction modulators. PMID:20140189

  14. Local differences in the Archbishopric of Santiago de Compostela (Galicia, Spain) in relation to the consanguinity structure, 1900-1979.

    PubMed

    Sánchez-Sellero, C; Fariña, J; Aínsua, R L; Varela, T A

    2001-08-01

    The microgeographic variability of consanguinity in the Archbishopric of Santiago de Compostela (Galicia) between 1900 and 1979 was studied. This Archbishopric covers 106 local councils integrated by 964 parishes, of which 677 (70.23%) were analyzed. Of the 307,094 marriages counted within this period, 15,739 corresponded to weddings between biologically related couples. Within the Archbishopric, eight geographical regions were considered: six coastal regions (Golfo Artabro, Bergantiños, Fisterra, Xallas, Santiago Oeste, and Rías Baixas) and two inland regions (Santiago Este and Terra de Montes). In order to evaluate the differences and similarities among them, the frequencies of all types of marriages (consanguineous and nonconsanguineous) were considered. First, a hierarchical grouping of the regions based on their chi-squared distances was performed. Then, in order to analyze relationships that are exclusively due to the structure of consanguinity, a correspondence analysis was performed and only the frequency of the different types of consanguineous marriages was taken into account. The results from both statistical analyses indicate special features of the Xallas region, both in the level of inbreeding (8.75%, the highest in the Archbishopric) and in the structure of consanguinity, for which a high proportion of uncle-niece marriages was found (6.22% of all consanguineous marriages). In all cases the structure of consanguinity provides informative nuances on the differences and similarities among population groups.

  15. Homeodomain-interacting protein kinase (Hipk) phosphorylates the small SPOC family protein Spenito.

    PubMed

    Dewald, D N; Steinmetz, E L; Walldorf, U

    2014-12-01

    The Drosophila homeodomain-interacting protein kinase (Hipk) is a versatile regulator involved in a variety of pathways, such as Notch and Wingless signalling, thereby acting in processes including the promotion of eye development or control of cell numbers in the nervous system. In vertebrates, extensive studies have related its homologue HIPK2 to important roles in the control of p53-mediated apoptosis and tumour suppression. Spenito (Nito) belongs to the group of small SPOC family proteins and has a role, amongst others, as a regulator of Wingless signalling downstream of Armadillo. In the present study, we show that both proteins have an enzyme-substrate relationship, adding a new interesting component to the broad range of Hipk interactions, and we map several phosphorylation sites of Nito. Furthermore, we were able to define a preliminary consensus motif for Hipk target sites, which will simplify the identification of new substrates of this kinase.

  16. The RGK family: a regulatory tail of small GTP-binding proteins.

    PubMed

    Kelly, Kathleen

    2005-12-01

    RGK proteins are small Ras-related GTP-binding proteins that function as potent inhibitors of voltage-dependent calcium channels, and two members of the family, Gem and Rad, modulate Rho-dependent remodeling of the cytoskeleton. Within the Ras superfamily, RGK proteins have distinct structural and regulatory characteristics. It is an open question as to whether RGK proteins catalyze GTP hydrolysis in vivo. Binding of calmodulin and the 14-3-3 protein to RGK proteins controls downstream pathways. Here, we discuss the structural and functional properties of RGK proteins and highlight recent work by Beguin and colleagues addressing the mechanism of Gem regulation by calmodulin and 14-3-3.

  17. Small GTP-binding proteins of the ras family: a conserved functional mechanism?

    PubMed

    Chardin, P

    1991-04-01

    Mutated ras genes can acquire a transforming potential and are frequently detected in human tumors. The mammalian ras gene family includes at least 35 distinct members that can be divided into three main groups on the basis of their sequence similarity to ras, rho, or rab genes. All these genes encode small GTP-binding proteins. Rho proteins are implicated in actin organization and control of cell shape, probably by interacting with the cytoskeleton and intracellular membranes. Rab proteins are involved in vesicular traffic, and appear to control the translocation of vesicles from donor to acceptor membranes. The precise function of ras proteins is unknown, although the prevailing view is that they act as transducers of mitogenic signals. We propose that ras proteins, by analogy with rho and rab, are involved in the lateral segregation of multi-protein complexes at the plasma membrane, and we suggest how this process may be important for mitogenic signal transduction.

  18. Spectrum of GJB2 mutations in Turkey comprises both Caucasian and Oriental variants: roles of parental consanguinity and assortative mating.

    PubMed

    Tekin, Mustafa; Duman, Türker; Boğoçlu, Gönül; Incesulu, Armağan; Comak, Elif; Ilhan, Inci; Akar, Nejat

    2003-05-01

    Considerable differences exist for the spectrum of GJB2 mutations in different populations. Screening for the c.35delG mutation in 256 independent probands, 154 multiplex (familial) and 102 simplex (sporadic), coming from different regions of Turkey revealed 37 (14.5%) homozygotes. The allele frequency of c.35delG ranged from 5% to 53% in different cities. Parental consanguinity was noted in 34% of c.35delG homozygotes, yet it was 55% in c.35delG negatives (p=0.034). Further screening for GJB2 mutations in multiplex families demonstrated the presence of c.167delT and L90P mutations as well as a novel complex mutation, c.236_239delTGCAinsAGATCCG, in single alleles, leading to compound heterozygosity with c.35delG. The homozygous E120del mutation was found in another case. The V27I polymorphism was detected in five alleles, one of which was associated with the E114G change. Assortative mating was a significant factor predicting to detect biallelic mutations in the GJB2 gene. These results confirm the overwhelming majority of c.35delG in the Turkish deaf individuals as well as the presence of other changes detected in Caucasian and Asian populations.

  19. Small Molecule Inhibition of the TNF Family Cytokine CD40 Ligand Through a Subunit Fracture Mechanism

    SciTech Connect

    L Silvian; J Friedman; K Strauch; T Cachero; E Day; F Qian; B Cunningham; A Fung; L Sun; et al.

    2011-12-31

    BIO8898 is one of several synthetic organic molecules that have recently been reported to inhibit receptor binding and function of the constitutively trimeric tumor necrosis factor (TNF) family cytokine CD40 ligand (CD40L, aka CD154). Small molecule inhibitors of protein-protein interfaces are relatively rare, and their discovery is often very challenging. Therefore, to understand how BIO8898 achieves this feat, we characterized its mechanism of action using biochemical assays and X-ray crystallography. BIO8898 inhibited soluble CD40L binding to CD40-Ig with a potency of IC{sub 50} = 25 {mu}M and inhibited CD40L-dependent apoptosis in a cellular assay. A co-crystal structure of BIO8898 with CD40L revealed that one inhibitor molecule binds per protein trimer. Surprisingly, the compound binds not at the surface of the protein but by intercalating deeply between two subunits of the homotrimeric cytokine, disrupting a constitutive protein-protein interface and breaking the protein's 3-fold symmetry. The compound forms several hydrogen bonds with the protein, within an otherwise hydrophobic binding pocket. In addition to the translational splitting of the trimer, binding of BIO8898 was accompanied by additional local and longer-range conformational perturbations of the protein, both in the core and in a surface loop. Binding of BIO8898 is reversible, and the resulting complex is stable and does not lead to detectable dissociation of the protein trimer. Our results suggest that a set of core aromatic residues that are conserved across a subset of TNF family cytokines might represent a generic hot-spot for the induced-fit binding of trimer-disrupting small molecules.

  20. Small bowel mucosal damage in familial Mediterranean fever: results of capsule endoscopy screening.

    PubMed

    Demir, Abdurrahman; Akyüz, Filiz; Göktürk, Suut; Evirgen, Sami; Akyüz, Umit; Örmeci, Aslı; Soyer, Özlem; Karaca, Cetin; Demir, Kadir; Gundogdu, Gökcen; Güllüoğlu, Mine; Erer, Burak; Kamalı, Sevil; Kaymakoglu, Sabahattin; Besisik, Fatih; Gül, Ahmet

    2014-12-01

    Familial Mediterranean fever (FMF) is the most common form of autoinflammatory diseases. We aimed to evaluate the small bowel mucosa by capsule endoscopy (CE) in FMF patients for investigation of other possible causes of abdominal pain. The study group consisted of 41 patients with FMF. A standard questionnaire was used to record the gastrointestinal symptoms, other clinical findings, Mediterranean fever gene (MEFV) mutations, and history of medications including non-steroidal anti-inflammatory drugs (NSAIDs). Gastroscopy, colonoscopy and small bowel CE were performed in all patients, and biopsies were taken from terminal ileum and duodenum. The mean age of the patients was 34 ± 11 years, 63% of them were female, and 76.5% of them were carrying MEFV exon 10 mutations. Only one patient used NSAIDs in addition to colchicine. In endoscopic investigations, gastric erosion was detected in only one patient, and no significant findings were detected in colonoscopy. CE showed small bowel mucosal defects in 44% (erosions in 26.8%, ulcer in 17.1%) and edema in 29.3% of the patients. Most (64%) of the ulcer and erosions were localized to jejunum, and only 24% were in ileum. Mitotic changes as an indirect finding of colchicine toxicity were not different from the changes observed in samples of independent group of patients with irritable bowel syndrome. Mucosal defect was observed in half of the FMF patients, which may be associated with underlying inflammation or chronic colchicine exposure. Detection of nonspecific chronic inflammation without mitotic changes supports that mucosal defects may be associated with the autoinflammatory process.

  1. Small G-protein Signaling in Neuronal Plasticity and Memory Formation: the Specific Role of Ras Family Proteins

    PubMed Central

    Ye, Xiaojing; Carew, Thomas J.

    2010-01-01

    Small G-proteins are an extensive family of proteins that bind and hydrolyze GTP. They are ubiquitous inside cells, regulating a wide range of cellular processes. Recently, many studies have examined the role of small G-proteins, particularly the Ras family of G-proteins, in memory formation. Once thought to be primarily involved in the transduction of a variety of extracellular signals during development, it is now clear that Ras family proteins also play critical roles in molecular processing underlying neuronal and behavioral plasticity. We here review a number of recent studies that explore how the signaling of Ras family proteins contributes to memory formation. Understanding these signaling processes is of fundamental importance both from a basic scientific perspective, with the goal of providing mechanistic insights into a critical aspect of cognitive behavior, and from a clinical perspective, with the goal of providing effective therapies for a range of disorders involving cognitive impairments. PMID:21040840

  2. Prognostic impact of EGFR mutation in non-small-cell lung cancer patients with family history of lung cancer.

    PubMed

    Kim, Jung Soo; Cho, Min Seong; Nam, Jong Hyeon; Kim, Hyun-Jung; Choi, Kyeng-Won; Ryu, Jeong-Seon

    2017-01-01

    A family history can be a valuable tool in the era of precision medicine. Although a few studies have described an association of family history of lung cancer with EGFR activating mutation, their impact on survival of lung cancer patients is unclear. The study included consecutive 829 non-small-cell lung cancer patients who received analysis of EGFR mutation in a prospective lung cancer cohort. Family history of lung cancer was obtained by face-to-face interviews at the time of diagnosis. An association of EGFR activating mutation with a family history of lung cancer in first-degree relatives was evaluated with multivariate logistic regression analysis, and its association with survival was estimated with Cox's proportional hazards model. Seventy five (9.0%) patients had family history of lung cancer. The EGFR mutation was commonly observed in patients with positive family history compared to those with no family history (46.7% v 31.3%, χ2 p = 0.007). The family history was significantly associated with the EGFR mutation (aOR and 95% CI: 2.01 and 1.18-3.60, p = 0.011). Patients with the positive family history survived longer compared to those without (MST, 17.9 v 13.0 months, log-rank p = 0.037). The presence of the EGFR mutation was associated with better survival in patients without the family history (aHR and 95% CI: 0.72 and 0.57-0.90, p = 0.005). However, this prognostic impact was not observed in patients with the positive family history (aHR and 95% CI: 1.01 and 0.50-2.36, p = 0.832). In comparison to patients without the family history, EGFR activating mutation was common, and it did not affect prognosis in patients with positive family history.

  3. Institutional Protocol to Manage Consanguinity Detected by Genetic Testing in Pregnancy in a Minor

    PubMed Central

    Chen, Laura P.; Beck, Anita E.; Tsuchiya, Karen D.; Chow, Penny M.; Mirzaa, Ghayda M.; Wiester, Rebecca T.

    2015-01-01

    Single-nucleotide polymorphism arrays and other types of genetic tests have the potential to detect first-degree consanguinity and uncover parental rape in cases of minor teenage pregnancy. We present 2 cases in which genetic testing identified parental rape of a minor teenager. In case 1, single-nucleotide polymorphism array in a patient with multiple developmental abnormalities demonstrated multiple long stretches of homozygosity, revealing parental rape of a teenage mother. In case 2, a vague maternal sexual assault history and diagnosis of Pompe disease by direct gene sequencing identified parental rape of a minor. Given the medical, legal, and ethical implications of such revelations, a protocol was developed at our institution to manage consanguinity identified via genetic testing. PMID:25687148

  4. CONSANGUINITY, GENETICS AND DEFINITIONS OF KINSHIP IN THE UK PAKISTANI POPULATION.

    PubMed

    Bittles, A H; Small, N A

    2016-11-01

    Consanguineous marriage is a controversial topic in many Western societies, with attention mainly focused on the health of immigrant communities from Asia and Africa. In the UK consanguinity is especially prevalent in the Pakistani community, which now numbers over 1.1 million. Less attention has been paid to the influence of hereditary population stratification within Pakistani communities, in particular biraderi (literally brotherhood) membership, which denotes male lineages that largely govern marriage partner choice and hence the transmission of disease genes. The various roles played by biraderi and their relationship to other socio-occupational and kinship terms, such as caste, quom and zat, are often overlooked in health-based studies. The interchangeable use of these different kinship terms without rigorous definition can create identity uncertainty and hinders inter-study comparisons. Where feasible, standardization of terminology would be both desirable and beneficial, with biraderi the preferred default term to identify specific social and genetic relationships within the Pakistani diaspora.

  5. Rate of Parental Consanguineous Marriage among Patients with Visual Impairments in Turkey

    PubMed Central

    AKKAYA, Sezen

    2016-01-01

    We aimed to describe the causes, characteristics, and rate of parental consanguineous marriage associated with patients with visual impairments in Turkey. This study involved 236 patients with visual impairments. The 10th revision of the International Classification of Diseases was used to categorize the causes of visual impairments (based on the main cause in both eyes). The mean age of the patients was 38.5 ± 24.2 years (range, 6–95 years), and most were in the 15–30-year age group (35.6%). There were more male patients (65%) than female patients. Blindness, severe visual impairment, and mild to moderate visual impairment were observed in 30 (12.7%), 84 (35.6%), and 122 (51.6%) patients, respectively. Choroidal and retinal diseases were identified as the main underlying cause of visual impairment (62.7%), followed by nystagmus (23.7%), optic tract and nerve diseases (11.0%), congenital cataracts (0.8%), and glaucoma (1.7%). Parental consanguinity was present for 26.3% of the patients, and it was significantly more common in the 15–30-year age group (50%) compared to the other age groups. In Turkey, the main cause of visual impairment was choroid and retinal diseases in all the age groups above 14 years, while nystagmus was the most common cause in the age group below 15 years. Parental consanguinity was significantly higher among the patients with macular dystrophy and those with retinitis pigmentosa than with retinopathy of prematurity, optic nerve diseases, age-related macular degeneration, and diabetic retinopathy. Genetic factors are known to be involved in the development of these diseases, indicating that the issue of consanguineous marriage remains a problem in Turkey. PMID:28293658

  6. A study of consanguineous marriage as a risk factor for developing comitant strabismus.

    PubMed

    Bagheri, Mansooreh; Farvardin, Majid; Saadat, Mostafa

    2015-04-01

    Inheritance has an important role in the etiology of comitant strabismus. Consanguineous marriage is a leading factor in birth defects in which inheritance has a role. The aim of this study is to reveal if consanguineous marriage increases the risk of developing comitant strabismus. We included 461 patients who underwent primary surgery for comitant strabismus in Shiraz University Khalili Hospital (Fars province, southern Iran) between years 2003 and 2013 in our study. All the patients were living in Shiraz, Iran. Patients were categorized into the following 4 groups: (1) intermittent or constant exotropia, (2) infantile esotropia, (3) non-accommodative acquired esotropia, and (4) accommodative acquired esotropia. A total of 421 healthy children who were born in Shiraz, at the same period of time, were also studied as a control group. Presence and type of the consanguineous marriages were evaluated in the parents of the patients and control group by a questionnaire. Mean of inbreeding coefficient (α) was calculated in each group of patients and was compared with those of control group. The proportion of parental first cousin marriage was 37.7 and 23.5 % among patient and control groups. The mean of inbreeding coefficients (α) were 0.0236, 0.0283, 0.0288, and 0.0236 in four groups of the patients, respectively. The mean of inbreeding coefficient was 0.0263 in total patients, which was significantly higher than 0.0164 of control group (T = 5.27, df = 880, P < 0.001). Patients with non-accommodative acquired esotropia had the highest mean of inbreeding coefficient (α) (0.0288). It seems that recessive form of inheritance plays an important role in the etiology of comitant strabismus. Modified screening programs may be needed for earlier detection of strabismus in the offspring of consanguineous couples.

  7. The clinical utility of molecular karyotyping for neurocognitive phenotypes in a consanguineous population.

    PubMed

    Al-Qattan, Sarah M; Wakil, Salma M; Anazi, Shamsa; Alazami, Anas M; Patel, Nisha; Shaheen, Ranad; Shamseldin, Hanan E; Hagos, Samya T; AlDossari, Haya M; Salih, Mustafa A; El Khashab, Heba Y; Kentab, Amal Y; AlNasser, Mohammed N; Bashiri, Fahad A; Kaya, Namik; Hashem, Mais O; Alkuraya, Fowzan S

    2015-09-01

    Molecular karyotyping has rapidly become the test of choice in patients with neurocognitive phenotypes, but studies of its clinical utility have largely been limited to outbred populations. In consanguineous populations, single-gene recessive causes of neurocognitive phenotypes are expected to account for a relatively high percentage of cases, thus diminishing the yield of molecular karyotyping. The aim of this study was to test the clinical yield of molecular karyotyping in the highly consanguineous population of Saudi Arabia. We have reviewed the data of 584 patients with neurocognitive phenotypes (mainly referred from pediatric neurology clinics), all evaluated by a single clinical geneticist. At least 21% of tested cases had chromosomal aberrations that are likely disease-causing. These changes include both known and novel deletion syndromes. The higher yield of molecular karyotyping in this study as compared with the commonly cited 11% can be explained by our ability to efficiently identify single-gene disorders, thus enriching the samples that underwent molecular karyotyping for de novo chromosomal aberrations. We show that we were able to identify a causal mutation in 37% of cases on a clinical basis with the help of autozygome analysis, thus bypassing the need for molecular karyotyping. Our study confirms the clinical utility of molecular karyotyping even in highly consanguineous populations.

  8. Consanguinity and endogamy in Northern Tunisia and its impact on non-syndromic deafness.

    PubMed

    Ben Arab, Saida; Masmoudi, Saber; Beltaief, Najeh; Hachicha, Slah; Ayadi, Hammadi

    2004-07-01

    Deafness is an important health problem in the Tunisian population, especially in isolates where the prevalence ranges from 2 to 8%. To evaluate the effect of inbred unions on deafness, a study was conducted on 5,020 individuals (160 are deaf) between 2000 and 2002 in the North of Tunisia. The coefficient of inbreeding for all individuals and the levels of inbreeding in ten districts were computed. The higher levels were obtained in the rural districts. Our study revealed that geographic isolation, social traditions, and parental involvement in mode selection all contribute to increase consanguinity in these regions. The mean inbreeding seems to be similar to those estimated in highly inbred isolates in the world. The relative risk of the 35delG mutation, the single most frequent allele for non-syndromic recessive deafness in Tunisia, was estimated from the observed inbreeding coefficient and found to be 10.76 (SD 7.74) for first-cousin marriages, which are the most common form of consanguineous marriage encountered. Our knowledge of the risk rate of deafness and our understanding of consanguinity is required for the prevention of genetic deafness in the Tunisian population. Copyright 2004 Wiley-Liss, Inc.

  9. A resonant family of dynamically cold small bodies in the near-Earth asteroid belt

    NASA Astrophysics Data System (ADS)

    de la Fuente Marcos, C.; de la Fuente Marcos, R.

    2013-07-01

    Near-Earth objects (NEOs) moving in resonant, Earth-like orbits are potentially important. On the positive side, they are the ideal targets for robotic and human low-cost sample return missions and a much cheaper alternative to using the Moon as an astronomical observatory. On the negative side and even if small in size (2-50 m), they have an enhanced probability of colliding with the Earth causing local but still significant property damage and loss of life. Here, we show that the recently discovered asteroid 2013 BS45 is an Earth co-orbital, the sixth horseshoe librator to our planet. In contrast with other Earth's co-orbitals, its orbit is strikingly similar to that of the Earth yet at an absolute magnitude of 25.8, an artificial origin seems implausible. The study of the dynamics of 2013 BS45 coupled with the analysis of NEO data show that it is one of the largest and most stable members of a previously undiscussed dynamically cold group of small NEOs experiencing repeated trappings in the 1:1 commensurability with the Earth. This new resonant family is well constrained in orbital parameter space and it includes at least 10 other transient members: 2003 YN107, 2006 JY26, 2009 SH2 and 2012 FC71 among them. 2012 FC71 represents the best of both worlds as it is locked in a Kozai resonance and is unlikely to impact the Earth. These objects are not primordial and may have originated within the Venus-Earth-Mars region or in the main-belt, then transition to Amor-class asteroid before entering Earth's co-orbital region. Objects in this group could be responsible for the production of Earth's transient irregular natural satellites.

  10. Novel homozygous PANK2 mutation identified in a consanguineous Chinese pedigree with pantothenate kinase-associated neurodegeneration.

    PubMed

    Li, Yan-Fang; Li, Hong-Fu; Zhang, Yan-Bin; Wu, Ji-Min

    2016-08-01

    Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal recessive neurodegenerative disorder resulting from pantothenate kinase 2 (PANK2) gene mutations. It is clinically characterized by early onset of extrapyramidal symptoms, with or without pigmentary retinopathy, optic atrophy and acanthocytosis. The specific radiographic appearance of PKAN is the eye-of-the-tiger sign. However, there are few studies regarding PKAN patients of Chinese Han ancestry. In the present study, a Chinese 20-year-old female with an 8-year history of unsteady walking and involuntary movements is described. Brain magnetic resonance imaging revealed eye-of-the-tiger sign. Following sequencing of PANK2, a novel homozygous c.863C>T (p.P288L) mutation was identified in the patient and heterozygous c.863C>T was identified in her consanguineous parents. The absence of this mutation in the 1000 Genomes database, The Exome Aggregation Consortium, and 200 controls demonstrated that this mutation was probably pathogenic for PKAN in this family. In addition, the PANK2 c.863C>T mutation was predicted to be deleterious by SIFT, disease causing by Mutation Taster and probably damaging by PolyPhen2.

  11. Novel homozygous PANK2 mutation identified in a consanguineous Chinese pedigree with pantothenate kinase-associated neurodegeneration

    PubMed Central

    Li, Yan-Fang; Li, Hong-Fu; Zhang, Yan-Bin; Wu, Ji-Min

    2016-01-01

    Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal recessive neurodegenerative disorder resulting from pantothenate kinase 2 (PANK2) gene mutations. It is clinically characterized by early onset of extrapyramidal symptoms, with or without pigmentary retinopathy, optic atrophy and acanthocytosis. The specific radiographic appearance of PKAN is the eye-of-the-tiger sign. However, there are few studies regarding PKAN patients of Chinese Han ancestry. In the present study, a Chinese 20-year-old female with an 8-year history of unsteady walking and involuntary movements is described. Brain magnetic resonance imaging revealed eye-of-the-tiger sign. Following sequencing of PANK2, a novel homozygous c.863C>T (p.P288L) mutation was identified in the patient and heterozygous c.863C>T was identified in her consanguineous parents. The absence of this mutation in the 1000 Genomes database, The Exome Aggregation Consortium, and 200 controls demonstrated that this mutation was probably pathogenic for PKAN in this family. In addition, the PANK2 c.863C>T mutation was predicted to be deleterious by SIFT, disease causing by Mutation Taster and probably damaging by PolyPhen2. PMID:27446545

  12. Small Molecule Inhibitors of BAF; A Promising Family of Compounds in HIV-1 Latency Reversal

    PubMed Central

    Stoszko, Mateusz; De Crignis, Elisa; Rokx, Casper; Khalid, Mir Mubashir; Lungu, Cynthia; Palstra, Robert-Jan; Kan, Tsung Wai; Boucher, Charles; Verbon, Annelies; Dykhuizen, Emily C.; Mahmoudi, Tokameh

    2015-01-01

    Persistence of latently infected cells in presence of Anti-Retroviral Therapy presents the main obstacle to HIV-1 eradication. Much effort is thus placed on identification of compounds capable of HIV-1 latency reversal in order to render infected cells susceptible to viral cytopathic effects and immune clearance. We identified the BAF chromatin remodeling complex as a key player required for maintenance of HIV-1 latency, highlighting its potential as a molecular target for inhibition in latency reversal. Here, we screened a recently identified panel of small molecule inhibitors of BAF (BAFi's) for potential to activate latent HIV-1. Latency reversal was strongly induced by BAFi's Caffeic Acid Phenethyl Ester and Pyrimethamine, two molecules previously characterized for clinical application. BAFi's reversed HIV-1 latency in cell line based latency models, in two ex vivo infected primary cell models of latency, as well as in HIV-1 infected patient's CD4 + T cells, without inducing T cell proliferation or activation. BAFi-induced HIV-1 latency reversal was synergistically enhanced upon PKC pathway activation and HDAC-inhibition. Therefore BAFi's constitute a promising family of molecules for inclusion in therapeutic combinatorial HIV-1 latency reversal. PMID:26870822

  13. Myocilin variations and familial glaucoma in Taxiarchis, a small Greek village

    PubMed Central

    Konstas, Anastasios G. P.; Samples, John R.; Kaltsos, Kostantinos; Economou, Athanasios; Dimopoulos, Antonios; Georgiadou, Irene; Petersen, Michael B.

    2008-01-01

    Purpose To initiate a prospective study of glaucoma in a Greek village reported over 30 years ago to have several large families with primary open-angle glaucoma (POAG). Methods A random group of 126 villagers from Taxiarchis, Greece was examined in the village community center. The detailed evaluation included ophthalmic and general history, measurement of blood pressure, intraocular pressure (IOP), and central corneal thickness (CCT) as well as evaluation of the optic nerve status. Results The incidence of glaucoma approached 18% in this small isolated village. Myocilin variants were present in almost half of the individuals screened with Arg76Lys and Thr377Met being the most common finding (25% and 17%, respectively). Over half of the individuals with the Thr377Met mutation were diagnosed with glaucoma. Two of these patients were homozygous for the Thr377Met mutation. Three individuals with the Arg76Lys polymorphism had glaucoma; however, two of these individuals also had the Thr377Met mutation. Only two patients with pseudoexfoliation were identified. Conclusions The incidence of glaucoma and the Thr377Met MYOC mutation in this population is much higher than that reported for other European populations. PMID:18449353

  14. Small Molecule Inhibitors of BAF; A Promising Family of Compounds in HIV-1 Latency Reversal.

    PubMed

    Stoszko, Mateusz; De Crignis, Elisa; Rokx, Casper; Khalid, Mir Mubashir; Lungu, Cynthia; Palstra, Robert-Jan; Kan, Tsung Wai; Boucher, Charles; Verbon, Annelies; Dykhuizen, Emily C; Mahmoudi, Tokameh

    2016-01-01

    Persistence of latently infected cells in presence of Anti-Retroviral Therapy presents the main obstacle to HIV-1 eradication. Much effort is thus placed on identification of compounds capable of HIV-1 latency reversal in order to render infected cells susceptible to viral cytopathic effects and immune clearance. We identified the BAF chromatin remodeling complex as a key player required for maintenance of HIV-1 latency, highlighting its potential as a molecular target for inhibition in latency reversal. Here, we screened a recently identified panel of small molecule inhibitors of BAF (BAFi's) for potential to activate latent HIV-1. Latency reversal was strongly induced by BAFi's Caffeic Acid Phenethyl Ester and Pyrimethamine, two molecules previously characterized for clinical application. BAFi's reversed HIV-1 latency in cell line based latency models, in two ex vivo infected primary cell models of latency, as well as in HIV-1 infected patient's CD4 + T cells, without inducing T cell proliferation or activation. BAFi-induced HIV-1 latency reversal was synergistically enhanced upon PKC pathway activation and HDAC-inhibition. Therefore BAFi's constitute a promising family of molecules for inclusion in therapeutic combinatorial HIV-1 latency reversal.

  15. Moxidectin and the avermectins: Consanguinity but not identity.

    PubMed

    Prichard, Roger; Ménez, Cécile; Lespine, Anne

    2012-12-01

    The avermectins and milbemycins contain a common macrocyclic lactone (ML) ring, but are fermentation products of different organisms. The principal structural difference is that avermectins have sugar groups at C13 of the macrocyclic ring, whereas the milbemycins are protonated at C13. Moxidectin (MOX), belonging to the milbemycin family, has other differences, including a methoxime at C23. The avermectins and MOX have broad-spectrum activity against nematodes and arthropods. They have similar but not identical, spectral ranges of activity and some avermectins and MOX have diverse formulations for great user flexibility. The longer half-life of MOX and its safety profile, allow MOX to be used in long-acting formulations. Some important differences between MOX and avermectins in interaction with various invertebrate ligand-gated ion channels are known and could be the basis of different efficacy and safety profiles. Modelling of IVM interaction with glutamate-gated ion channels suggest different interactions will occur with MOX. Similarly, profound differences between MOX and the avermectins are seen in interactions with ABC transporters in mammals and nematodes. These differences are important for pharmacokinetics, toxicity in animals with defective transporter expression, and probable mechanisms of resistance. Resistance to the avermectins has become widespread in parasites of some hosts and MOX resistance also exists and is increasing. There is some degree of cross-resistance between the avermectins and MOX, but avermectin resistance and MOX resistance are not identical. In many cases when resistance to avermectins is noticed, MOX produces a higher efficacy and quite often is fully effective at recommended dose rates. These similarities and differences should be appreciated for optimal decisions about parasite control, delaying, managing or reversing resistances, and also for appropriate anthelmintic combination.

  16. Moxidectin and the avermectins: Consanguinity but not identity

    PubMed Central

    Prichard, Roger; Ménez, Cécile; Lespine, Anne

    2012-01-01

    The avermectins and milbemycins contain a common macrocyclic lactone (ML) ring, but are fermentation products of different organisms. The principal structural difference is that avermectins have sugar groups at C13 of the macrocyclic ring, whereas the milbemycins are protonated at C13. Moxidectin (MOX), belonging to the milbemycin family, has other differences, including a methoxime at C23. The avermectins and MOX have broad-spectrum activity against nematodes and arthropods. They have similar but not identical, spectral ranges of activity and some avermectins and MOX have diverse formulations for great user flexibility. The longer half-life of MOX and its safety profile, allow MOX to be used in long-acting formulations. Some important differences between MOX and avermectins in interaction with various invertebrate ligand-gated ion channels are known and could be the basis of different efficacy and safety profiles. Modelling of IVM interaction with glutamate-gated ion channels suggest different interactions will occur with MOX. Similarly, profound differences between MOX and the avermectins are seen in interactions with ABC transporters in mammals and nematodes. These differences are important for pharmacokinetics, toxicity in animals with defective transporter expression, and probable mechanisms of resistance. Resistance to the avermectins has become widespread in parasites of some hosts and MOX resistance also exists and is increasing. There is some degree of cross-resistance between the avermectins and MOX, but avermectin resistance and MOX resistance are not identical. In many cases when resistance to avermectins is noticed, MOX produces a higher efficacy and quite often is fully effective at recommended dose rates. These similarities and differences should be appreciated for optimal decisions about parasite control, delaying, managing or reversing resistances, and also for appropriate anthelmintic combination. PMID:24533275

  17. Desbuquois syndrome: clinical and radiological report of the first two Chinese cases from a consanguineous family.

    PubMed

    Lam, W F; Chan, H B; Sillence, D O

    2003-12-01

    Two siblings from China have been observed with severe short stature of prenatal onset and developmental delay. The radiographic features were characteristic of Desbuquois syndrome. The association of a genetic skeletal dysplasia and developmental delay is a relatively rare combination, although this syndrome is readily diagnosable from its distinctive radiographic features.

  18. Service Family Support -- A Small-Scale Project of Educational Psychologists Working with Parents

    ERIC Educational Resources Information Center

    Hogg, Jane; Hart, Anne; Collins, Zoe V.

    2014-01-01

    Being in a Service family can be a difficult position for children and parents alike due to high levels of mobility, parental separation, and the remaining parent's stress and emotional well-being. A Service family is defined as a family with one or both parents employed by the Ministry of Defence (MOD). The current project looked at the…

  19. Consistent Small-Sample Variances for Six Gamma-Family Measures of Ordinal Association

    ERIC Educational Resources Information Center

    Woods, Carol M.

    2009-01-01

    Gamma-family measures are bivariate ordinal correlation measures that form a family because they all reduce to Goodman and Kruskal's gamma in the absence of ties (1954). For several gamma-family indices, more than one variance estimator has been introduced. In previous research, the "consistent" variance estimator described by Cliff and…

  20. Service Family Support -- A Small-Scale Project of Educational Psychologists Working with Parents

    ERIC Educational Resources Information Center

    Hogg, Jane; Hart, Anne; Collins, Zoe V.

    2014-01-01

    Being in a Service family can be a difficult position for children and parents alike due to high levels of mobility, parental separation, and the remaining parent's stress and emotional well-being. A Service family is defined as a family with one or both parents employed by the Ministry of Defence (MOD). The current project looked at the…

  1. Consistent Small-Sample Variances for Six Gamma-Family Measures of Ordinal Association

    ERIC Educational Resources Information Center

    Woods, Carol M.

    2009-01-01

    Gamma-family measures are bivariate ordinal correlation measures that form a family because they all reduce to Goodman and Kruskal's gamma in the absence of ties (1954). For several gamma-family indices, more than one variance estimator has been introduced. In previous research, the "consistent" variance estimator described by Cliff and…

  2. The Tutte polynomial of an infinite family of outerplanar, small-world and self-similar graphs

    NASA Astrophysics Data System (ADS)

    Liao, Yunhua; Fang, Aixiang; Hou, Yaoping

    2013-10-01

    In this paper we recursively describe the Tutte polynomial of an infinite family of outerplanar, small-world and self-similar graphs. In particular, we study the Abelian Sandpile Model on these graphs and obtain the generating function of the recurrent configurations. Further, we give some exact analytical expression for the Tutte polynomial at several special points

  3. Expression and strain variation of the novel “Small Open Reading Frame” 3 (smorf) multigene family in Babesia bovis

    USDA-ARS?s Scientific Manuscript database

    Small open reading frame (smorf) genes comprise the second largest Babesia bovis multigene family. All known 44 variant smorf genes are located in close chromosomal proximity to ves1 genes, which encode proteins that mediate cytoadhesion and contribute to immune evasion. In this study, we characte...

  4. The squash aspartic proteinase inhibitor SQAPI is widely present in the cucurbitales, comprises a small multigene family, and is a member of the phytocystatin family.

    PubMed

    Christeller, John T; Farley, Peter C; Marshall, Richelle K; Anandan, Ananda; Wright, Michele M; Newcomb, Richard D; Laing, William A

    2006-12-01

    The squash (Cucurbita maxima) phloem exudate-expressed aspartic proteinase inhibitor (SQAPI) is a novel aspartic acid proteinase inhibitor, constituting a fifth family of aspartic proteinase inhibitors. However, a comparison of the SQAPI sequence to the phytocystatin (a cysteine proteinase inhibitor) family sequences showed approximately 30% identity. Modeling SQAPI onto the structure of oryzacystatin gave an excellent fit; regions identified as proteinase binding loops in cystatin coincided with regions of SQAPI identified as hypervariable, and tryptophan fluorescence changes were also consistent with a cystatin structure. We show that SQAPI exists as a small gene family. Characterization of mRNA and clone walking of genomic DNA (gDNA) produced 10 different but highly homologous SQAPI genes from Cucurbita maxima and the small family size was confirmed by Southern blotting, where evidence for at least five loci was obtained. Using primers designed from squash sequences, PCR of gDNA showed the presence of SQAPI genes in other members of the Cucurbitaceae and in representative members of Coriariaceae, Corynocarpaceae, and Begoniaceae. Thus, at least four of seven families of the order Cucurbitales possess member species with SQAPI genes, covering approximately 99% of the species in this order. A phylogenetic analysis of these Cucurbitales SQAPI genes indicated not only that SQAPI was present in the Cucurbitales ancestor but also that gene duplication has occurred during evolution of the order. Phytocystatins are widespread throughout the plant kingdom, suggesting that SQAPI has evolved recently from a phytocystatin ancestor. This appears to be the first instance of a cystatin being recruited as a proteinase inhibitor of another proteinase family.

  5. Development of EGFR family small molecule inhibitors for anticancer intervention: an overview of approved drugs and clinical candidates.

    PubMed

    Cheng, Weiyan; Hu, Yongzhou; Sheng, Rong

    2014-01-01

    The epidermal growth factor receptor (EGFR) family includes four structurally related receptor tyrosine kinases, termed as HER1 (EGFR, erbB1), HER2 (erbB2), HER3 (erbB3), and HER4 (erbB4). Given its intimate role in the development of several solid tumors, excessive HER signaling provides a unique opportunity for anticancer intervention. Along with extensive pharmacological studies validating the therapeutic potential of targeting the EGFR family for cancer therapy, kinase inhibitors of this family are continuously coming up and entering clinical studies. Herein, we review the EGFR family small molecule kinase inhibitors which have been approved or progressed into clinical studies, mainly focusing on their mechanisms of action, structure-activity relationships, binding modes, synthetic routes, and clinical status.

  6. Contribution of family labour to the profitability and competitiveness of small-scale dairy production systems in central Mexico.

    PubMed

    Posadas-Domínguez, Rodolfo Rogelio; Arriaga-Jordán, Carlos Manuel; Martínez-Castañeda, Francisco Ernesto

    2014-01-01

    The objective of this work was to determine the effect of family labour on the profitability and competitiveness of small-scale dairy farms in the highlands of Central Mexico. Economic data from 37 farms were analysed from a stratified statistical sampling with a Neyman assignment. Three strata were defined taking herd size as criterion. Stratum 1: herds from 3 to 9 cows plus replacements, Stratum 2: herds from 10 to 19 cows and Stratum 3: herds from 20 to 30 cows. The policy analysis matrix was used as the method to determine profitability and competitiveness. The coefficient of private profitability (CPP) when the economic cost of family labour is included in the cost structure was 8.0 %, 31.0 % and 46.0 %. When the economic cost of family labour is not included, CPP increase to 47.0 %, 57.0 % and 66.0 % for each strata, respectively. The private cost ratio (PCR) when family labour is included was 0.79, 0.51 and 0.42 for strata 1, 2 and 3, respectively. When family labour is not included, the PCR was 0.07, 0.25 and 0.26. Net profit per litre of milk including family labour was US$0.03 l(-1) for Stratum 1, US$0.09 for Stratum 2 and US$0.12 l(-1) for Stratum 3; but increased to $0.12, 0.14 and 0.15, respectively, when the economic cost of family labour is not included. It is concluded that family labour is a crucial factor in the profitability and competitiveness of small-scale dairy production.

  7. Genetic heterogeneity and consanguinity lead to a “double hit”: Homozygous mutations of MYO7A and PDE6B in a patient with retinitis pigmentosa

    PubMed Central

    Goldenberg-Cohen, Nitza; Banin, Eyal; Zalzstein, Yael; Cohen, Ben; Rotenstreich, Ygal; Rizel, Leah; Basel-Vanagaite, Lina

    2013-01-01

    Purpose Retinitis pigmentosa (RP), the most genetically heterogeneous disorder in humans, actually represents a group of pigmentary retinopathies characterized by night blindness followed by visual-field loss. RP can appear as either syndromic or nonsyndromic. One of the most common forms of syndromic RP is Usher syndrome, characterized by the combination of RP, hearing loss, and vestibular dysfunction. Methods The underlying cause of the appearance of syndromic and nonsyndromic RP in three siblings from a consanguineous Israeli Muslim Arab family was studied with whole-genome homozygosity mapping followed by whole exome sequencing. Results The family was found to segregate novel mutations of two different genes: myosin VIIA (MYO7A), which causes type 1 Usher syndrome, and phosphodiesterase 6B, cyclic guanosine monophosphate-specific, rod, beta (PDE6B), which causes nonsyndromic RP. One affected child was homozygous for both mutations. Since the retinal phenotype seen in this patient results from overlapping pathologies, one might expect to find severe retinal degeneration. Indeed, he was diagnosed with RP based on an abnormal electroretinogram (ERG) at a young age (9 months). However, this early diagnosis may be biased, as two of his older siblings had already been diagnosed, leading to increased awareness. At the age of 32 months, he had relatively good vision with normal visual fields. Further testing of visual function and structure at different ages in the three siblings is needed to determine whether the two RP-causing genes mutated in this youngest sibling confer increased disease severity. Conclusions This report further supports the genetic heterogeneity of RP, and demonstrates how consanguinity could increase intrafamilial clustering of multiple hereditary diseases. Moreover, this report provides a unique opportunity to study the clinical implications of the coexistence of pathogenic mutations in two RP-causative genes in a human patient. PMID:23882135

  8. [Small-scale, homelike care environments for people with dementia: effects on residents, family caregivers and nursing staff].

    PubMed

    Verbeek, H; Zwakhalen, S M G; van Rossum, E; Kempen, G I J M; Hamers, J P H

    2013-12-01

    Institutional dementia care is increasingly directed towards small-scale and homelike care environments, in The Netherlands as well as abroad. In these facilities, a small number of residents, usually six to eight, live together, and normal daily household activities and social participation are emphasized. In a quasi-experimental study, we studied the effects of small-scale, homelike care environments on residents (n = 259), family caregivers (n = 206) and nursing staff (n = 305). We compared two types of institutional nursing care during a 1 year period (baseline assessment and follow-up measurements at 6 and 12 months): (28) small-scale, homelike care environments and (21) psychogeriatric wards in traditional nursing homes. A matching procedure was applied to increase comparability of residents at baseline regarding functional status and cognition. This study was unable to demonstrate convincing overall effects of small-scale, homelike care facilities. On our primary outcome measures, such as quality of life and behaviour of residents and job satisfaction and motivation of nursing staff, no differences were found with traditional nursing homes. We conclude that small-scale, homelike care environments are not necessarily a better care environment than regular nursing homes and other types of living arrangements should be considered carefully. This provides opportunities for residents and their family caregivers to make a choice which care facility suits their wishes and beliefs best.

  9. Multicentric Castleman Disease in an HHV8-Infected Child Born to Consanguineous Parents With Systematic Review

    PubMed Central

    Moshous, Despina; Cassar, Olivier; Reguerre, Yves; Byun, Minji; Pedergnana, Vincent; Canioni, Danielle; Gessain, Antoine; Oksenhendler, Eric; Fieschi, Claire; Mahlaoui, Nizar; Rivière, Jean-Pierre; Herbigneaux, Rose-Marie; Muszlak, Matthias; Arnaud, Jean-Pierre; Fischer, Alain; Picard, Capucine; Blanche, Stéphane; Plancoulaine, Sabine

    2012-01-01

    Childhood multicentric Castleman disease (MCD) is a rare and unexplained lymphoproliferative disorder. We report a human herpesvirus-8 (HHV-8)-infected child, born to consanguineous Comorian parents, who displayed isolated MCD in the absence of any known immunodeficiency. We also systematically review the clinical features of the 32 children previously reported with isolated and unexplained MCD. The characteristics of this patient and the geographic areas of origin of most previous cases suggest that pediatric MCD is associated with HHV-8 infection. Moreover, as previously suggested for Kaposi sarcoma, MCD in childhood may result from inborn errors of immunity to HHV-8 infection. PMID:22157133

  10. Therapeutic Trial for Patients With Ewing Sarcoma Family of Tumor and Desmoplastic Small Round Cell Tumors

    ClinicalTrials.gov

    2017-04-11

    Desmoplastic Small Round Cell Tumor; Ewing Sarcoma of Bone or Soft Tissue; Localized Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor

  11. Consanguinity and prevalence patterns of inherited disease in the UK Pakistani community.

    PubMed

    Corry, Peter C

    2014-01-01

    The aim of this paper is to describe the current knowledge about inherited diseases in UK children of Pakistani origin, who now number over 300,000, and to investigate disease associations with parental consanguinity. Published data on the overall prevalence of inherited diseases were reviewed in conjunction with published and unpublished information from the city of Bradford where there is a large resident Pakistani community. There is significant literature on infant mortality, congenital anomalies, disabilities and many clinical conditions, often drawing attention to ethnic variations and an increased disease prevalence in UK Pakistani children. A further analysis is frequently necessary to differentiate both between genetic and non-genetic causes, and Pakistani and non-Pakistani children, who collectively have been labelled as 'Asian' or 'South Asian'. The analysis suggests that much of the increased mortality and morbidity in UK Pakistani children is due to autosomal recessive conditions. Evidence suggests that this finding is associated with the custom of consanguineous marriage, but future studies might also explore the role of community endogamy. Prevalence data from the first and second post-migration generations could additionally be useful in informing health planning in Pakistan. © 2014 S. Karger AG, Basel.

  12. The Effect of Consanguineous Marriage on Mental Health among the Students of the Shahrekord University of Medical Sciences

    PubMed Central

    Hosseinpour, Maryam; Deris, Fatemeh; Solati-Dehkordi, Kamal; Heidari-Soreshjani, Sheida; Karimi, Negar; Teimori, Hossein

    2016-01-01

    Introduction In Iran, after unintentional accidents, mental health problems are the second leading burden of disease. Consanguineous marriage is very common in Iran and the association between parental consanguinity and mental health is an important issue that has not yet been studied sufficiently in Iran. Aim To investigate the effect of consanguinity and the degree of relationship on different levels of mental health. Materials and Methods In this cross-sectional study, conducted in the Shahrekord University of Medical Sciences, two groups of students were enrolled. The first group consisted of 156 students that had consanguineous parent (case group) and the second group was 156 students whose parents had non-blood relationship (control group). The students were evaluated using General Health Questionnaire (GHQ-28). Statistical analysis was conducted by Pearson’s correlation coefficient, independent t-test and the one-way analysis of variance. Odd ratio was used to estimate the relative risk. Results Over 30% of the individuals were suffering from mental health problems. The most and least common mental health problems in both groups were social dysfunction (54.5% in the case group and the control group 50%) and depression (15.4% in the case group and 17.3% in the control group), respectively. No statistically significant difference was observed in the frequency of overall mental health and its subscales between student with non-consanguineous parent (control group) and the students that had consanguineous parent (case group) (p>0.05) and the status of mental health was not significantly different among student with different degree of kinship (p>0.05). Conclusion The study revealed that social dysfunction was very common among the study students and also there were no relationship between parental consanguineous marriage and mental health. Parental consanguinity and genetic factors may not be the major causes of high prevalence of mental health problems in

  13. Detection of the YORP effect for small asteroids in the Karin family

    NASA Astrophysics Data System (ADS)

    Nesvorny, David; Carruba, Valerio; Vokrouhlicky, David

    2016-10-01

    The Karin family formed by a collisional breakup of a ~40-km parent asteroid only 5.75 Myr ago. The young age can be demonstrated by numerically integrating the orbits of Karin family members backward in time and showing the convergence of orbital elements. Previous work has pointed out that the convergence is not ideal if the backward integration only accounts for the gravitational perturbations from the Solar System planets. It improves when the thermal radiation force known as the Yarkovsky effect is accounted for. This method can be used to estimate the spin obliquities of Karin family members. Here we show that the obliquity distribution of diameter D=1-2 km asteroids in the Karin family is bimodal, as expected if the YORP effect acted to move obliquities toward extreme values (0 or 180 deg). The measured magnitude of the effect is consistent with the standard YORP model. Specifically, the strength of the YORP effect is inferred to be roughly 70% of the nominal YORP strength obtained for a collection of random Gaussian spheroids. The surface thermal conductivity is found to be 0.07-0.2 W/m/K (thermal inertia 300-500 in the SI units). These results are consistent with surfaces composed of rough and rocky regolith. The obliquity values predicted here for 480 members of the Karin cluster can be validated by the lightcurve inversion method. In broader context, the bimodal distribution of obliquities in the Karin cluster can be thought as an initial stage of dynamical evolution that later leads to a characteristically bi-lobed distribution of family members in the semimajor axis (e.g., Eos, Merxia or Erigone families).

  14. Assessing the local need for family and child care services: a small area utilization analysis.

    PubMed

    Percy, A; Carr-Hill, R; Dixon, P; Jamison, J Q

    2000-01-01

    This article reports the findings of a study to develop a new method for allocating resources to family and child care services within Northern Ireland. Downloads from financial and client databases, together with a survey of social worker case activity, were used to estimate utilization costs across 500 local areas. Regression techniques were then used to account for variations in these costs in terms of local socioeconomic conditions. The resultant needs index represents a fair and equitable means of allocating central family and child care budgets to local units of management and service delivery.

  15. Family Involvement in Creative Teaching Practices for All in Small Rural Schools

    ERIC Educational Resources Information Center

    Vigo Arrazola, Begoña; Soriano Bozalongo, Juana

    2015-01-01

    Parental involvement is interpreted as a key form of support that can contribute to the establishment of inclusive practices in schools, but this can be difficult in sparsely populated areas. Using ethnographic methods of participant observation, informal conversations and document analysis, this article therefore focuses on family involvement…

  16. Family Involvement in Creative Teaching Practices for All in Small Rural Schools

    ERIC Educational Resources Information Center

    Vigo Arrazola, Begoña; Soriano Bozalongo, Juana

    2015-01-01

    Parental involvement is interpreted as a key form of support that can contribute to the establishment of inclusive practices in schools, but this can be difficult in sparsely populated areas. Using ethnographic methods of participant observation, informal conversations and document analysis, this article therefore focuses on family involvement…

  17. Familial hemophagocytic lymphohistiocytosis may present during adulthood: clinical and genetic features of a small series.

    PubMed

    Sieni, Elena; Cetica, Valentina; Piccin, Andrea; Gherlinzoni, Filippo; Sasso, Ferdinando Carlo; Rabusin, Marco; Attard, Luciano; Bosi, Alberto; Pende, Daniela; Moretta, Lorenzo; Aricò, Maurizio

    2012-01-01

    Familial Hemophagocytic lymphohistiocytosis (FHL) is a rare immune deficiency with defective cytotoxic function. The age at onset is usually young and the natural course is rapidly fatal if untreated. A later onset of the disease has been sporadically reported even in adolescents and adults. We report the results of our retrospective data collection of all cases diagnosed with FHL at an age of 18 years or older and enrolled in the Italian Registry of HLH. All cases were diagnosed with FHL based on evidence of genetic defect in one FHL-related gene. A total of 11 patients were diagnosed with FHL. They were 9 males and 2 females, from 10 unrelated families; their age ranged between 18 and 43 years (median, 23 years). Family history was unremarkable in eight families at the time of the diagnosis. Their genetic diagnoses are: FHL2 (n = 6), FHL3 (n = 2), FHL5 (n = 1), XLP1 (n = 2). Clinical, molecular and functional data are described. These data confirm that FHL may present beyond the pediatric age and up to the fifth decade. FHL2 due to perforin defect is the most frequently reported subtype. Adult specialists should consider FHL in the differential diagnosis of patients with cytopenia and liver or central nervous system disorders, especially when a lymphoproliferative disease is suspected but eventually not confirmed. FHL may turn to be fatal within a short time course even in adults. This risk, together with the continuous improvement in the transplant technique, especially in the area of transplant from matched unrelated donor, resulting in reduced treatment related mortality, might suggest a wider use of SCT in this population. Current diagnostic approach allows prompt identification of patients by flow-cytometry screening, then confirmed by the genetic study, and treatment with chemo-immunotherapy followed by stem cell transplantation.

  18. Familial Hemophagocytic Lymphohistiocytosis May Present during Adulthood: Clinical and Genetic Features of a Small Series

    PubMed Central

    Piccin, Andrea; Gherlinzoni, Filippo; Sasso, Ferdinando Carlo; Rabusin, Marco; Attard, Luciano; Bosi, Alberto; Pende, Daniela; Moretta, Lorenzo; Aricò, Maurizio

    2012-01-01

    Familial Hemophagocytic lymphohistiocytosis (FHL) is a rare immune deficiency with defective cytotoxic function. The age at onset is usually young and the natural course is rapidly fatal if untreated. A later onset of the disease has been sporadically reported even in adolescents and adults. We report the results of our retrospective data collection of all cases diagnosed with FHL at an age of 18 years or older and enrolled in the Italian Registry of HLH. All cases were diagnosed with FHL based on evidence of genetic defect in one FHL-related gene. A total of 11 patients were diagnosed with FHL. They were 9 males and 2 females, from 10 unrelated families; their age ranged between 18 and 43 years (median, 23 years). Family history was unremarkable in eight families at the time of the diagnosis. Their genetic diagnoses are: FHL2 (n = 6), FHL3 (n = 2), FHL5 (n = 1), XLP1 (n = 2). Clinical, molecular and functional data are described. These data confirm that FHL may present beyond the pediatric age and up to the fifth decade. FHL2 due to perforin defect is the most frequently reported subtype. Adult specialists should consider FHL in the differential diagnosis of patients with cytopenia and liver or central nervous system disorders, especially when a lymphoproliferative disease is suspected but eventually not confirmed. FHL may turn to be fatal within a short time course even in adults. This risk, together with the continuous improvement in the transplant technique, especially in the area of transplant from matched unrelated donor, resulting in reduced treatment related mortality, might suggest a wider use of SCT in this population. Current diagnostic approach allows prompt identification of patients by flow-cytometry screening, then confirmed by the genetic study, and treatment with chemo-immunotherapy followed by stem cell transplantation. PMID:22970278

  19. Expansion of the residential conservation service program to multi-family and small commercial buildings

    SciTech Connect

    1980-11-01

    Alternative regulatory provisions are considered which might permit achievement of the building energy conservation regulatory goals at a lower cost. Major issues, regulatory and legislative options, and cost-benefit analyses are discussed for multi-family and commercial buildings. The following are presented: related government programs, urban and community impact analysis, institutional impacts, energy cost, Residential Conservation Service coverage, methods of analysis, and regional studies. (MHR)

  20. Back pain among persons working on small or family farms--eight Colorado counties, 1993-1996.

    PubMed

    1999-04-23

    In the United States, work-related back pain often results in lost wages, reduced productivity, and increased medical costs. However, national surveillance data about these injuries, such as occupationally acquired back pain among workers on small or family farms, are limited. To characterize back pain in a farming population, researchers at Colorado State University interviewed adult farmers residing in eight northeastern Colorado counties (Larimer, Logan, Morgan, Phillips, Sedgewick, Washington, Weld, and Yuma) during 1993-1996, using the Colorado Farm Family Health and Hazard Survey (CFFHHS). This report summarizes the findings of CFFHHS, which indicate that back pain is common among farmers and most frequently attributed to repeated activities (RAs) (e.g. lifting, pushing, pulling, bending, twisting, and reaching).

  1. A Novel Family of Small Molecules that Enhance the Intracellular Delivery and Pharmacological Effectiveness of Antisense and Splice Switching Oligonucleotides.

    PubMed

    Wang, Ling; Ariyarathna, Yamuna; Ming, Xin; Yang, Bing; James, Lindsey I; Kreda, Silvia M; Porter, Melissa; Janzen, William; Juliano, Rudolph L

    2017-08-18

    The pharmacological effectiveness of oligonucleotides has been hampered by their tendency to remain entrapped in endosomes, thus limiting their access to cytosolic or nuclear targets. We have previously reported a group of small molecules that enhance the effects of oligonucleotides by causing their release from endosomes. Here, we describe a second novel family of oligonucleotide enhancing compounds (OECs) that is chemically distinct from the compounds reported previously. We demonstrate that these molecules substantially augment the actions of splice switching oligonucleotides (SSOs) and antisense oligonucleotides (ASOs) in cell culture. We also find enhancement of SSO effects in a murine model. These new compounds act by increasing endosome permeability and causing partial release of entrapped oligonucleotides. While they also affect the permeability of lysosomes, they are clearly different from typical lysosomotropic agents. Current members of this compound family display a relatively narrow window between effective dose and toxic dose. Thus, further improvements are necessary before these agents can become suitable for therapeutic use.

  2. On the adaptive origins and maladaptive consequences of human inbreeding: parasite prevalence, immune functioning, and consanguineous marriage.

    PubMed

    Hoben, Ashley D; Buunk, Abraham P; Fincher, Corey L; Thornhill, Randy; Schaller, Mark

    2010-11-13

    We propose that consanguineous marriages arise adaptively in response to high parasite prevalence and function to maintain coadapted gene complexes and associated local adaptation that defend against local pathogens. Therefore, a greater prevalence of inbreeding by consanguineous marriage is expected in geographical regions that historically have had high levels of disease-causing parasites. Eventually such marriages may, under the contemporary high movement of people with modern transportation, jeopardize the immunity of those who practice inbreeding as this leads to an increased susceptibility to novel pathogens. Therefore, a greater frequency of inbreeding is expected to predict higher levels of contemporary mortality and morbidity from infectious diseases. This parasite model of human inbreeding was supported by an analysis involving 72 countries worldwide. We found that historically high levels of pathogen prevalence were related positively to the proportion of consanguineous marriages, and that a higher prevalence of such marriages was associated with higher contemporary mortality and morbidity due to pathogens. Our study addresses plausible alternative explanations. The results suggest that consanguineous marriage is an adaptive consequence of historical pathogen ecologies, but is maladaptive in contemporary disease ecologies.

  3. Meckel Gruber Syndrome: Second trimester diagnosis of a case in a non-consanguineous marriage

    PubMed Central

    Alam, Areej; Adhi, Mehreen; Bano, Raffat; Zubair, Aisha; Mushtaq, Ammara

    2013-01-01

    Meckel-Gruber Syndrome (MKS) is a rare, autosomal recessive genetic disorder, incompatible with life. It is characterized by enlarged polycystic kidneys and post axial polydactyly. Foetal or neonatal death is caused by pulmonary hypoplasia. We report a case of a 35 year old woman who presented at 7 weeks of gestation of her sixth pregnancy. A transabdominal anomaly ultrasound performed for her current pregnancy at 18 weeks of gestation showed features consistent with MKS. The termination of pregnancy was declined and a live newborn female was delivered via an emergency caeserean section at 34 weeks of gestation due to previous history of lower segment caesarean section (LSCS) & leaking. Physical examination of the neonate confirmed the features of MKS. The neonate died within 4-5 hours of birth. This case represented a second trimester diagnosis of a recurrent case of MKS in a non-consanguineous marriage. PMID:24353549

  4. Meckel Gruber Syndrome: Second trimester diagnosis of a case in a non-consanguineous marriage.

    PubMed

    Alam, Areej; Adhi, Mehreen; Bano, Raffat; Zubair, Aisha; Mushtaq, Ammara

    2013-01-01

    Meckel-Gruber Syndrome (MKS) is a rare, autosomal recessive genetic disorder, incompatible with life. It is characterized by enlarged polycystic kidneys and post axial polydactyly. Foetal or neonatal death is caused by pulmonary hypoplasia. We report a case of a 35 year old woman who presented at 7 weeks of gestation of her sixth pregnancy. A transabdominal anomaly ultrasound performed for her current pregnancy at 18 weeks of gestation showed features consistent with MKS. The termination of pregnancy was declined and a live newborn female was delivered via an emergency caeserean section at 34 weeks of gestation due to previous history of lower segment caesarean section (LSCS) & leaking. Physical examination of the neonate confirmed the features of MKS. The neonate died within 4-5 hours of birth. This case represented a second trimester diagnosis of a recurrent case of MKS in a non-consanguineous marriage.

  5. Consanguineous marriages and marriage payment: a study among three south Indian caste groups.

    PubMed

    Reddy, P G

    1988-01-01

    The present study aims at understanding the interrelations between consanguineous marriages and marriage payment. The data are collected from three castes inhabiting two regions of Nellore district, Andhra Pradesh, South India. It is evident from the study that the dowry system is more prevalent among higher castes, while the bride wealth system is more common among the lower castes in the hierarchy. Further, it can be seen that the dowry system is more prevalent in developed regions, while bride-wealth is more common in backward regions. Marriage payment is found to be less common in close kin marriages than in unrelated marriages. Most of the uncle-niece marriages are without any marriage payment, in all the castes. However, most of the matrilateral cross-cousin and patrilateral cross-cousin marriages are also without any marriage payment in the Devanga.

  6. Domestic violence in consanguineous marriages - findings from Pakistan Demographic and Health Survey 2012-13.

    PubMed

    Shaikh, Masood Ali

    2016-10-01

    Domestic violence is a pandemic and estimated to affect one in three women globally, in their lifetime. Marriages within blood relations in Pakistan are common. In this study a secondary analysis of Pakistan Demographic and Health Survey 2012-13 was done to study the prevalence and profile of domestic violence in the context of consanguineous marriages in Pakistan. Almost 65% of women had some kind of blood relationship with their husbands. Women having a blood relationship with husbands were more likely to report having ever been subjected to marital control behaviours, emotional and physical violence by their husbands, compared to ones without such relationship. However, these associations fail to reach statistical significance; underscoring the ubiquitous nature of marital control and violence. More effective public health education campaigns for just and equal treatment of wives by their husbands to speedily curb the scourge of domestic violence in the country are needed.

  7. State-of-the-art of small molecule inhibitors of the TAM family: the point of view of the chemist.

    PubMed

    Baladi, Tom; Abet, Valentina; Piguel, Sandrine

    2015-11-13

    The TAM family of tyrosine kinases receptors (Tyro3, Axl and Mer) is implicated in cancer development, autoimmune reactions and viral infection and is therefore emerging as an effective and attractive therapeutic target. To date, only a few small molecules have been intentionally designed to block the TAM kinases, while most of the inhibitors were developed for blocking different protein kinases and then identified through selectivity profile studies. This minireview will examine in terms of chemical structure the different compounds able to act on either one, two or three TAM kinases with details about structure-activity relationships, drug-metabolism and pharmacokinetics properties where they exist.

  8. Syndrome Keratitis-Ichtyosis-Deafness (KID) chez un enfant togolais issu d'un mariage consanguin

    PubMed Central

    Kombaté, Koussak; Saka, Bayaki; Landoh, Dadja Essoya; Mouhari-Toure, Abass; Akakpo, Séfako; Belei, Eric; Gnassingbé, Wanguena; Djibril, Mohaman Awalou; Tchangaï-Walla, Kissem; Pitché, Palokinam

    2015-01-01

    Le syndrome KID est une affection génétique rare associant kératite, ichtyose et surdité. Nous rapportons un cas dont la surdité s'est compliquée de mutisme chez un enfant togolais issu d'un mariage consanguin.Il s'agissait d'une fillette de 9 ans admise en dermatologie pour une peau sèche et une kératodermie palmoplantaire évoluant depuis l'enfance, une surdité sévère et un mutisme total évoluant depuis la naissance. Il n'y avait pas d'histoire familiale connue de syndrome KID. Les parents de cet enfant sont des cousins germains. A l'examen, on notait une kératodermie palmoplantaire typique en cuir grossier, une peau sèche ichtyosiforme finement squameuse avec un aspect pachydermique aux genoux et un aspect arlequin aux jambes. L'examen ophtalmologique avait noté une blépharo-conjonctivite, une xérophtalmie, une photophobie et une absence de sourcils. L'examen ORL avait objectivé une hypotrophie des pavillons des oreilles, une surdité sévère et un mutisme total. La particularité de cette observation réside dans la sévérité de l'atteinte auditive qui s'est compliquée de mutisme. Notre enfant étant née de parents consanguins sains, sans histoire familiale de KID, nous pensons que le mode de transmission est probablement sporadique. Une étude moléculaire du cas index et de ses parents, non réalisée à cause de notre plateau technique limité aurait pu le confirmer. PMID:26664520

  9. Localization of the genetic defect in familial adenomatous polyposis within a small region of chromosome 5

    PubMed Central

    Nakamura, Yusuke; Lathrop, Mark; Leppert, Mark; Dobbs, Marc; Wasmuth, John; Wolff, Erica; Carlson, Mary; Fujimoto, Esther; Krapcho, Karen; Sears, Tena; Woodward, Scott; Hughes, J.; Burt, Randy; Gardner, Eldon; Lalouel, Jean-Marc; White, Ray

    1988-01-01

    Familial adenomatous polyposis (FAP), a Mendelian disorder that includes familial polyposis coli (FPC) and Gardner syndrome (GS), has an autosomal dominant mode of inheritance. It is characterized by hundreds to thousands of adenomatous polyps that can progress to carcinoma of the colon, suggesting that the gene that harbors the FAP germ-line mutation may play an important role in the somatic genetic pathway to colon cancer. The defect responsible for FAP was recently mapped to the long arm of chromosome 5 by linkage between the FPC phenotype and a locus defined by DNA probe pC11p11 (D5S71), located at 5q21–22. Because an important next step in the paradigm for identification of a disease gene is to obtain a more precise localization, we isolated and mapped by linkage six additional polymorphic DNA markers in the FAP region. Subsequent linkage analysis in six pedigrees, three having the FPC phenotype and three segregating GS, placed the FAP locus very close to a new marker, YN5.48 (D5S81), that is approximately 17 centimorgans distal to C11p11 on the genetic map. The analysis revealed no evidence of genetic heterogeneity between the two phenotypes, a question that had not been clearly resolved by the earlier studies. The new set of markers in the near vicinity of the FAP locus represents a further step toward isolation of the genetic defect and provides the opportunity for preclinical diagnosis of risk status for colon cancer among individuals in families that are segregating adenomatous polyposis. PMID:2903664

  10. New Opportunitie s for Small Satellite Programs Provided by the Falcon Family of Launch Vehicles

    NASA Astrophysics Data System (ADS)

    Dinardi, A.; Bjelde, B.; Insprucker, J.

    2008-08-01

    The Falcon family of launch vehicles, developed by Space Exploration Technologies Corporation (SpaceX), are designed to provide the world's lowest cost access to orbit. Highly reliable, low cost launch services offer considerable opportunities for risk reduction throughout the life cycle of satellite programs. The significantly lower costs of Falcon 1 and Falcon 9 as compared with other similar-class launch vehicles results in a number of new business case opportunities; which in turn presents the possibility for a paradigm shift in how the satellite industry thinks about launch services.

  11. Actions of Rho family small G proteins and p21-activated protein kinases on mitogen-activated protein kinase family members.

    PubMed Central

    Frost, J A; Xu, S; Hutchison, M R; Marcus, S; Cobb, M H

    1996-01-01

    The mitogen-activated protein (MAP) kinases are a family of serine/threonine kinases that are regulated by distinct extracellular stimuli. The currently known members include extracellular signal-regulated protein kinase 1 (ERK1), ERK2, the c-Jun N-terminal kinase/stress-activated protein kinases (JNK/SAPKs), and p38 MAP kinases. We find that overexpression of the Ste20-related enzymes p21-activated kinase 1 (PAK1) and PAK2 in 293 cells is sufficient to activate JNK/SAPK and to a lesser extent p38 MAP kinase but not ERK2. Rat MAP/ERK kinase kinase 1 can stimulate the activity of each of these MAP kinases. Although neither activated Rac nor the PAKs stimulate ERK2 activity, overexpression of either dominant negative Rac2 or the N-terminal regulatory domain of PAK1 inhibits Ras-mediated activation of ERK2, suggesting a permissive role for Rac in the control of the ERK pathway. Furthermore, constitutively active Rac2, Cdc42hs, and RhoA synergize with an activated form of Raf to increase ERK2 activity. These findings reveal a previously unrecognized connection between Rho family small G proteins and the ERK pathway. PMID:8668187

  12. Genealogical and molecular analysis of a family-based cohort of congenital heart disease patients from the São Miguel Island (Azores, Portugal).

    PubMed

    Cabral, Rita; Pires, Renato; Anjos, Rui; Branco, Claudia C; Maciel, Paula; Mota-Vieira, Luisa

    2016-11-01

    Congenital heart disease (CHD) is one common birth malformation, accounting for ∼30% of total congenital abnormalities. Considering the unknown role of consanguinity in causing CHD, this study hypothesised that consanguineous unions and/or familial aggregation may be frequent in the Azorean Island of São Miguel (Portugal). To that end, a retrospective observational study was performed based on genealogical and molecular analyses. The study enrolled 112 CHD patients from São Miguel Island, which allowed the assessment of type of family (simplex or multiplex), parental consanguinity and grandparental endogamy. Based on 15 STR markers, inbreeding coefficients (FIS) in the CHD cohort and healthy control group (n = 114) were estimated. Multiplex families were 37.6% (n = 41/109), a rate considerably higher than previously described in the literature (< 15%). Moreover, 9.2% (n = 10/109) of the CHD families were consanguineous, mostly derived from third cousin unions, and 20.2% (n = 22/109) presented full grandparental endogamy. Higher FIS values were found in patients with parental consanguinity (0.0371) and patent ductus arteriosus (0.0277). This study analysed several genealogical and genetic features related with CHD, revealing the presence of parental consanguinity and extensive familial aggregation in the CHD patients from São Miguel Island.

  13. A frame-shift mutation in the SLC34A2 gene in three patients with pulmonary alveolar microlithiasis in an inbred family.

    PubMed

    Dogan, Omer Tamer; Ozsahin, Sefa Levent; Gul, Eylem; Arslan, Sulhattin; Koksal, Binnur; Berk, Serdar; Ozdemir, Ozturk; Akkurt, Ibrahim

    2010-01-01

    Pulmonary alveolar microlithiasis (PAM) is a rare disease characterized by the presence of small calculi in the alveolar space. The SLC34A2 is thought to be responsible for the disease. We encountered three siblings of an inbred family who have PAM. We examined the family of the proband who was admitted with dyspnea on exertion and cough, and eventually was diagnosed with PAM. Genetic analysis revealed that both parents (a consanguineous marriage) of the proband were carriers with heterozygous mutation of SLC34A2 gene, and three of their children were diagnosed with PAM with homozygous mutation in the SLC34A2 gene. These findings suggest that impaired activity of the SLC34A2 gene may be responsible for familial PAM.

  14. Working Families at the Margins: The Uncertain Future of America's Small Towns. Hearing Before the Select Committee on Children, Youth, and Families. House of Representatives, One Hundred First Congress, First Session.

    ERIC Educational Resources Information Center

    Congress of the U.S., Washington, DC. House Select Committee on Children, Youth, and Families.

    Poverty affects many rural two-parent families, even with one or both parents working. High suicide rates, increased violence, families separated in order to find work, homelessness, and hunger afflict the rural and small town poor. This document contains testimony from poor and homeless rural people; the director of the Center on Budget and…

  15. Age distribution of human gene families shows significant roles of both large- and small-scale duplications in vertebrate evolution.

    PubMed

    Gu, Xun; Wang, Yufeng; Gu, Jianying

    2002-06-01

    The classical (two-round) hypothesis of vertebrate genome duplication proposes two successive whole-genome duplication(s) (polyploidizations) predating the origin of fishes, a view now being seriously challenged. As the debate largely concerns the relative merits of the 'big-bang mode' theory (large-scale duplication) and the 'continuous mode' theory (constant creation by small-scale duplications), we tested whether a significant proportion of paralogous genes in the contemporary human genome was indeed generated in the early stage of vertebrate evolution. After an extensive search of major databases, we dated 1,739 gene duplication events from the phylogenetic analysis of 749 vertebrate gene families. We found a pattern characterized by two waves (I, II) and an ancient component. Wave I represents a recent gene family expansion by tandem or segmental duplications, whereas wave II, a rapid paralogous gene increase in the early stage of vertebrate evolution, supports the idea of genome duplication(s) (the big-bang mode). Further analysis indicated that large- and small-scale gene duplications both make a significant contribution during the early stage of vertebrate evolution to build the current hierarchy of the human proteome.

  16. Label-based routing for a family of small-world Farey graphs

    PubMed Central

    Zhai, Yinhu; Wang, Yinhe

    2016-01-01

    We introduce an informative labelling method for vertices in a family of Farey graphs, and deduce a routing algorithm on all the shortest paths between any two vertices in Farey graphs. The label of a vertex is composed of the precise locating position in graphs and the exact time linking to graphs. All the shortest paths routing between any pair of vertices, which number is exactly the product of two Fibonacci numbers, are determined only by their labels, and the time complexity of the algorithm is O(n). It is the first algorithm to figure out all the shortest paths between any pair of vertices in a kind of deterministic graphs. For Farey networks, the existence of an efficient routing protocol is of interest to design practical communication algorithms in relation to dynamical processes (including synchronization and structural controllability) and also to understand the underlying mechanisms that have shaped their particular structure. PMID:27167605

  17. Label-based routing for a family of small-world Farey graphs

    NASA Astrophysics Data System (ADS)

    Zhai, Yinhu; Wang, Yinhe

    2016-05-01

    We introduce an informative labelling method for vertices in a family of Farey graphs, and deduce a routing algorithm on all the shortest paths between any two vertices in Farey graphs. The label of a vertex is composed of the precise locating position in graphs and the exact time linking to graphs. All the shortest paths routing between any pair of vertices, which number is exactly the product of two Fibonacci numbers, are determined only by their labels, and the time complexity of the algorithm is O(n). It is the first algorithm to figure out all the shortest paths between any pair of vertices in a kind of deterministic graphs. For Farey networks, the existence of an efficient routing protocol is of interest to design practical communication algorithms in relation to dynamical processes (including synchronization and structural controllability) and also to understand the underlying mechanisms that have shaped their particular structure.

  18. Label-based routing for a family of small-world Farey graphs.

    PubMed

    Zhai, Yinhu; Wang, Yinhe

    2016-05-11

    We introduce an informative labelling method for vertices in a family of Farey graphs, and deduce a routing algorithm on all the shortest paths between any two vertices in Farey graphs. The label of a vertex is composed of the precise locating position in graphs and the exact time linking to graphs. All the shortest paths routing between any pair of vertices, which number is exactly the product of two Fibonacci numbers, are determined only by their labels, and the time complexity of the algorithm is O(n). It is the first algorithm to figure out all the shortest paths between any pair of vertices in a kind of deterministic graphs. For Farey networks, the existence of an efficient routing protocol is of interest to design practical communication algorithms in relation to dynamical processes (including synchronization and structural controllability) and also to understand the underlying mechanisms that have shaped their particular structure.

  19. Small-group, interactive education and the effect on asthma control by children and their families.

    PubMed

    Watson, Wade T A; Gillespie, Cathy; Thomas, Nicola; Filuk, Shauna E; McColm, Judy; Piwniuk, Michelle P; Becker, Allan B

    2009-09-01

    Effective approaches to education about asthma need to be identified. We evaluated the impact on asthma control by children and their caregivers of an intervention involving small-group, interactive education about asthma. We randomly assigned children who visited an emergency department for an exacerbation of asthma (n = 398) to either of 2 groups. Children assigned to the control group followed the usual care recommended by their primary care physician. Those assigned to the intervention group participated in a small-group, interactive program of education about asthma. We examined changes in the number of visits to the emergency department during the year after the intervention. During the year after enrolment, children in the intervention group made significantly fewer visits to the emergency department (0.45 visits per child) compared with those in the control group (0.75 visits per child) (p = 0.004). The likelihood of a child in the intervention group requiring emergency care was reduced by 38% (relative risk [RR] 0.62, 95% confidence interval CI 0.48-0.81, p = 0.004). Fewer courses of oral corticosteroids (0.63 per child) were required by children in the intervention group than by those in the control group (0.85 per child) (p = 0.006). We observed significant improvements in the symptom domain of the questionnaire on pediatric asthma quality-of-life (p = 0.03) and the activity domain of the questionnaire on caregivers' quality of life (p = 0.05). Parents of children in the intervention group missed less work because of their child's asthma after participating in the educational program (p = 0.04). No impact on hospital admissions was observed. Education about asthma, especially in a small-group, interactive format, improved clinically important outcomes and overall care of children with asthma.

  20. Small-group, interactive education and the effect on asthma control by children and their families

    PubMed Central

    Watson, Wade T.A.; Gillespie, Cathy; Thomas, Nicola; Filuk, Shauna E.; McColm, Judy; Piwniuk, Michelle P.; Becker, Allan B.

    2009-01-01

    Background Effective approaches to education about asthma need to be identified. We evaluated the impact on asthma control by children and their caregivers of an intervention involving small-group, interactive education about asthma. Methods We randomly assigned children who visited an emergency department for an exacerbation of asthma (n = 398) to either of 2 groups. Children assigned to the control group followed the usual care recommended by their primary care physician. Those assigned to the intervention group participated in a small-group, interactive program of education about asthma. We examined changes in the number of visits to the emergency department during the year after the intervention. Results During the year after enrolment, children in the intervention group made significantly fewer visits to the emergency department (0.45 visits per child) compared with those in the control group (0.75 visits per child) (p = 0.004). The likelihood of a child in the intervention group requiring emergency care was reduced by 38% (relative risk [RR] 0.62, 95% confidence interval CI 0.48–0.81, p = 0.004). Fewer courses of oral corticosteroids (0.63 per child) were required by children in the intervention group than by those in the control group (0.85 per child) (p = 0.006). We observed significant improvements in the symptom domain of the questionnaire on pediatric asthma quality-of-life (p = 0.03) and the activity domain of the questionnaire on caregivers’ quality of life (p = 0.05). Parents of children in the intervention group missed less work because of their child’s asthma after participating in the educational program (p = 0.04). No impact on hospital admissions was observed. Interpretation Education about asthma, especially in a small-group, interactive format, improved clinically important outcomes and overall care of children with asthma. PMID:19687105

  1. Genetically heterogeneous selective intestinal malabsorption of vitamin B12: founder effects, consanguinity, and high clinical awareness explain aggregations in Scandinavia and the Middle East.

    PubMed

    Tanner, Stephan M; Li, Zhongyuan; Bisson, Ryan; Acar, Ceren; Oner, Cihan; Oner, Reyhan; Cetin, Mualla; Abdelaal, Mohamed A; Ismail, Essam A; Lissens, Willy; Krahe, Ralf; Broch, Harald; Gräsbeck, Ralph; de la Chapelle, Albert

    2004-04-01

    Selective intestinal malabsorption of vitamin B(12) causing juvenile megaloblastic anemia (MGA; MIM# 261100) is a recessively inherited disorder that is believed to be rare except for notable clusters of cases in Finland, Norway, and the Eastern Mediterranean region. The disease can be caused by mutations in either the cubilin (CUBN; MGA1; MIM# 602997) or the amnionless (AMN; MIM# 605799) gene. To explain the peculiar geographical distribution, we hypothesized that mutations in one of the genes would mainly be responsible for the disease in Scandinavia, and mutations in the other gene in the Mediterranean region. We studied 42 sibships and found all cases in Finland to be due to CUBN (three different mutations) and all cases in Norway to be due to AMN (two different mutations), while in Turkey, Israel, and Saudi Arabia, there were two different AMN mutations and three different CUBN mutations. Haplotype evidence excluded both CUBN and AMN conclusively in five families and tentatively in three families, suggesting the presence of at least one more gene locus that can cause MGA. We conclude that the Scandinavian cases are typical examples of enrichment by founder effects, while in the Mediterranean region high degrees of consanguinity expose rare mutations in both genes. We suggest that in both regions, physician awareness of this disease causes it to be more readily diagnosed than elsewhere; thus, it may well be more common worldwide than previously thought.

  2. Tandem Duplication Events in the Expansion of the Small Heat Shock Protein Gene Family in Solanum lycopersicum (cv. Heinz 1706).

    PubMed

    Krsticevic, Flavia J; Arce, Débora P; Ezpeleta, Joaquín; Tapia, Elizabeth

    2016-10-13

    In plants, fruit maturation and oxidative stress can induce small heat shock protein (sHSP) synthesis to maintain cellular homeostasis. Although the tomato reference genome was published in 2012, the actual number and functionality of sHSP genes remain unknown. Using a transcriptomic (RNA-seq) and evolutionary genomic approach, putative sHSP genes in the Solanum lycopersicum (cv. Heinz 1706) genome were investigated. A sHSP gene family of 33 members was established. Remarkably, roughly half of the members of this family can be explained by nine independent tandem duplication events that determined, evolutionarily, their functional fates. Within a mitochondrial class subfamily, only one duplicated member, Solyc08g078700, retained its ancestral chaperone function, while the others, Solyc08g078710 and Solyc08g078720, likely degenerated under neutrality and lack ancestral chaperone function. Functional conservation occurred within a cytosolic class I subfamily, whose four members, Solyc06g076570, Solyc06g076560, Solyc06g076540, and Solyc06g076520, support ∼57% of the total sHSP RNAm in the red ripe fruit. Subfunctionalization occurred within a new subfamily, whose two members, Solyc04g082720 and Solyc04g082740, show heterogeneous differential expression profiles during fruit ripening. These findings, involving the birth/death of some genes or the preferential/plastic expression of some others during fruit ripening, highlight the importance of tandem duplication events in the expansion of the sHSP gene family in the tomato genome. Despite its evolutionary diversity, the sHSP gene family in the tomato genome seems to be endowed with a core set of four homeostasis genes: Solyc05g014280, Solyc03g082420, Solyc11g020330, and Solyc06g076560, which appear to provide a baseline protection during both fruit ripening and heat shock stress in different tomato tissues.

  3. Tandem Duplication Events in the Expansion of the Small Heat Shock Protein Gene Family in Solanum lycopersicum (cv. Heinz 1706)

    PubMed Central

    Krsticevic, Flavia J.; Arce, Débora P.; Ezpeleta, Joaquín; Tapia, Elizabeth

    2016-01-01

    In plants, fruit maturation and oxidative stress can induce small heat shock protein (sHSP) synthesis to maintain cellular homeostasis. Although the tomato reference genome was published in 2012, the actual number and functionality of sHSP genes remain unknown. Using a transcriptomic (RNA-seq) and evolutionary genomic approach, putative sHSP genes in the Solanum lycopersicum (cv. Heinz 1706) genome were investigated. A sHSP gene family of 33 members was established. Remarkably, roughly half of the members of this family can be explained by nine independent tandem duplication events that determined, evolutionarily, their functional fates. Within a mitochondrial class subfamily, only one duplicated member, Solyc08g078700, retained its ancestral chaperone function, while the others, Solyc08g078710 and Solyc08g078720, likely degenerated under neutrality and lack ancestral chaperone function. Functional conservation occurred within a cytosolic class I subfamily, whose four members, Solyc06g076570, Solyc06g076560, Solyc06g076540, and Solyc06g076520, support ∼57% of the total sHSP RNAm in the red ripe fruit. Subfunctionalization occurred within a new subfamily, whose two members, Solyc04g082720 and Solyc04g082740, show heterogeneous differential expression profiles during fruit ripening. These findings, involving the birth/death of some genes or the preferential/plastic expression of some others during fruit ripening, highlight the importance of tandem duplication events in the expansion of the sHSP gene family in the tomato genome. Despite its evolutionary diversity, the sHSP gene family in the tomato genome seems to be endowed with a core set of four homeostasis genes: Solyc05g014280, Solyc03g082420, Solyc11g020330, and Solyc06g076560, which appear to provide a baseline protection during both fruit ripening and heat shock stress in different tomato tissues. PMID:27565886

  4. Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families.

    PubMed

    Akawi, Nadia; McRae, Jeremy; Ansari, Morad; Balasubramanian, Meena; Blyth, Moira; Brady, Angela F; Clayton, Stephen; Cole, Trevor; Deshpande, Charu; Fitzgerald, Tomas W; Foulds, Nicola; Francis, Richard; Gabriel, George; Gerety, Sebastian S; Goodship, Judith; Hobson, Emma; Jones, Wendy D; Joss, Shelagh; King, Daniel; Klena, Nikolai; Kumar, Ajith; Lees, Melissa; Lelliott, Chris; Lord, Jenny; McMullan, Dominic; O'Regan, Mary; Osio, Deborah; Piombo, Virginia; Prigmore, Elena; Rajan, Diana; Rosser, Elisabeth; Sifrim, Alejandro; Smith, Audrey; Swaminathan, Ganesh J; Turnpenny, Peter; Whitworth, James; Wright, Caroline F; Firth, Helen V; Barrett, Jeffrey C; Lo, Cecilia W; FitzPatrick, David R; Hurles, Matthew E

    2015-11-01

    Discovery of most autosomal recessive disease-associated genes has involved analysis of large, often consanguineous multiplex families or small cohorts of unrelated individuals with a well-defined clinical condition. Discovery of new dominant causes of rare, genetically heterogeneous developmental disorders has been revolutionized by exome analysis of large cohorts of phenotypically diverse parent-offspring trios. Here we analyzed 4,125 families with diverse, rare and genetically heterogeneous developmental disorders and identified four new autosomal recessive disorders. These four disorders were identified by integrating Mendelian filtering (selecting probands with rare, biallelic and putatively damaging variants in the same gene) with statistical assessments of (i) the likelihood of sampling the observed genotypes from the general population and (ii) the phenotypic similarity of patients with recessive variants in the same candidate gene. This new paradigm promises to catalyze the discovery of novel recessive disorders, especially those with less consistent or nonspecific clinical presentations and those caused predominantly by compound heterozygous genotypes.

  5. Studying p53 family proteins in yeast: Induction of autophagic cell death and modulation by interactors and small molecules

    SciTech Connect

    Leão, Mariana; Gomes, Sara; Bessa, Cláudia; Soares, Joana; Raimundo, Liliana; Monti, Paola; Fronza, Gilberto; Pereira, Clara; Saraiva, Lucília

    2015-01-01

    In this work, the yeast Saccharomyces cerevisiae was used to individually study human p53, p63 (full length and truncated forms) and p73. Using this cell system, the effect of these proteins on cell proliferation and death, and the influence of MDM2 and MDMX on their activities were analyzed. When expressed in yeast, wild-type p53, TAp63, ΔNp63 and TAp73 induced growth inhibition associated with S-phase cell cycle arrest. This growth inhibition was accompanied by reactive oxygen species production and autophagic cell death. Furthermore, they stimulated rapamycin-induced autophagy. On the contrary, none of the tested p53 family members induced apoptosis either per se or after apoptotic stimuli. As previously reported for p53, also TAp63, ΔNp63 and TAp73 increased actin expression levels and its depolarization, suggesting that ACT1 is also a p63 and p73 putative yeast target gene. Additionally, MDM2 and MDMX inhibited the activity of all tested p53 family members in yeast, although the effect was weaker on TAp63. Moreover, Nutlin-3a and SJ-172550 were identified as potential inhibitors of the p73 interaction with MDM2 and MDMX, respectively. Altogether, the yeast-based assays herein developed can be envisaged as a simplified cell system to study the involvement of p53 family members in autophagy, the modulation of their activities by specific interactors (MDM2 and MDMX), and the potential of new small molecules to modulate these interactions. - Highlights: • p53, p63 and p73 are individually studied in the yeast S. cerevisiae. • p53 family members induce ROS production, cell cycle arrest and autophagy in yeast. • p53 family members increase actin depolarization and expression levels in yeast. • MDM2 and MDMX inhibit the activity of p53 family members in yeast. • Yeast can be a useful tool to study the biology and drugability of p53, p63 and p73.

  6. Methylation of sulfhydryl groups: a new function for a family of small molecule plant O-methyltransferases.

    PubMed

    Coiner, Heather; Schröder, Gudrun; Wehinger, Elke; Liu, Chang-Jun; Noel, Joseph P; Schwab, Wilfried; Schröder, Joachim

    2006-04-01

    In plants, type I and II S-adenosyl-l-methionine-dependent O-methyltransferases (OMTs) catalyze most hydroxyl group methylations of small molecules. A homology-based RT-PCR strategy using Catharanthus roseus (Madagascar periwinkle) RNA previously identified six new type I plant OMT family members. We now describe the molecular and biochemical characterization of a seventh protein. It shares 56-58% identity with caffeic acid OMTs (COMTs), but it failed to methylate COMT substrates, and had no activity with flavonoids. However, the in vitro incubations revealed unusually high background levels without added substrates. A search for the responsible component revealed that the enzyme methylated dithiothreitol (DTT), the reducing agent added for enzyme stabilization. Unexpectedly, product analysis revealed that the methylation occurred on a sulfhydryl moiety, not on a hydroxyl group. Analysis of 34 compounds indicated a broad substrate range, with a preference for small hydrophobic molecules. Benzene thiol (Km 220 microm) and furfuryl thiol (Km 60 microm) were the best substrates (6-7-fold better than DTT). Small isosteric hydrophobic substrates with hydroxyl groups, like phenol and guaiacol, were also methylated, but the activities were at least 5-fold lower than with thiols. The enzyme was named C. roseus S-methyltransferase 1 (CrSMT1). Models based on the COMT crystal structure suggest that S-methylation is mechanistically identical to O-methylation. CrSMT1 so far is the only recognized example of an S-methyltransferase in this protein family. Its properties indicate that a few changes in key residues are sufficient to convert an OMT into a S-methyltransferase (SMT). Future functional investigations of plant methyltransferases should consider the possibility that the enzymes may direct methylation at sulfhydryl groups.

  7. Methylation of sulfhydryl groups: a new function for a family of small molecule plant O-methyltransferases

    PubMed Central

    Coiner, Heather; Schröder, Gudrun; Wehinger, Elke; Liu, Chang-Jun; Noel, Joseph P.; Schwab, Wilfried; Schröder, Joachim

    2010-01-01

    Summary In plants, type I and II S-adenosyl-L-methionine-dependent O-methyltransferases (OMTs) catalyze most hydroxyl group methylations of small molecules. A homology-based RT-PCR strategy using Catharanthus roseus (Madagascar periwinkle) RNA previously identified six new type I plant OMT family members. We now describe the molecular and biochemical characterization of a seventh protein. It shares 56–58% identity with caffeic acid OMTs (COMTs), but it failed to methylate COMT substrates, and had no activity with flavonoids. However, the in vitro incubations revealed unusually high background levels without added substrates. A search for the responsible component revealed that the enzyme methylated dithiothreitol (DTT), the reducing agent added for enzyme stabilization. Unexpectedly, product analysis revealed that the methylation occurred on a sulfhydryl moiety, not on a hydroxyl group. Analysis of 34 compounds indicated a broad substrate range, with a preference for small hydrophobic molecules. Benzene thiol (Km 220 μM) and furfuryl thiol (Km 60 μM) were the best substrates (6–7-fold better than DTT). Small isosteric hydrophobic substrates with hydroxyl groups, like phenol and guaiacol, were also methylated, but the activities were at least 5-fold lower than with thiols. The enzyme was named C. roseus S-methyltransferase 1 (CrSMT1). Models based on the COMT crystal structure suggest that S-methylation is mechanistically identical to O-methylation. CrSMT1 so far is the only recognized example of an S-methyltransferase in this protein family. Its properties indicate that a few changes in key residues are sufficient to convert an OMT into a S-methyltransferase (SMT). Future functional investigations of plant methyltransferases should consider the possibility that the enzymes may direct methylation at sulfhydryl groups. PMID:16623883

  8. Cloning and characterization of a small family 19 chitinase from moss (Bryum coronatum).

    PubMed

    Taira, Toki; Mahoe, Yoko; Kawamoto, Noriko; Onaga, Shoko; Iwasaki, Hironori; Ohnuma, Takayuki; Fukamizo, Tamo

    2011-05-01

    Chitinase-A (BcChi-A) was purified from a moss, Bryum coronatum, by several steps of column chromatography. The purified BcChi-A was found to be a molecular mass of 25 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and an isoelectric point of 3.5. A cDNA encoding BcChi-A was cloned by rapid amplification of cDNA ends and polymerase chain reaction. It consisted of 1012 nucleotides and encoded an open reading frame of 228 amino acid residues. The predicted mature BcChi-A consists of 205 amino acid residues and has a molecular weight of 22,654. Sequence analysis indicated that BcChi-A is glycoside hydrolase family-19 (GH19) chitinase lacking loops I, II, IV and V, and a C-terminal loop, which are present in the catalytic domain of plant class I and II chitinases. BcChi-A is a compact chitinase that has the fewest loop regions of the GH19 chitinases. Enzymatic experiments using chitooligosaccharides showed that BcChi-A has higher activity toward shorter substrates than class II enzymes. This characteristic is likely due to the loss of the loop regions that are located at the end of the substrate-binding cleft and would be involved in substrate binding of class II enzymes. This is the first report of a chitinase from mosses, nonvascular plants.

  9. Evaluation of a Teaching Kit for Family and Consumer Science Classrooms: Motivating Students to Use a Food Thermometer with Small Cuts of Meat

    ERIC Educational Resources Information Center

    Edwards, Zena; Edlefsen, Miriam; Hillers, Virginia; McCurdy, Sandra M.

    2005-01-01

    The U.S. Dept. of Agriculture recommends use of food thermometers to safely cook small cuts of meat, yet most consumers do not use them. Consumers lack knowledge about how and why to use food thermometers with small cuts of meat. Opportunities exist for family and consumer science classes to provide education about thermometers to adolescents, who…

  10. Evaluation of a Teaching Kit for Family and Consumer Science Classrooms: Motivating Students to Use a Food Thermometer with Small Cuts of Meat

    ERIC Educational Resources Information Center

    Edwards, Zena; Edlefsen, Miriam; Hillers, Virginia; McCurdy, Sandra M.

    2005-01-01

    The U.S. Dept. of Agriculture recommends use of food thermometers to safely cook small cuts of meat, yet most consumers do not use them. Consumers lack knowledge about how and why to use food thermometers with small cuts of meat. Opportunities exist for family and consumer science classes to provide education about thermometers to adolescents, who…

  11. Inhibition of TGF-β signaling in tumor cells by small molecule Src family kinase inhibitors.

    PubMed

    Bartscht, Tobias; Rosien, Benjamin; Rades, Dirk; Kaufmann, Roland; Biersack, Harald; Lehnerta, Hendrik; Ungefroren, Hendrik

    2017-01-02

    In a series of studies carried out over the last couple of years in various cell types, it was observed that the experimentally used Src family kinase inhibitors PP1 and PP2 and the clinically used Src/Abl inhibitors AZM475271 and dasatinib are potent inhibitors of TGF-β mediated cellular responses such as Smad and p38 mitogen-activated protein kinase phosphorylation, Smad-dependent transcriptional activation, growth inhibition, epithelial-mesenchymal transition (EMT), and cell motility. While for PP1/PP2 it was demonstrated shown that these agents directly inhibit the kinase activity of the TGF-β type I receptor activin receptor-like kinase 5, the mechanism of the anti-TGF-β effect of AZM475271 and dasatinib is less clear. In contrast, the anti-TGF-β effect of yet another Src/Abl inhibitor, bosutinib, is more variable with respect to the type of the TGF-β response and the cell type affected, and lacks a clear dose-dependency. In the light of their strong anti-activin receptor-like kinase 5 kinase effect, PP1 and PP2 should not be used when studying the role of c-Src as downstream mediators in TGF-β/activin receptor-like kinase 5 signaling. On the other hand, based upon in vitro findings, it is conceivable that part of the therapeutic effects of AZM475271 and dasatinib seen in preclinical and clinical studies with solid tumors was caused by inhibition of prometastatic TGF-β rather than Src signaling. If AZM475271 and dasatinib can indeed act as dual Src / TGF-β inhibitors in vivo, this may be beneficial for prevention of metastatic disease in more advanced tumor stages.

  12. Larsen syndrome in two generations of an Italian family.

    PubMed Central

    Ventruto, V; Festa, F; Sebastio, L; Sebastio, G

    1976-01-01

    This paper describes a familial case of Larsen syndrome. Typical anomalies were present in the propositus and 2 of his 6 daughters. In addition, all patients had progressive deafness and the 2 daughters had cleft palate. The certain exclusion of any consanguinity between the couple, suggests, in this instance, the dominant mode of transmission of the syndrome. Images PMID:1018317

  13. Structural Insights into the Activation of Human Relaxin Family Peptide Receptor 1 by Small-Molecule Agonists.

    PubMed

    Hu, Xin; Myhr, Courtney; Huang, Zaohua; Xiao, Jingbo; Barnaeva, Elena; Ho, Brian A; Agoulnik, Irina U; Ferrer, Marc; Marugan, Juan J; Southall, Noel; Agoulnik, Alexander I

    2016-03-29

    The GPCR relaxin family peptide receptor 1 (RXFP1) mediates the action of relaxin peptide hormone, including its tissue remodeling and antifibrotic effects. The peptide has a short half-life in plasma, limiting its therapeutic utility. However, small-molecule agonists of human RXFP1 can overcome this limitation and may provide a useful therapeutic approach, especially for chronic diseases such as heart failure and fibrosis. The first small-molecule agonists of RXFP1 were recently identified from a high-throughput screening, using a homogeneous cell-based cAMP assay. Optimization of the hit compounds resulted in a series of highly potent and RXFP1 selective agonists with low cytotoxicity, and excellent in vitro ADME and pharmacokinetic properties. Here, we undertook extensive site-directed mutagenesis studies in combination with computational modeling analysis to probe the molecular basis of the small-molecule binding to RXFP1. The results showed that the agonists bind to an allosteric site of RXFP1 in a manner that closely interacts with the seventh transmembrane domain (TM7) and the third extracellular loop (ECL3). Several residues were determined to play an important role in the agonist binding and receptor activation, including a hydrophobic region at TM7 consisting of W664, F668, and L670. The G659/T660 motif within ECL3 is crucial to the observed species selectivity of the agonists for RXFP1. The receptor binding and activation effects by the small molecule ML290 were compared with the cognate ligand, relaxin, providing valuable insights on the structural basis and molecular mechanism of receptor activation and selectivity for RXFP1.

  14. [Teaching and counseling families with small children in an urban area about minor illnesses of childhood].

    PubMed

    Lindenskov, L; Johannessen, J; Beich, C; Andersen, K V

    2001-02-19

    Parents' knowledge of and experience with illness in their children are often limited. They find it difficult to take the responsibility when their children are ill. They seek help immediately from the health care system, although the symptoms are mild. We wanted to discover whether teaching parents about minor illness in children and counselling over the telephone during acute illness would mean that parents sought help less often from the health care system, when their children became ill. This article deals with the teaching of the parents. The project had an intervention group of 91 children aged 12-35 months and a control group of 400 children aged 9-33 months. The intervention group was instructed for two hours twice in the local day nursery and telephone counselling from a nurse trained in children's acute illnesses was made available from 4 pm to 11 pm on weekdays and from 10 am to 11 pm at weekends during the period 20th October 1998 to 1st May 1999. No visible change was seen in the use of the health care system in either group, but there was a small change in favour of the intervention group in the use of a general practitioner instead of calling the emergency medical service. Eighty per cent of the counselling dealt with common acute illnesses; 75% ended without referral. There was no visible difference in the use of the health care system in either group. Parents were happy with the offer of teaching and telephone counselling, but it should have been given when the infants started at the nursery. They felt their children were too old at the time the project started. We suggest a continuation of antenatal classes in the form of "parent preparation classes", where one subject could be minor acute illnesses in children.

  15. A novel member of the rho family of small GTP-binding proteins is specifically required for cytokinesis

    PubMed Central

    1996-01-01

    Several members of the rho/rac family of small GTP-binding proteins are known to regulate the distribution of the actin cytoskeleton in various subcellular processes. We describe here a novel rac protein, racE, which is specifically required for cytokinesis, an actomyosin-mediated process. The racE gene was isolated in a molecular genetic screen devised to isolate genes required for cytokinesis in Dictyostelium. Phenotypic characterization of racE mutants revealed that racE is not essential for any other cell motility event, including phagocytosis, chemotaxis, capping, or development. Our data provide the first genetic evidence for the essential requirement of a rho-like protein, specifically in cytokinesis, and suggest a role for these proteins in coordinating cytokinesis with the mitotic events of the cell cycle. PMID:8682867

  16. Usefulness of Small Intestinal Endoscopy in a Case of Adult-onset Familial Mediterranean Fever Associated with Jejunoileitis.

    PubMed

    Kitade, Takashi; Horiki, Noriyuki; Katsurahara, Masaki; Totoki, Toshiaki; Harada, Tetsuro; Tano, Shunsuke; Yamada, Reiko; Hamada, Yasuhiko; Inoue, Hiroyuki; Tanaka, Kyosuke; Gabazza, Esteban C; Hayashi, Hiroyuki; Tanaka, Masanori; Takei, Yoshiyuki

    2015-01-01

    A 66-year-old Japanese man consulted our institution due to paroxysmal and repetitive bouts of fever and abdominal pain that had persisted for more than one week. Capsule and double-balloon endoscopy (DBE) showed petal-shaped mucosal redness with white hemming in the jejunum and ileum, and histopathology of the biopsy specimens revealed villous atrophy and cryptitis with extensive severe neutrophil infiltration. A genetic examination disclosed compound heterozygous MEFV mutations (E84K, P369S), and familial Mediterranean fever was diagnosed. Treatment with colchicine and infliximab was very effective in inducing the complete disappearance of symptoms and normalization of the endoscopic findings. To the best of our knowledge, this is the first report to describe the findings of small intestinal endoscopic images obtained using capsule and DBE.

  17. Molecular characterization and evolution of the SPRR family of keratinocyte differentiation markers encoding small proline-rich proteins

    SciTech Connect

    Gibbs, S.; Fijneman, R.; Wiegant, J.; Van De Putte, P.; Backendorf, C. ); Van Kessel, A.D. )

    1993-06-01

    SPRR genes (formerly SPR) encode a novel class of polypeptides (small proline rich proteins) that are strongly induced during differentiation of human epidermal keratinocytes in vitro and in vivo. Recently the authors found that the N- and C-terminal domains of these proteins show strong sequence homology to loricrin and involucrin, suggesting that SPRR proteins constitute a new class of cornified envelope precursor proteins. Here they show that SPRR proteins are encoded by closely related members of a gene family, consisting of two genes for SPRR1, approximately seven genes for SPRR2, and a single gene for SPRR3. All SPRR genes are closely linked within a 300-kb DNA segment on human chromosome 1 band q21-q22, a region where the related loricrin and involucrin genes have also been mapped. The most characteristic feature of the SPRR gene family resides in the structure of the central segments of the encoded polypeptides that are built up from tandemly repeated units of either eight (SPRR1 and SPRR3) or nine (SPRR2) amino acids with the general consensus *K*PEP**. Sequencing data of the different members, together with their clustered chromosomal organization, strongly suggest that this gene family has evolved from a single progenitor gene by multiple intra- and intergenic duplications. Analysis of the different SPRR subfamilies reveals a gene-specific bias to either intra- or intergenic duplication. The authors propose that a process of homogenization has acted on the different members of one subfamily, whereas the different subfamilies appear to have diverged from each other, at the levels of both protein structure and gene regulation. 25 refs., 7 figs., 2 tab.

  18. Juvenile systemic lupus erythematosus in the Sultanate of Oman: clinical and immunological comparison between familial and non-familial cases.

    PubMed

    Abdwani, R; Hira, M; Al-Nabhani, D; Al-Zakwani, I

    2011-03-01

    Consanguineous marriage is quite prevalent in the Sultanate of Oman, with up to 45% of marriages being consanguineous. The aim of this study was to determine demographic, clinical and serological characteristics between familial and non-familial cases of juvenile systemic lupus erythematosus (SLE) in a highly consanguineous region such as Oman. Hospital medical records were retrospectively reviewed for 44 consecutive children with juvenile SLE seen at Sultan Qaboos University Hospital, 16 with familial SLE and 28 with non-familial SLE. All the children included in the study were Omani, diagnosed before 13 years of age, and fulfilled the 1982 revised ACR criteria. Analyses were performed using descriptive statistics. There were largely no significant differences in the clinical and serological manifestations between the two cohorts. However, the familial SLE group was associated with worse SLEDAI score at onset of diagnosis compared with the non-familial cohort (12 vs. 17; p = 0.003) suggesting a greater severity of disease in the familial group. Even though the rate of familial SLE is higher in Oman (36%) compared with the Western world (10-12%), it appears that familial and non-familial SLE cases are in fact similar disease entities in both the West and the Middle Eastern countries.

  19. Frequent overexpression of ErbB--receptor family members in brain metastases of non-small cell lung cancer patients.

    PubMed

    Berghoff, Anna Sophie; Magerle, Manuel; Ilhan-Mutlu, Ayseguel; Dinhof, Carina; Widhalm, Georg; Dieckman, Karin; Marosi, Christine; Wöhrer, Adelheid; Hackl, Monika; Zöchbauer-Müller, Sabine; Preusser, Matthias; Birner, Peter

    2013-12-01

    The ErbB receptor family has been implicated in brain metastases (BM) formation in various cancer types and specific targeted therapies are available. We investigated the overexpression of EGFR, HER2 and HER3 in BM of non-small cell lung cancer (NSCLC) patients to get a better insight on pathobiology of BM and potential drugable targets. We performed immunohistochemical analysis of EGFR, HER2 and HER3 on tissue microarrays of 131 NSCLC-BM. Fifty-one of 131 (38.9%) specimens were considered as positive for EGFR overexpression, 12/131 (9.2%) for HER2 and 27/131 (20.6%) for HER3 respectively. Sixty-nine of 131 (52.7%) of the cases showed overexpression of at least one marker. Four of 131 (3.1%) were positive for all three markers. Strong correlation was observed between HER2 and HER3 overexpression (p = 0.009; Chi-square test after Bonferroni-Holmes correction). No statistically significant correlation of EGFR, HER2 or HER3 overexpression with clinico-pathological parameters including overall survival times was observed. We observed overexpression of ErbB receptor family members, which represent established therapeutic targets in various primary tumours, in approximately half of NSCLC-BM. Further studies should investigate the role of the ErbB pathway in development of and as a therapeutic target in BM of NSCLC patients. © 2013 APMIS. Published by John Wiley & Sons Ltd.

  20. Discovery and Pharmacological Characterization of JNJ-42756493 (Erdafitinib), a Functionally Selective Small-Molecule FGFR Family Inhibitor.

    PubMed

    Perera, Timothy P S; Jovcheva, Eleonora; Mevellec, Laurence; Vialard, Jorge; De Lange, Desiree; Verhulst, Tinne; Paulussen, Caroline; Van De Ven, Kelly; King, Peter; Freyne, Eddy; Rees, David C; Squires, Matthew; Saxty, Gordon; Page, Martin; Murray, Christopher W; Gilissen, Ron; Ward, George; Thompson, Neil T; Newell, David R; Cheng, Na; Xie, Liang; Yang, Jennifer; Platero, Suso J; Karkera, Jayaprakash D; Moy, Christopher; Angibaud, Patrick; Laquerre, Sylvie; Lorenzi, Matthew V

    2017-06-01

    Fibroblast growth factor (FGF) signaling plays critical roles in key biological processes ranging from embryogenesis to wound healing and has strong links to several hallmarks of cancer. Genetic alterations in FGF receptor (FGFR) family members are associated with increased tumor growth, metastasis, angiogenesis, and decreased survival. JNJ-42756493, erdafitinib, is an orally active small molecule with potent tyrosine kinase inhibitory activity against all four FGFR family members and selectivity versus other highly related kinases. JNJ-42756493 shows rapid uptake into the lysosomal compartment of cells in culture, which is associated with prolonged inhibition of FGFR signaling, possibly due to sustained release of the inhibitor. In xenografts from human tumor cell lines or patient-derived tumor tissue with activating FGFR alterations, JNJ-42756493 administration results in potent and dose-dependent antitumor activity accompanied by pharmacodynamic modulation of phospho-FGFR and phospho-ERK in tumors. The results of the current study provide a strong rationale for the clinical investigation of JNJ-42756493 in patients with tumors harboring FGFR pathway alterations. Mol Cancer Ther; 16(6); 1010-20. ©2017 AACR. ©2017 American Association for Cancer Research.

  1. Associations of recurrent miscarriages with chromosomal abnormalities, thrombophilia allelic polymorphisms and/or consanguinity in Saudi Arabia.

    PubMed

    Turki, Rola F; Assidi, Mourad; Banni, Huda A; Zahed, Hanan A; Karim, Sajjad; Schulten, Hans-Juergen; Abu-Elmagd, Muhammad; Rouzi, Abdulrahim A; Bajouh, Osama; Jamal, Hassan S; Al-Qahtani, Mohammed H; Abuzenadah, Adel M

    2016-10-10

    Recurrent pregnancy loss (RPL) or recurrent spontaneous abortion is an obstetric complication that affects couples at reproductive age. Previous reports documented a clear relationship between parents with chromosomal abnormalities and both recurrent miscarriages and infertility. However, limited data is available from the Arabian Peninsula which is known by higher rates of consanguineous marriages. The main goal of this study was to determine the prevalence of chromosomal abnormalities and thrombophilic polymorphisms, and to correlate them with RPL and consanguinity in Saudi Arabia. Cytogenetic analysis of 171 consent patients with RPL was performed by the standard method of 72-h lymphocyte culture and GTG banding. Allelic polymorphisms of three thrombophilic genes (Factor V Leiden, Prothrombin A20210G, MTHFR C677T) were performed using PCR-RFLP (restriction fragment length polymorphism) and gel electrophoresis. Data analysis revealed that 7.6 % of patients were carrier of numerical or structural chromosomal abnormalities. A high rate of translocations (46 %) was associated to increased incidence of RPL. A significant correlation between consanguineous RPL patients and chromosomal abnormalities (P < 0.05) was found. Both Factor V Leiden and Prothrombin A20210G allelic polymorphisms were significantly associated with a higher prevalence of RPL. This study demonstrated a strong association between RPL and the prevalence of chromosomal abnormalities and inherited thrombophilia. Given the high rate of consanguineous marriages in the Saudi population, these results underline the importance of systematic cytogenetic investigation and genetic counseling preferably at the premarital stage or at least during early pregnancy phase through preimplantation genetic diagnosis (PGD).

  2. Consanguinity and kinship in Down syndrome in Saguenay Lac-Saint-Jean (Québec).

    PubMed

    de Braekeleer, M; Landry, T; Cholette, A

    1994-01-01

    Genealogies of 67 cases of Down syndrome (DS) cytogenetically proven as trisomy 21 born in Saguenay-Lac-Saint-Jean were reconstructed using a population register. Genealogies of three controls for each patient matched on sex, date and place of birth were also reconstructed. The mean kinship coefficient was slightly, but not significantly (p > 0.05), increased in the DS group compared to the control group (0.000222 versus 0.000165). The increase was mostly the result of two patients being related as uncle-nephew. The mean inbreeding coefficient was also higher, although not significantly (p > 0.05), in the DS group than in the control group (0.001348 versus 0.000848). Nine consanguineous marriages (13.4%) were identified in the DS group compared to 17 of 201 (8.5%) in the control group. These results may suggest, as previously reported by Roberts et al. in Shetland, that some recessive element is involved in the etiology of DS, possibly in preventing the loss of the trisomic 21 fetus.

  3. Consanguineous mating, specialization, and the environment: how multiple variable interactions affect the evolution of dioecy.

    PubMed

    Sinclair, Jordan P; Maxwell, Glenn D; Freeman, D Carl

    2013-06-01

    The evolution of dioecy in plants is usually modeled as a consequence of self-fertilization. While increased seed and pollen production and dispersal patterns of specialized unisexuals have been examined, mating among relatives and interaction effects have been largely ignored. Here, we examine multiple variables simultaneously providing a more ecologically realistic set of conditions favoring the evolution of dioecy. • We developed two complementary models to explore the evolution of dioecious plants. In both models, we examined the effects of inbreeding, compensation, and specialization on unisexual invasibility and were able to directly measure the influence of related matings on such a system. • Our results support previous studies indicating dispersal specialization, consanguineous mating, and inbreeding depression facilitate the evolution of dioecy. However, our results suggest that it is the interaction effect of multiple forces acting simultaneously that allows for unisexual invasion at thresholds and frequencies witnessed in nature. Additionally, our results suggest that subdioecious populations often result, and depending on population conditions, dioecy evolves at different rates, lending importance to the ecological and life history conditions of the species. • Mating among relatives significantly enhances the invasibility of a unisexual mutant into a hermaphroditic population and lowers the levels of inbreeding depression required for invasion than previously reported conditions for unisexual invasion especially, if we consider multiple pressures simultaneously.

  4. Rapid multipoint linkage analysis of recessive traits in nuclear families, including homozygosity mapping

    SciTech Connect

    Kruglyak, L.; Daly, M.J.; Lander, E.S. |

    1995-02-01

    Homozygosity mapping is a powerful strategy for mapping rare recessive traits in children of consanguineous marriages. Practical applications of this strategy are currently limited by the inability of conventional linkage analysis software to compute, in reasonable time, multipoint LOD scores for pedigrees with inbreeding loops. We have developed a new algorithm for rapid multipoint likelihood calculations in small pedigrees, including those with inbreeding loops. The running time of the algorithm grows, at most, linearly with the number of loci considered simultaneously. The running time is not sensitive to the presence of inbreeding loops, missing genotype information, and highly polymorphic loci. We have incorporated this algorithm into a software package, MAPMAKER/HOMOZ, that allows very rapid multipoint mapping of disease genes in nuclear families, including homozygosity mapping. Multipoint analysis with dozens of markers can be carried out in minutes on a personal workstation. 23 refs., 4 figs., 1 tab.

  5. The Role of Irreversible HER Family Inhibition in the Treatment of Patients with Non-Small Cell Lung Cancer

    PubMed Central

    2011-01-01

    Small-molecule tyrosine kinase inhibitors (TKIs) of the human epidermal growth factor receptor (HER) include the reversible epidermal growth factor receptor (EGFR/HER-1) inhibitors gefitinib and erlotinib. EGFR TKIs have demonstrated activity in the treatment of patients with non-small cell lung cancer (NSCLC) harboring activating EGFR mutations; however, multiple mechanisms of resistance limit the benefit of these drugs. Although resistance to EGFR TKIs can be intrinsic and correlated with molecular lesions such as in Kirsten rat sarcoma viral oncogene homolog (KRAS; generally observed in a wild-type EGFR background), acquired resistance to EGFR TKIs can evolve in the setting of activating EGFR mutations, such as in the case of EGFR T790M mutations. Several irreversible inhibitors that target multiple members of the HER family simultaneously are currently in clinical development for NSCLC and may have a role in the treatment of TKI-sensitive and TKI-resistant disease. These include PF00299804, an inhibitor of EGFR/HER-1, HER-2, and HER-4, and afatinib (BIBW 2992), an inhibitor of EGFR/HER-1, HER-2, and HER-4. Results of large, randomized trials of these agents may help to determine their potential for the treatment of NSCLC. PMID:22016476

  6. Atypical 18p- syndrome associated with partial trisomy 16p in a chromosomally unbalanced child of consanguineous parents with an identical balanced translocation.

    PubMed

    Kupchik, Gabriel S; Barrett, Shannon K; Babu, Arvind; Charria-Ortiz, Gustavo; Velinov, Milen; Macera, Michael J

    2005-01-01

    A 2 month old male infant was found to have mild growth retardation, prominent forehead, low set ears, low nasal bridge, rounded facies, cleft palate, webbed neck, shawl scrotum, and absent right kidney. The propositus, a product of a consanguineous marriage, had extremely rare abnormal cytogenetic findings. His karyotype contained three derivative chromosomes that originated from a familial translocation, t(16;18)(p13.3;p11.2) carried by both parents. Based on parental studies, the infant's unbalanced karyotype was defined as: [46,XY,t(16;18)(p13.3;p11.2), der(18)t(16;18).ish t(16;18)(16ptel-,16qtel+,18ptel+,wcp16+,wcp18+;16ptel+,18ptel-,wcp16+,wcp18+), der(18)t(16;18)(16ptel+,18ptel-,wcp16+,wcp18+)]. We describe this child at 2 months of age with a follow up at 4 1/2 years, exhibiting a mixed clinical picture with features of both 18p- and partial trisomy 16p13.3.

  7. MKBP, a Novel Member of the Small Heat Shock Protein Family, Binds and Activates the Myotonic Dystrophy Protein Kinase

    PubMed Central

    Suzuki, Atsushi; Sugiyama, Yuki; Hayashi, Yukiko; Nyu-i, Nobuo; Yoshida, Michihiko; Nonaka, Ikuya; Ishiura, Sho-ichi; Arahata, Kiichi; Ohno, Shigeo

    1998-01-01

    Muscle cells are frequently subjected to severe conditions caused by heat, oxidative, and mechanical stresses. The small heat shock proteins (sHSPs) such as αB-crystallin and HSP27, which are highly expressed in muscle cells, have been suggested to play roles in maintaining myofibrillar integrity against such stresses. Here, we identified a novel member of the sHSP family that associates specifically with myotonic dystrophy protein kinase (DMPK). This DMPK-binding protein, MKBP, shows a unique nature compared with other known sHSPs: (a) In muscle cytosol, MKBP exists as an oligomeric complex separate from the complex formed by αB-crystallin and HSP27. (b) The expression of MKBP is not induced by heat shock, although it shows the characteristic early response of redistribution to the insoluble fraction like other sHSPs. Immunohistochemical analysis of skeletal muscle cells shows that MKBP localizes to the cross sections of individual myofibrils at the Z-membrane as well as the neuromuscular junction, where DMPK has been suggested to be concentrated. In vitro, MKBP enhances the kinase activity of DMPK and protects it from heat-induced inactivation. These results suggest that MKBP constitutes a novel stress-responsive system independent of other known sHSPs in muscle cells and that DMPK may be involved in this system by being activated by MKBP. Importantly, since the amount of MKBP protein, but not that of other sHSP family member proteins, is selectively upregulated in skeletal muscle from DM patients, an interaction between DMPK and MKBP may be involved in the pathogenesis of DM. PMID:9490724

  8. Ataxia telangiectasia: Family management

    PubMed Central

    Seshachalam, Arun; Cyriac, Sanju; Reddy, Neelesh; Gnana, Sagar T.

    2010-01-01

    Ataxia telangiectasia (AT) is a rare autosomal recessive disease resulting in progressive degeneration of multiple systems in the body. Both A-T homozygote and heterozygote are at increased risk of developing malignancy. We report a family in which three generations were affected by this disorder. Our index case is a 12-year-old female child, born of second degree consanguineous marriage diagnosed to have ataxia telangiectasia at the age of four years, now presented with fever and neck swelling of one month duration. Family history suggestive of ataxia telangiectasia in maternal uncle and younger sibling was present. History of premature coronary artery disease and death in paternal grandfather was present. On evaluation, child was diagnosed to have Alk negative anaplastic large T cell lymphoma. Management included genetic counseling, examination of all the family members, identification of A-T homozygote and providing appropriate care, regular surveillance of the heterozygote for malignancy. PMID:20838492

  9. The effect of consanguineous marriage on reading disability in the Arab community.

    PubMed

    Abu-Rabia, Salim; Maroun, Lateefeh

    2005-02-01

    The present study examined the effect of consanguineous marriage in the Arab community on reading disabilities of offspring. It examined whether the rate of reading disabilities was higher among offspring of first-cousin parents than offspring of unrelated parents; and whether reading-disabled children of first-cousin parents were more disabled in phonological awareness and phonological decoding than reading-disabled children of unrelated parents and normally reading younger children. These questions were investigated among 814 pupils of the 4th, 5th, and 6th grades, using word recognition and reading comprehension tests. Two experimental groups were chosen from this population. These were a reading-disabled group of 22 pupils who were children of first-cousin marriages and 21 pupils who were children of unrelated parents. A control group was also selected, consisting of 21 younger normally reading pupils at the same reading level. All the groups were tested on non-words, real words, phonological, orthographic and working memory measures. The results indicated that the rate of reading disabilities among children of first-cousin parents was higher than that of with children of second-cousin parents, distantly related parents, or unrelated parents. Further, no differences were found in phonological awareness and decoding between the two reading-disabled groups. Moreover, the results indicate a significant advantage of the younger normal readers over the reading-disabled children in the measures of phonological awareness, decoding, and orthographical knowledge that requires spelling. However, in reading common words and choosing words in context, the performance of the reading-disabled groups and the normally reading group were similar. It has been suggested that further research is needed to evaluate the role of intelligence, nevertheless our results provide new evidence for a genetic basis to reading disabilities.

  10. Responding to the increased genetic risk associated with customary consanguineous marriage among minority ethnic populations: lessons from local innovations in England.

    PubMed

    Salway, Sarah; Ali, Parveen; Ratcliffe, Giles; Such, Elizabeth; Khan, Nasaim; Kingston, Helen; Quarrell, Oliver

    2016-07-01

    Populations practising customary consanguineous marriage have a higher incidence of autosomal recessive genetic disorders than those in which reproductive partners are usually unrelated. In the absence of any national-level response, English service developments to address the additional needs of families living with or at risk of such disorders have been locally led. These interventions remain in their infancy here, as elsewhere in Europe, and important questions remain regarding how appropriate, effective and sustainable responses can be operationalised in practice. This formative service review employed four local case studies together with wider consultation exercises over a 4-year period (2011-2015) to document recent responses to this area of need, issues arising and lessons to inform future work. Service components included the following: enhancements to genetic services to provide family-centred, culturally competent approaches to counselling and testing; community genetic literacy approaches; and capacity development among health professionals. Local approaches were, however, very varied in their detail, scope, level of investment and longevity. The provisions of culturally competent genetic counselling services and community-level genetic literacy interventions were generally well received by those who accessed them. Coordinated action across all service components appeared important for an effective service, but healthcare professionals, particularly general practitioners, were often difficult to engage in this agenda. An evaluative culture and engagement in a wider community of practice had supported service development across sites. However, sustaining investment was challenging, particularly where new services were not well integrated into core provision and where commissioning was driven by expectations of short-term reductions in infant mortality and disability.

  11. The Quality of Teachers' Interactive Conversations with Preschool Children from Low-Income Families during Small-Group and Large-Group Activities

    ERIC Educational Resources Information Center

    Chen, Jennifer J.; de Groot Kim, Sonja

    2014-01-01

    This study examined the quality of preschool teachers' interactive conversations with three- and four-year-olds in two Head Start classrooms serving children from low-income families in the United States. Over a period of 20?weeks, 10 bi-weekly observations of conversations (totaling 15?h per classroom) were conducted in one small-group (Play…

  12. Ras-like family small GTPases genes in Nilaparvata lugens: Identification, phylogenetic analysis, gene expression and function in nymphal development

    PubMed Central

    Wang, Weixia; Li, Kailong; Wan, Pinjun; Lai, Fengxiang; Fu, Qiang; Zhu, Tingheng

    2017-01-01

    Twenty-nine cDNAs encoding Ras-like family small GTPases (RSGs) were cloned and sequenced from Nilaparvata lugens. Twenty-eight proteins are described here: 3 from Rho, 2 from Ras, 9 from Arf and 14 from Rabs. These RSGs from N.lugens have five conserved G-loop motifs and displayed a higher degree of sequence conservation with orthologues from insects. RT-qPCR analysis revealed NlRSGs expressed at all life stages and the highest expression was observed in hemolymph, gut or wing for most of NlRSGs. RNAi demonstrated that eighteen NlRSGs play a crucial role in nymphal development. Nymphs with silenced NlRSGs failed to molt, eclosion or development arrest. The qRT-PCR analysis verified the correlation between mortality and the down-regulation of the target genes. The expression level of nuclear receptors, Kr-h1, Hr3, FTZ-F1 and E93 involved in 20E and JH signal pathway was impacted in nymphs with silenced twelve NlRSGs individually. The expression of two halloween genes, Cyp314a1 and Cyp315a1 involved in ecdysone synthesis, decreased in nymphs with silenced NlSar1 or NlArf1. Cyp307a1 increased in nymphs with silenced NlArf6. In N.lugens with silenced NlSRβ, NlSar1 and NlRab2 at 9th day individually, 0.0% eclosion rate and almost 100.0% mortality was demonstrated. Further analysis showed NlSRβ could be served as a candidate target for dsRNA-based pesticides for N.lugens control. PMID:28241066

  13. Ras-like family small GTPases genes in Nilaparvata lugens: Identification, phylogenetic analysis, gene expression and function in nymphal development.

    PubMed

    Wang, Weixia; Li, Kailong; Wan, Pinjun; Lai, Fengxiang; Fu, Qiang; Zhu, Tingheng

    2017-01-01

    Twenty-nine cDNAs encoding Ras-like family small GTPases (RSGs) were cloned and sequenced from Nilaparvata lugens. Twenty-eight proteins are described here: 3 from Rho, 2 from Ras, 9 from Arf and 14 from Rabs. These RSGs from N.lugens have five conserved G-loop motifs and displayed a higher degree of sequence conservation with orthologues from insects. RT-qPCR analysis revealed NlRSGs expressed at all life stages and the highest expression was observed in hemolymph, gut or wing for most of NlRSGs. RNAi demonstrated that eighteen NlRSGs play a crucial role in nymphal development. Nymphs with silenced NlRSGs failed to molt, eclosion or development arrest. The qRT-PCR analysis verified the correlation between mortality and the down-regulation of the target genes. The expression level of nuclear receptors, Kr-h1, Hr3, FTZ-F1 and E93 involved in 20E and JH signal pathway was impacted in nymphs with silenced twelve NlRSGs individually. The expression of two halloween genes, Cyp314a1 and Cyp315a1 involved in ecdysone synthesis, decreased in nymphs with silenced NlSar1 or NlArf1. Cyp307a1 increased in nymphs with silenced NlArf6. In N.lugens with silenced NlSRβ, NlSar1 and NlRab2 at 9th day individually, 0.0% eclosion rate and almost 100.0% mortality was demonstrated. Further analysis showed NlSRβ could be served as a candidate target for dsRNA-based pesticides for N.lugens control.

  14. Wisdom, insight and pragmatism. In the early days of Islam, Muslim society was familiar with the concept of the small family.

    PubMed

    Jullundri, R A

    1996-01-01

    In the context of rapid population growth, Pakistan's main political parties have stressed the importance of the small family norm and the need to adopt modern methods of family planning. Some Ulama, however, have argued that family planning does not conform to the traditions of Islam under the assumption that the levels of sexual perversion and female physical and psychological ailments would increase were family planning widely practiced. The author counters that the opposition of the few Ulama to family planning is based not upon theology and jurisprudence, but rather upon socioeconomic grounds. Islam may be the only divine religion which supports human free will such that a man can organize his affairs according to his own social and economic circumstances. Common belief is, however, that adherence to Islam impedes progress and prosperity. Muslims themselves are responsible for the perpetuation of such an impression. Muslim societies now face several social problems, one of which is their relatively lower acceptance of family planning. Muslim countries share problems in the following areas with regard to family planning: management, women's status in Muslim society, and low educational status.

  15. Consanguinity and founder effect for Gaucher disease mutation G377S in a population from Tabuleiro do Norte, Northeastern Brazil.

    PubMed

    Chaves, R G; Pereira, L da Veiga; de Araújo, F T; Rozenberg, R; Carvalho, M D F; Coelho, J C; Michelin-Tirelli, K; Chaves, M de Freitas; Cavalcanti, G B

    2015-10-01

    Gaucher's disease (GD) is caused by a β-glucocerebrosidase deficiency, leading to the accumulation of glucocerebroside in the reticuloendothelial system. The prevalence of GD in Tabuleiro do Norte (TN) (1:4000) is the highest in Brazil. The purpose of this study was to present evidence of consanguinity and founder effect for the G377S mutation (c.1246G>A) among GD patients in TN based on enzyme, molecular and genealogical studies. Between March 2009 and December 2010, 131 subjects at risk for GD (GC in dried blood ≤2.19 nmol/h/ml) and 5 confirmed GD patients from the same community were submitted for molecular analysis to characterize the genetic profile of the population. Based on the enzymatic and molecular analysis, the subjects were classified into three categories: affected (n = 5), carrier (n = 20) and non-carrier (n = 111). All carriers were (G377S/wt). Affected subjects were homozygous (G377S/G377S). The identification of a single mutation in carriers and homozygotes from different generations, the history of the community and the genealogy study suggest that the high prevalence of GD in this population may be due to a combination of consanguinity and founder effect for the G377S mutation. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. A new family programme in Zhejiang province.

    PubMed

    Xu, B

    1994-04-01

    Zhejiang Province in China has promoted a new family planning program since April 1993. The program stresses delayed marriage and childbearing, fewer and healthier births, modernization of family life, and prosperity through hard work. The people are receptive to the new program out of a desire for an improved standard of living. The objective is to build small, modern families who 1) practice deferred marriage and childbearing; 2) voluntarily practice family planning and have no unplanned births; 3) practice avoidance of consanguineous marriage, become sterilized if a carrier of a hereditary disease of chromosomal abnormality, and use premarital education and counseling and proper prenatal care; 4) uphold the laws and maintain discipline in action to avoid criminal behavior; 5) establish families that respect the old, care for children, and help their neighbors; 6) complete 9 years of compulsory education; and 7) create well being through hard work. The program is compatible with the strategy of the "three stresses" and an integrated approach. IEC and service provision are important components in program implementation. The target population are the masses and grassroots cadres, particularly those in the childbearing ages. IEC will be directed in different ways to different groups. Those aged 18-35 years will receive education. Face to face interaction with family planning workers and lectures will be directed to grassroots cadres. The mass media will be employed to reach the masses. The messages will include information and persuasion to adopt new families, accept family planning regulations, and learn about contraceptive use, healthy births and childrearing, education, health care, sex education, and income generation skills. Classes will be conducted for groups, such as teenagers, unmarried youth, pregnant women, and lactating women. Priority will be given to couples that accept the certificates for one child; favoritism will be granted for allocation of

  17. Activation of Relaxin Family Receptor 1 from Different Mammalian Species by Relaxin Peptide and Small-Molecule Agonist ML290

    PubMed Central

    Huang, Zaohua; Myhr, Courtney; Bathgate, Ross A. D.; Ho, Brian A.; Bueno, Amaya; Hu, Xin; Xiao, Jingbo; Southall, Noel; Barnaeva, Elena; Agoulnik, Irina U.; Marugan, Juan J.; Ferrer, Marc; Agoulnik, Alexander I.

    2015-01-01

    Relaxin peptide (RLN), which signals through the relaxin family peptide 1 (RXFP1) GPCR receptor, has shown therapeutic effects in an acute heart failure clinical trial. We have identified a small-molecule agonist of human RXFP1, ML290; however, it does not activate the mouse receptor. To find a suitable animal model for ML290 testing and to gain mechanistic insights into the interaction of various ligands with RXFP1, we have cloned rhesus macaque, pig, rabbit, and guinea pig RXFP1s and analyzed their activation by RLN and ML290. HEK293T cells expressing macaque or pig RXFP1 responded to relaxin and ML290 treatment as measured by an increase of cAMP production. Guinea pig RXFP1 responded to relaxin but had very low response to ML290 treatment only at highest concentrations used. The rabbit RXFP1 amino acid sequence was the most divergent, with a number of unique substitutions within the ectodomain and the seven-transmembrane domain (7TM). Two splice variants of rabbit RXFP1 derived through alternative splicing of the fourth exon were identified. In contrast to the other species, rabbit RXFP1s were activated by ML290, but not with human, pig, mouse, or rabbit RLNs. Using FLAG-tagged constructs, we have shown that both rabbit RXFP1 variants are expressed on the cell surface. No binding of human Eu-labeled RLN to rabbit RXFP1 was detected, suggesting that in this species, RXFP1 might be non-functional. We used chimeric rabbit–human and guinea pig–human constructs to identify regions important for RLN or ML290 receptor activation. Chimeras with the human ectodomain and rabbit 7TM domain were activated by RLN, whereas substitution of part of the guinea pig 7TM domain with the human sequence only partially restored ML290 activation, confirming the allosteric mode of action for the two ligands. Our data demonstrate that macaque and pig models can be used for ML290 testing. PMID:26347712

  18. Comparison of the expression patterns of two small gene families of S gene family receptor kinase genes during the defence response in Brassica oleracea and Arabidopsis thaliana.

    PubMed

    Pastuglia, Martine; Swarup, Ranjan; Rocher, Anne; Saindrenan, Patrick; Roby, Dominique; Dumas, Christian; Cock, J Mark

    2002-01-09

    SFR2, a member of the S gene family of receptor kinases, has been shown to be rapidly induced by wounding and bacterial infection suggesting that this gene may play a role in the defence response in Brassica. In this study we have compared the response of SFR2 to that of two other members of the SFR gene family in Brassica (SFR1 and SFR3) and to the closely-related ARK genes of Arabidopsis. Different patterns of mRNA accumulation were observed for different members of these families. SFR1 transcripts only accumulated in response to bacterial infection and their abundance was not significantly affected by wounding. Neither treatment induced accumulation of SFR3 transcripts. ARK1 and ARK3 resembled SFR2 in that their mRNAs accumulated in response to both wounding and bacterial infection. Both SFR1 and SFR2 mRNAs accumulated in response to exogenously applied salicylic acid (SA) and SA was shown to be required for induction of expression from the SFR2 promoter in Arabidopsis. However, the timing of the increase in endogenous SA levels following bacterial infiltration in Brassica indicates that the accumulation of SFR mRNA in the first few hours after infiltration does not occur in response to an increase in SA levels. We discuss the possibility that induction of SFR gene expression by SA may contribute to potentialization of the defence response. Taken together with previous studies that indicate a possible role during development, the data presented here suggest that the SFR and ARK gene families may have overlapping roles in both defence and during development.

  19. Familial chondrocalcinosis in the Chiloe Islands, Chile.

    PubMed Central

    Reginato, A J; Hollander, J L; Martinez, V; Valenzuela, F; Schiapachasse, V; Covarrubias, E; Jacobelli, S; Arinoviche, R; Silcox, D; Ruiz, F

    1975-01-01

    Studies about chondrocalcinosis in the Chiloe Islands (Chile) showed the high frequency of the disease there and how most of it is aggregated in a few highly involved families. Pedigrees and the high degree of consanguinity among parents of index cases pointed to a recessive inheritance. The presence of common Caucasian anthropological features of genetic value in the patients and the lack of Indian mixture in three of the involved families, documented back to 1600, suggest a Caucasian origin of the mutation. Biochemical studies of the patients' synovial fluid showed a significant rise in pyrophosphate concentration. Calcium, phosphorus, and alkaline phosphatase concentrations were not different from a control group. PMID:168817

  20. Community engagement and education: addressing the needs of South Asian families with genetic disorders.

    PubMed

    Khan, Nasaim; Kerr, Gifford; Kingston, Helen

    2016-10-01

    Consanguineous marriage is common among the South Asian heritage community in the UK. While conferring social and cultural benefits, consanguinity is associated with an increased risk of autosomal recessive disorders and an increase in childhood death and disability. We have previously developed a genetic service to address the needs of this community. We report the extension of this service to include community-based initiatives aimed at promoting understanding of genetic issues related to consanguinity and improving access to genetic services. Our approach was to develop integrated clinical, educational and community engagement initiatives that would be sustainable on a long-term basis. The service provided for South Asian families by a specialist genetic counsellor was extended, and a series of genetics education and awareness sessions were provided for a diverse range of frontline healthcare workers. Two community genetic outreach worker posts were established to facilitate the engagement of the local South Asian population with genetics. The education and awareness sessions helped address the lack of genetic knowledge among primary health care professionals and community workers. Engagement initiatives by the genetic outreach worker raised awareness of genetic issues in the South Asian community and families affected by autosomal recessive disorders. All three elements of the extended service generated positive feedback. A three-stranded approach to addressing the needs of consanguineous families affected by autosomal recessive disorders as recommended by the World Health Organisation is suggested to be an acceptable, effective and sustainable approach to delivery of service in the UK.

  1. Affinal and Consanguineal Kin as a Social Support for the Rural Elderly. Paper of the Journal Series of the North Carolina Agricultural Research Service, Raleigh, NC.

    ERIC Educational Resources Information Center

    Kivett, Vira R.

    Although the support network of elderly individuals has received increased attention recently, most research has focused on the parent child relationship without examining other levels of kin interrelations. To examine the help received by rural-transitional older adults from their consanguineous kin (adult children, grandchildren, siblings,…

  2. Does anonymous sperm donation increase the risk for unions between relatives and the incidence of autosomal recessive diseases due to consanguinity?

    PubMed

    Serre, Jean-Louis; Leutenegger, Anne-Louise; Bernheim, Alain; Fellous, Marc; Rouen, Alexandre; Siffroi, Jean-Pierre

    2014-03-01

    In France gamete donation and notably sperm donation are anonymous. It has been claimed that anonymous artificial insemination by donor (AID) could highly contribute to an increase in the level of consanguinity and the incidence of autosomal recessive diseases, due to the unions between offspring of anonymous donors, unaware of their biological kinship, with the special case of unions between half-siblings. The actual incidence of consanguinity due to AID was compared with that resulting from the two other main sources of consanguinity and recessive diseases, i.e. voluntary unions between related individuals or inadvertent unions between the offspring of a common unknown male ancestor (false paternity). From these data, we estimated that expected unions in France between half sibs per year are 0.12 between offspring of sperm donors (1.2 every 10 years) and 0.5 between offspring of common male ancestors through false paternity (5 every 10 years). More generally, the inadvertent unions between false paternity offspring are roughly four times more frequent than those resulting from anonymous AID. We estimated that in the future, when AID has been in practice for several generations, out the 820 000 annual births in France, respectively, 6 and 25 births will be consanguineous through an unknown common ancestor related to anonymous AID and to a false paternity, both of which are negligible when compared with the 1256 children born from first-degree cousins. About 672 children per year are born with a recessive genetic disease due to the panmictic risk and additional affected cases due to consanguinity would be 34.54 for first-cousin offspring, 0.33 for offspring of individuals related due to false paternity and 0.079 for offspring of individuals related due to anonymous AID. Anonymous AID would therefore be responsible for 0.46% of consanguineous births and for 0.01% of recessive diseases. Therefore, the effect of anonymous AID on half-sibling unions, consanguinity and

  3. Age-standardized Incidence Rates for Leukemia Associated with Consanguineous Marriages in 68 Countries, an Ecological Study

    PubMed Central

    Saadat, Mostafa

    2015-01-01

    Consanguineous marriage that defines as a union between biologically related persons has a variety of known deleterious correlations with factors that affect public health within human populations. To investigate the association between the mean of inbreeding coefficient (α) and incidence of leukemia, the present ecological study on 68 countries was carried out. Statistical analysis showed that the age-standardized incidence rate of leukemia positively correlated with log10GNI per capita (r=0.699, df=66, P<0.001) and negatively correlated with log10α (r=−0.609, df=66, P<0.001). Controlling log10GNI per capita, a significant negative correlation between log10α and the age-standardized incidence rate of leukemia was observed (r=−0.392, df=65, P=0.001). The countries were stratified according to their annual GNI per capita, low and high-income countries with GNI per capita less than and more than 10,000$, respectively. Statistical analysis showed that in high-income countries, after controlling for log10GNI per capita, the correlation between the age-standardized incidence rate of leukemia and log10α was still significant (r=−0.600, df=36, P<0.001). It should be noted that there was no significant association between the age-standardized mortality rate due to leukemia and log10α (P>0.05). The present finding indicates that the rate of leukemia, age-standardized for incidence, is lower in countries with a high prevalence of consanguineous marriages. PMID:25960855

  4. Consanguinity rate and delay in diagnosis in Turkish patients with combined immunodeficiencies: a single-center study.

    PubMed

    Azarsiz, Elif; Gulez, Nesrin; Edeer Karaca, Neslihan; Aksu, Guzide; Kutukculer, Necil

    2011-02-01

    Combined immunodeficiency diseases comprise a group of disorders with different molecular basis. Clinical and immunological phenotypes for each group are extremely heterogenous. The frequency of combined immunodeficiencies may vary in different countries. The most frequent forms of combined immunodeficiency show inherited defects in development of T and/or B lymphocytes. These defects are classified according to immunologic phenotype and are categorized into T-B+ or T-B- including forms with or without natural killer lymphocytes. We report here twenty-three patients (female/male: 12/11) with combined immunodeficiency showing different immunological and clinical phenotypes, majority of whom were admitted because of severe upper and lower respiratory tract infections. Mean age of the study group, mean age at onset of the symptoms, and diagnosis were 47.5 ± 42.2, 11.2 ± 17.3, and 19.5 ± 23.8 months, respectively. There was nearly 8 months time delay between beginning of symptoms and diagnosis. Within the combined immunodeficiency phenotypes, T-B-NK+ category was the most frequent phenotype. Consanguinity was positive in 73.9% (n = 17) of patients while it was about 80.0% (n = 8) in deceased ten children. Bone marrow or umblical cord stem cell transplantation was applied to 11 of them. Three patients deceased after transplantation and seven patients deceased without transplantation. Twelve patients are being followed by prophylactic treatment. In conclusion; combined immunodeficiencies are frequent in our country because of high rate of consanguinity. T-B- combined immunodeficiencies are more often observed, and infants presenting severe infections beginning in the first 3 months of life have to be examined for combined immunodeficiencies. Shortening of time delay in diagnosis will increase success of life-saving treatment.

  5. Birth-spacing patterns in Huaning County, Yunnan Province, PRC: is the adoption of a small family norm sustainable?

    PubMed

    Löfstedt, Petra; Ghilagaber, Gebrenegus; Johansson, Annika

    2007-01-01

    China's family planning programs have emphasized delayed marriage and longer spacing between births. Since 1970, the fertility has declined from 6 to 1.8 births and the mean age at first marriage has gone up but the recommended spacing intervals have not been fully realized. Despite the fertility decline it is being debated among scholars whether China has completed a sustainable demographic transition or not, especially in rural areas. The aim of this study was to analyze trends in the timing and patterns of marriage and childbearing in relation to successive family planning policies. A cluster random sample of 1,336 women aged 15-64 at the time of the survey (2000) was selected in one rural county in Yunnan province. Life-table techniques were used to analyze the cumulative proportion of women marrying and having a certain number of births. Cox's hazard regression model was used to estimate the effects of various covariates on the "hazard" for a woman to have a second birth. Our findings demonstrate how childbearing patterns have changed in the direction of delayed marriage, a decreased interval between first marriage and first child, and significantly longer spacing between the first and second child. This transformation of childbearing patterns corresponds well with the requirements of the policies. Considering the characteristics of Yunnan, it seems likely that the changing fertility behavior has been more influenced by a strictly enforced family planning policy than by societal changes leading to the adoption of a new, smaller family norm.

  6. The increasing importance of small-scale forestry: evidence from family forest ownership patterns in the United States

    Treesearch

    Y. Zhang; X. Liao; B.J. Butler; J. Schelhas

    2009-01-01

    The state-level distribution of the size of family forest holdings in the contiguous United States was examined using data collected by the USDA Forest Service in 1993 and 2003. Regressions models were used to analyze the factors influencing the mean size and structural variation among states and between the two periods. Population density, percent of the population at...

  7. New-Concept Part-Time Employment as a Work-Family Adaptive Strategy for Women Professionals with Small Children

    ERIC Educational Resources Information Center

    Hill, E. Jeffrey; Martinson, Vjollca; Ferris, Maria

    2004-01-01

    This study investigates how the option for new-concept part-time (NPT) employment influences the ability of mothers of preschool children working in professional occupations to successfully integrate work and family responsibilities. Female NPT professionals (n=279) and female full-time (FT) professionals (n=250) were compared. The NPT group…

  8. Ras-dva, a member of novel family of small GTPases, is required for the anterior ectoderm patterning in the Xenopus laevis embryo.

    PubMed

    Tereshina, Maria B; Zaraisky, Andrey G; Novoselov, Vladimir V

    2006-02-01

    Ras-like small GTPases are involved in the regulation of many processes essential for the specification of the vertebrate body plan. Recently, we identified the gene of novel small GTPase Ras-dva, which is specifically expressed at the anterior margin of the neural plate of the Xenopus laevis embryo. Now, we demonstrate that Ras-dva and its homologs in other species constitute a novel protein family, distinct from the previously known families of small GTPases. We show that the expression of Ras-dva begins during gastrulation throughout the anterior ectoderm and is activated by the homeodomain transcription factor Otx2; however, later on, Ras-dva expression is inhibited in the anterior neural plate by another homeodomain factor Xanf1. Downregulation of Ras-dva functioning by the dominant-negative mutant or by the antisense morpholino oligonucleotides results in severe malformations of the forebrain and derivatives of the cranial placodes. Importantly, although the observed abnormalities can be rescued by co-injection of the Ras-dva mRNA, they cannot be rescued by the mRNA of the closest Ras-dva homolog from another family of small GTPases, Ras. This fact indicates functional specificity of the Ras-dva signaling pathway. At the molecular level, downregulation of Ras-dva inhibits the expression of several regulators of the anterior neural plate and folds patterning, such as Otx2, BF-1 (also known as Foxg1), Xag2, Pax6, Slug and Sox9, and interferes with FGF8 signaling within the anterior ectoderm. By contrast, expression of the epidermal regulator BMP4 and its target genes, Vent1, Vent2b and Msx1, is upregulated. Together, the data obtained indicate that Ras-dva is an essential component of the signaling network that patterns the early anterior neural plate and the adjacent ectoderm in the Xenopus laevis embryos.

  9. Small molecule inhibitor of formin homology 2 domains (SMIFH2) reveals the roles of the formin family of proteins in spindle assembly and asymmetric division in mouse oocytes.

    PubMed

    Kim, Hak-Cheol; Jo, Yu-Jin; Kim, Nam-Hyung; Namgoong, Suk

    2015-01-01

    Dynamic actin reorganization is the main driving force for spindle migration and asymmetric cell division in mammalian oocytes. It has been reported that various actin nucleators including Formin-2 are involved in the polarization of the spindle and in asymmetric cell division. In mammals, the formin family is comprised of 15 proteins. However, their individual roles in spindle migration and/or asymmetric division have not been elucidated yet. In this study, we employed a newly developed inhibitor for formin family proteins, small molecule inhibitor of formin homology 2 domains (SMIFH2), to assess the functions of the formin family in mouse oocyte maturation. Treatment with SMIFH2 during in vitro maturation of mouse oocytes inhibited maturation by decreasing cytoplasmic and cortical actin levels. In addition, treatment with SMIFH2, especially at higher concentrations (500 μM), impaired the proper formation of meiotic spindles, indicating that formins play a role in meiotic spindle formation. Knockdown of the mDia2 formins caused a similar decrease in oocyte maturation and abnormal spindle morphology, mimicking the phenotype of SMIFH2-treated cells. Collectively, these results suggested that besides Formin-2, the other proteins of the formin, including mDia family play a role in asymmetric division and meiotic spindle formation in mammalian oocytes.

  10. From "New Genetics" to Everyday Knowledge: Ideas about How Genetic Diseases Are Transmitted in Two Large Brazilian Families

    ERIC Educational Resources Information Center

    Santos, Silvana; Bizzo, Nelio

    2005-01-01

    This study focuses on everyday or lay understandings of inheritance. In the northeastern Brazil, 100 individuals were interviewed in order to describe how they explain the origin of genetic disorders affecting their relatives for several generations. There were involved 60 individuals from a large consanguineous family with many members affected…

  11. From "New Genetics" to Everyday Knowledge: Ideas about How Genetic Diseases Are Transmitted in Two Large Brazilian Families

    ERIC Educational Resources Information Center

    Santos, Silvana; Bizzo, Nelio

    2005-01-01

    This study focuses on everyday or lay understandings of inheritance. In the northeastern Brazil, 100 individuals were interviewed in order to describe how they explain the origin of genetic disorders affecting their relatives for several generations. There were involved 60 individuals from a large consanguineous family with many members affected…

  12. Fragment-based discovery of a new family of non-peptidic small-molecule cyclophilin inhibitors with potent antiviral activities

    PubMed Central

    Ahmed-Belkacem, Abdelhakim; Colliandre, Lionel; Ahnou, Nazim; Nevers, Quentin; Gelin, Muriel; Bessin, Yannick; Brillet, Rozenn; Cala, Olivier; Douguet, Dominique; Bourguet, William; Krimm, Isabelle; Pawlotsky, Jean-Michel; Guichou, Jean- François

    2016-01-01

    Cyclophilins are peptidyl-prolyl cis/trans isomerases (PPIase) that catalyse the interconversion of the peptide bond at proline residues. Several cyclophilins play a pivotal role in the life cycle of a number of viruses. The existing cyclophilin inhibitors, all derived from cyclosporine A or sanglifehrin A, have disadvantages, including their size, potential for side effects unrelated to cyclophilin inhibition and drug–drug interactions, unclear antiviral spectrum and manufacturing issues. Here we use a fragment-based drug discovery approach using nucleic magnetic resonance, X-ray crystallography and structure-based compound optimization to generate a new family of non-peptidic, small-molecule cyclophilin inhibitors with potent in vitro PPIase inhibitory activity and antiviral activity against hepatitis C virus, human immunodeficiency virus and coronaviruses. This family of compounds has the potential for broad-spectrum, high-barrier-to-resistance treatment of viral infections. PMID:27652979

  13. Identification of very small open reading frames in the genomes of Holmes Jungle virus, Ord River virus, and Wongabel virus of the genus Hapavirus, family Rhabdoviridae

    PubMed Central

    Gubala, Aneta; Walsh, Susan; McAllister, Jane; Weir, Richard; Davis, Steven; Melville, Lorna; Mitchell, Ian; Bulach, Dieter; Gauci, Penny; Skvortsov, Alex; Boyle, David

    2017-01-01

    Viruses of the family Rhabdoviridae infect a broad range of hosts from a variety of ecological and geographical niches, including vertebrates, arthropods, and plants. The arthropod-transmitted members of this family display considerable genetic diversity and remarkable genomic flexibility that enable coding for various accessory proteins in different locations of the genome. Here, we describe the genome of Holmes Jungle virus, isolated from Culex annulirostris mosquitoes collected in northern Australia, and make detailed comparisons with the closely related Ord River and Wongabel viruses, with a focus on identifying very small open reading frames (smORFs) in their genomes. This is the first systematic prediction of smORFs in rhabdoviruses, emphasising the intricacy of the rhabdovirus genome and the knowledge gaps. We speculate that these smORFs may be of importance to the life cycle of the virus in the arthropod vector. PMID:28747815

  14. Familial aggregation of colorectal cancer in Egypt.

    PubMed

    Soliman, A S; Bondy, M L; Levin, B; El-Badawy, S; Khaled, H; Hablas, A; Ismail, S; Adly, M; Mahgoub, K G; McPherson, R S; Beasley, R P

    1998-09-11

    We have investigated the familial aggregation of colorectal cancer and hereditary nonpolyposis colorectal cancer (HNPCC) in Egypt because of the high incidence of colorectal cancer in Egyptian children and young adults and the prevalence of consanguinity there. In a pilot study, we conducted detailed interviews with 111 Egyptian colorectal cancer patients and 111 healthy Egyptian controls about their family histories of colorectal cancer, and other cancers, consanguinity, age at diagnosis, symptoms and recurrence. Eight patients (7.2%) had one or more first- or second-degree relatives under age 40 with colorectal cancer, suggestive of HNPCC by the Amsterdam criteria. One of these families had a typical history of HNPCC, with 4 relatives having colorectal cancer in 3 generations; 3 of these relatives were younger than age 45 at colon cancer diagnosis, and other relatives had extracolonic tumors. Another 14 patients (12.6%) had a first- or second-degree relative with a family history of other neoplasms such as endometrial, urinary and hepatobiliary cancers that could also be related to HNPCC. Four patients with early-onset colon cancer and a family history of other HNPCC-related cancers reported that their parents were first-degree cousins.

  15. An annotated catalogue of the gamasid mites associated with small mammals in Asiatic Russia. The family Laelapidae s. str. (Acari: Mesostigmata: Gamasina).

    PubMed

    Vinarski, Maxim V; Korallo-Vinarskaya, Natalia P

    2016-05-16

    Twenty-nine species of mites of the family Laelapidae s. str. have been recorded as associated with small mammals (rodents, insectivores) in Asiatic Russia (Siberia and the Russian Far East). These species belong to two subfamilies (Laelapinae, Myonyssinae) and six genera: Androlaelaps Berlese, 1903, Dipolaelaps Zemskaya & Piontkovskaya, 1960, Laelaps C.L. Koch, 1836, Hyperlaelaps Zakhvatkin, 1948, Myonyssus Tiraboschi, 1904, Oryctolaelaps Lange, 1955. A list of the species, with data on synonymy, geographic ranges, and relationships with mammal hosts is provided. Some considerations concerning patterns of distribution of the parasitic Laelaptidae of Asiatic Russia are presented as well as their classifications from the point of view of known host association records.

  16. Economic Openness and the Marginalization of Small Family Farmers: Aligning Curriculum To Meet the Needs of Rural Adolescents in Brazil.

    ERIC Educational Resources Information Center

    Moore, Audrey-Marie Schuh

    Economic liberalization and the rise of global competition have increased the importance of agricultural, technical, and business skills for small farmers in Brazil. However, many rural farmers are unable to attend agricultural technical schools due to low educational attainment. The first section of this paper discusses the impact that…

  17. A small family of sushi-class retrotransposon-derived genes in mammals and their relation to genomic imprinting.

    PubMed

    Youngson, Neil A; Kocialkowski, Sylvia; Peel, Nina; Ferguson-Smith, Anne C

    2005-10-01

    Ty3/gypsy retrotransposons are rare in mammalian genomes despite their abundance in invertebrate and other vertebrate classes. Here we identify a family of nine conserved mammalian genes with homology to Ty3/gypsy retrotransposons but which have lost their ability to autonomously retrotranspose. Of these, five map to the X chromosome while the remaining four are autosomal. Comparative phylogenetic analyses show them to have strongest homology to the sushi-ichi element from Fugu rubripes. Two of the autosomal gene members, Peg10 and Rtl1, are known to be imprinted, being expressed from the paternally inherited chromosome homologue. This suggests, consistent with the host-parasite response theory of the evolution of the imprinting mechanism, that parental-origin specific epigenetic control may be mediated by genomic "parasitic" elements such as these. Alternatively, these elements may preferentially integrate into regions that are differentially modified on the two homologous chromosomes such as imprinted domains and the X chromosome and acquire monoallelic expression. We assess the imprinting status of the remaining autosomal members of this family and show them to be biallelically expressed in embryo and placenta. Furthermore, the methylation status of Rtl1 was assayed throughout development and was found to resemble that of actively, silenced repetitive elements rather than imprinted sequences. This indicates that the ability to undergo genomic imprinting is not an inherent property of all members of this family of retroelements. Nonetheless, the conservation but functional divergence between the different members suggests that they have undergone positive selection and acquired distinct endogenous functions within their mammalian hosts.

  18. Multiple small "imaging" branch-duct type intraductal papillary mucinous neoplasms (IPMNs) in familial pancreatic cancer: indicator for concomitant high grade pancreatic intraepithelial neoplasia?

    PubMed

    Bartsch, D K; Dietzel, K; Bargello, M; Matthaei, E; Kloeppel, G; Esposito, I; Heverhagen, J T; Gress, T M; Slater, E P; Langer, P

    2013-03-01

    Most screening programs for familial pancreatic cancer are currently based on endoscopic ultrasonography and/or magnetic resonance imaging (MRI). Cystic lesions, especially those suspicious for small intraductal pancreatic mucinous neoplasms (IPMNs) of the branch ducts, can be visualized in up to 40 % of individuals at risk, but their pathological importance in the setting of FPC is yet not well established. Individuals at risk from a prospective screening program for familial pancreatic cancer with small "imaging" IPMNs of the branch-duct type (BD-IPMN) who underwent pancreatic resection were analysed regarding clinico-pathological data and the locations of pancreatic lesions. Five of 125 individuals at risk who underwent screening had multiple small (size 2-10 mm) unicystic lesions and/or multicystic single lesions in the pancreatic body and tail suspicious for BD-IPMNs upon MRI imaging and decided to undergo surgical resection after interdisciplinary counselling, although none fulfilled the consensus criteria for IPMN resection. Histological examination revealed BD-IPMNs with low or moderate dysplasia of the gastric type in combination with multifocal PanIN2 and PanIN3 lesions in 4 individuals. The remaining patient had only tiny ductectasias in the pancreatic tail with multifocal PanIN 2 lesions in the entire gland and one PanIN3 lesion in the pancreatic head. Intriguingly, the location of the most dysplastic histological lesions (PanIN3) did not correspond to the preoperatively detected lesions and were not visible in preoperative imaging. In the setting of FPC, the presence of multiple small "imaging" BD-IPMNs may indicate the presence of high-grade PanIN lesions elsewhere in the pancreas.

  19. Mechanism for attenuation of DNA binding by MarR family transcriptional regulators by small molecule ligands.

    PubMed

    Perera, Inoka C; Lee, Yong-Hwan; Wilkinson, Steven P; Grove, Anne

    2009-07-31

    Members of the multiple antibiotic resistance regulator (MarR) family control gene expression in a variety of metabolic processes in bacteria and archaea. Hypothetical uricase regulator (HucR), which belongs to the ligand-responsive branch of the MarR family, regulates uricase expression in Deinococcus radiodurans by binding a shared promoter region between uricase and HucR genes. We show here that HucR responds only to urate and, to a lesser extent, to xanthine by attenuated DNA binding, compared to other intermediates of purine degradation. Using molecular-dynamics-guided mutational analysis, we identified the ligand-binding site in HucR. Electrophoretic mobility shift assays and intrinsic Trp fluorescence have identified W20 from the N-terminal helix and R80 from helix 3, which serves as a scaffold for the DNA recognition helix, as being essential for ligand binding. Using structural data combined with in silico and in vitro analyses, we propose a mechanism for the attenuation of DNA binding in which a conformational change initiated by charge repulsion due to a bound ligand propagates to DNA recognition helices. This mechanism may apply generally to MarR homologs that bind anionic phenolic ligands.

  20. Consanguinity in Centre d'Étude du Polymorphisme Humain (CEPH) pedigrees.

    PubMed

    Stevens, Eric L; Heckenberg, Greg; Baugher, Joseph D; Roberson, Elisha D O; Downey, Thomas J; Pevsner, Jonathan

    2012-06-01

    A set of Centre d'Étude du Polymorphisme Humain (CEPH) cell lines serves as a large reference collection that has been widely used as a benchmark for allele frequencies in the analysis of genetic variants, to create linkage maps of the human genome, to study the genetics of gene expression, to provide samples to the HapMap and 1000 Genomes projects, and for a variety of other applications. An explicit feature of the CEPH collection is that these multigenerational families represent reference panels of known relatedness, consisting mostly of three-generation pedigrees with large sibships, two parents, and grandparents. We applied identity-by-state (IBS) and identity-by-descent (IBD) methods to high-density genotype data from 186 CEPH individuals in 13 families. We identified unexpected relatedness between nominally unrelated grandparents both within and between pedigrees. For one pair, the estimated Cotterman coefficient of relatedness k1 exceeded 0.2, consistent with one-eighth sharing (eg, first-cousins). Unexpectedly, significant IBD2 values were discovered in both second-degree and parent-child relationships. These were accompanied by regions of homozygosity in the offspring, which corresponded to blocks lacking IBS0 in purportedly unrelated parents, consistent with inbreeding. Our findings support and extend a 1999 report, based on the use of short tandem-repeat polymorphisms, that several CEPH families had regions of homozygosity consistent with autozygosity. We benchmarked our IBD approach (called kcoeff) against both RELPAIR and PREST software packages. Our findings may affect the interpretation of previous studies and the design of future studies that rely on the CEPH resource.

  1. Catastrophic disruption in the solar system - Asteroid collisional history, origin of Hirayama families and disruption of small satellites

    NASA Technical Reports Server (NTRS)

    Davis, D. R.

    1986-01-01

    The process of collisional catastrophic disruption has played a significantly role in structuring the solar system. Diverse populations of bodies such as the asteroid belt, small satellites of Jupiter and Saturn and perhaps even the rings of Saturn have been created or substantially changed by catastrophic distruption. Understanding the outcome of large scale impacts is essential to learning about the early history of the solar system in the asteroid zone and the reason why a planet failed to form there.

  2. Familial Gigantiform Cementoma

    PubMed Central

    Ma, Chunyue; Wang, Hongwei; He, Guang; Qin, Xingjun

    2016-01-01

    Abstract Familial gigantiform cementoma is an exceedingly rare but distinct subtype of cemento-osseous-fibrous lesion. Undocumented radiographic changes and related bone metabolism disorder are herein hypothesized and discussed. We present an adolescent case with recurrent familial gigantiform cementoma who received surgical intervention in our hospital. Apart from typical multiquadrant and expansile abnormalies involving both jaws, he also suffered from several times of fractures in lower extremity. Furthermore, radiographic examinations of calvaria, pelvis, femoris, tibia, and fibula all revealed radiolucent areas signifying diffuse osteopenic bone losses. Some of his consanguineous relatives bore the same burden of fractures during pubertal period. Considering these polyostotic conditions, a correlation of congenital bone metabolism disorder in cases with familial gigantiform cementoma, named “calcium steal disorder,” was thus proposed. Familial gigantiform cementoma is closely associated with “calcium steal disorder.” Whole-body dual-energy absorptiometry should be considered as a routine examination for fracture-related risk prediction. PMID:26945411

  3. Respiratory Protection Behavior and Respiratory Indices among Poultry House Workers on Small, Family-Owned Farms in North Carolina: A Pilot Project.

    PubMed

    Kearney, Gregory D; Gallagher, Barbara; Shaw, Robert

    2016-01-01

    The aim of this pilot study was to evaluate respiratory behavior and respiratory indices of poultry workers on family-owned, poultry farms with 10 or less employees in North Carolina. A field study was conducted to collect data on participants (N = 24) using spirometry, fractional exhaled nitric oxide (Feno), and an interviewer-administered questionnaire. The majority of workers (76%) ranked respiratory protection as being important, yet 48% reported never or rarely wearing respiratory protection when working in dusty conditions. A large percent of workers reported eye (55%) and nasal (50%) irritation and dry cough (50%). On average, pulmonary lung function and Feno tests were normal among nonsmokers. In bivariate analysis, significant associations were identified between working 7 days on the farm (P = .01), with eye irritation, and working 5 or fewer years in poultry farming (P = .01). Poultry workers on family-owned farms spend a considerable amount of work time in poultry houses and report acute respiratory-related health symptoms. Administrative controls among small, family-owned poultry farms are necessary to improve and promote safety and health to its employees.

  4. Differences in construction costs and chemical composition between deciduous and evergreen woody species are small as compared to differences among families.

    PubMed

    Villar, Rafael; Robleto, Jeannette Ruiz; De Jong, Yvonne; Poorter, Hendrik

    2006-08-01

    We tested to what extent differences in construction costs (CC) and chemical composition of woody species are attributed to leaf habit. Eight evergreen and eight deciduous species belonging to six families were selected to form eight phylogenetic independent contrasts (PICs). The plants were grown from seed in a glasshouse. Differences in leaf, stem and root CC between evergreen and deciduous species were minor, the proportion of variance explained by leaf habit generally being less than 6%. Surprisingly, differences in leaf chemical composition between deciduous and evergreen species were small as well. Variation in CC and chemical composition among families was substantial, the factor 'family' explaining 50-85% of variance. We therefore conclude that in this case, phylogeny is a more important factor than functional group. Leaves of the fast-growing species in this experiment showed high levels of minerals, organic acids, proteins and lipids, whereas leaves of the slow-growing species had higher concentrations of soluble phenolics, lignin as well as higher carbon/nitrogen (C/N) ratio. These relationships suggest a trade-off between growth and defence. In contrast, CC of leaves, stems, roots or whole plants showed no or only a weak correlation with relative growth rate (RGR). The C/N ratio of the leaves is an easily measured parameter that correlated strongly in a negative way with the RGR of the plants and reflected better the balance between investment in structure and physiological functioning than CC.

  5. The significance of PIWI family expression in human lung embryogenesis and non-small cell lung cancer

    PubMed Central

    Navarro, Alfons; Tejero, Rut; Viñolas, Nuria; Cordeiro, Anna; Marrades, Ramon M.; Fuster, Dolors; Caritg, Oriol; Moises, Jorge; Muñoz, Carmen; Molins, Laureano; Ramirez, Josep; Monzo, Mariano

    2015-01-01

    The expression of Piwi-interacting RNAs, small RNAs that bind to PIWI proteins, was until recently believed to be limited to germinal stem cells. We have studied the expression of PIWI genes during human lung embryogenesis and in paired tumor and normal tissue prospectively collected from 71 resected non-small-cell lung cancer patients. The mRNA expression analysis showed that PIWIL1 was highly expressed in 7-week embryos and downregulated during the subsequent weeks of development. PIWIL1 was expressed in 11 of the tumor samples but in none of the normal tissue samples. These results were validated by immunohistochemistry, showing faint cytoplasmic reactivity in the PIWIL1-positive samples. Interestingly, the patients expressing PIWIL1 had a shorter time to relapse (TTR) (p = 0.006) and overall survival (OS) (p = 0.0076) than those without PIWIL1 expression. PIWIL2 and 4 were downregulated in tumor tissue in comparison to the normal tissue (p < 0.001) and the patients with lower levels of PIWIL4 had shorter TTR (p = 0.048) and OS (p = 0.033). In the multivariate analysis, PIWIL1 expression emerged as an independent prognostic marker. Using 5-Aza-dC treatment and bisulfite sequencing, we observed that PIWIL1 expression could be regulated in part by methylation. Finally, an in silico study identified a stem-cell expression signature associated with PIWIL1 expression. PMID:25742785

  6. Phevor Combines Multiple Biomedical Ontologies for Accurate Identification of Disease-Causing Alleles in Single Individuals and Small Nuclear Families

    PubMed Central

    Singleton, Marc V.; Guthery, Stephen L.; Voelkerding, Karl V.; Chen, Karin; Kennedy, Brett; Margraf, Rebecca L.; Durtschi, Jacob; Eilbeck, Karen; Reese, Martin G.; Jorde, Lynn B.; Huff, Chad D.; Yandell, Mark

    2014-01-01

    Phevor integrates phenotype, gene function, and disease information with personal genomic data for improved power to identify disease-causing alleles. Phevor works by combining knowledge resident in multiple biomedical ontologies with the outputs of variant-prioritization tools. It does so by using an algorithm that propagates information across and between ontologies. This process enables Phevor to accurately reprioritize potentially damaging alleles identified by variant-prioritization tools in light of gene function, disease, and phenotype knowledge. Phevor is especially useful for single-exome and family-trio-based diagnostic analyses, the most commonly occurring clinical scenarios and ones for which existing personal genome diagnostic tools are most inaccurate and underpowered. Here, we present a series of benchmark analyses illustrating Phevor’s performance characteristics. Also presented are three recent Utah Genome Project case studies in which Phevor was used to identify disease-causing alleles. Collectively, these results show that Phevor improves diagnostic accuracy not only for individuals presenting with established disease phenotypes but also for those with previously undescribed and atypical disease presentations. Importantly, Phevor is not limited to known diseases or known disease-causing alleles. As we demonstrate, Phevor can also use latent information in ontologies to discover genes and disease-causing alleles not previously associated with disease. PMID:24702956

  7. The production of Multiple Small Peptaibol Families by Single 14-Module Peptide Synthetases in Trichoderma/Hypocrea

    SciTech Connect

    Degenkolb, Thomas; Aghchehb, Razieh Karimi; Dieckmann, Ralf; Neuhof, Torsten; Baker, Scott E.; Druzhinina, Irina S.; Kubicek, Christian P.; Brückner, Hans; von Dohren, Hans

    2012-03-01

    The most common peptaibibiotic structures are 11-residue peptaibols found widely distributed in the genus Trichoderma/Hypocrea. Frequently associated are 14-residue peptaibols sharing partial sequence identity. Genome sequencing projects of 3 Trichoderma strains of the major clades reveal the presence of up to 3 types of nonribosomal peptide synthetases with 7, 14, or 18-20 amino acid adding modules. We here provide evidence that the 14-module NRPS type found in T. virens, T. reesei (teleomorph Hypocrea jecorina) and T. atroviride produces both 11- and 14- residue peptaibols based on the disruption of the respective NRPS gene of T. reesei, and bioinformatic analysis of their amino acid activating domains and modules. The structures of these peptides may be predicted from the gene structures and have been confirmed by analysis of families of 11- and 14-residue peptaibols from the strain 618, termed hypojecorins A (23 sequences determined, 4 new) and B (3 new sequences), and the recently established trichovirins A from T. virens. The distribution of 11- and 14-residue products is strain-specific and depends on growth conditions as well. Possible mechanisms of module skipping are discussed.

  8. Identification of small molecule agonists of human relaxin family receptor 1 (RXFP1) by utilizing a homogenous cell-based cAMP assay

    PubMed Central

    Chen, Catherine Z.; Southall, Noel; Xiao, Jingbo; Marugan, Juan J.; Ferrer, Marc; Hu, Xin; Jones, Raisa E.; Feng, Shu; Agoulnik, Irina U.

    2016-01-01

    The relaxin hormone is involved in a variety of biological functions including female reproduction and parturition, regulation of cardiovascular, renal, pulmonary, and hepatic functions. It regulates extracellular matrix remodeling, cell invasiveness, proliferation, differentiation, and overall tissue homeostasis. The G protein-coupled receptor (GPCR) RXFP1, relaxin family receptor 1, is a cognate relaxin receptor that mainly signals through cyclic AMP second messenger. While agonists of the receptor could have a wide range of pharmacological utility, up to date, there are no reported small molecule agonists for relaxin receptors. Here, we report the development of quantitative high-throughput platform for RXFP1 agonist screen based on homogenous cell-based HTRF cAMP assay technology. Two small molecules of similar structure were independently identified from a screen of more than 365,677 compounds. Neither compound showed activity in a counter screen with HEK293T cells transfected with an unrelated GPCR vasopressin 1b receptor. These small molecule agonists also demonstrated selectivity against the RXFP2 receptor, providing a basis for future medicinal chemistry optimization of selective relaxin receptor agonists. PMID:23212924

  9. A novel frameshift mutation in the first exon of the 21-OH gene found in homozygosity in an apparently nonconsanguineous family.

    PubMed

    Ezquieta, B; Oyarzábal, M; Jariego, C M; Varela, J M; Chueca, M

    1999-01-01

    Congenital adrenal hyperplasia is most frequently due to steroid 21-hydroxylase (21-OH) deficiency. Due to the existence of a pseudogene in tandem duplicated with the 21-OH gene, asymmetric recombination causes the majority of the molecular defects underlying this deficiency: gene conversions and deletions of the functional gene. Screening for a small array of mutations, those existing in the pseudogene together with deletions, allows the characterization of most mutated alleles, 91% in the Spanish population. We report the case of a boy from a nonconsanguineous family, diagnosed during the neonatal period of a salt-wasting form of the deficiency, in which this screening did not allow the characterization of the paternal or the maternal allele. This infrequent finding in a nonconsanguineous family was further investigated. Single-strand conformation polymorphism screening for new mutations revealed an abnormally migrating pattern when polymerase chain reaction fragments from 21-OH gene exon 1 of the patient and relatives were analyzed. Upon direct sequencing, the insertion of a T at position 64 (64insT, frameshift generating a stop codon at exon 2) was found in homozygosity in the patient. Microsatellite typing in the HLA region revealed the patient to be homozygous for five markers (heterozygosities 0.62 to 0.74). Apparently this new mutation was generated several generations ago and has been preserved for years. Consanguinity had been discarded for several generations, although both families could be traced back to a small rural area in Navarra (Spain).

  10. Phenotypic heterogeneity in a family with a small atypical microduplication of chromosome 22q11.2 involving TBX1.

    PubMed

    Weisfeld-Adams, James D; Edelmann, Lisa; Gadi, Inder K; Mehta, Lakshmi

    2012-12-01

    The chromosome 22q11.2 region is commonly involved in non-allelic homologous recombination (NAHR) events. Microduplications of 22q11.2, usually involving a 3 Mb or 1.5 Mb region constitute the 22q11 microduplication syndrome. Both microdeletions and microduplications of 22q11.21 are reported to share several phenotypic characteristics, including dysmorphic facial features, velopharyngeal insufficiency, congenital heart disease, urogenital abnormalities, and immunologic defects. We report a child who presented at 8 months of age for evaluation of microcephaly and mild motor delay. Head circumference at birth, at 8 months, and at 19 months of age was below the 3rd centile. Other findings included left-sided cryptorchidism and developmental dysplasia of the left hip. In addition, echocardiography revealed a restrictive patent ductus arteriosus. Chromosomal microarray analysis using Affymetrix Genome-Wide Human SNP Array 6.0 revealed a novel 437 kb interstitial duplication at 22q11.21, involving TBX1, whose breakpoints did not coincide with known low copy repeat (LCR) regions. The same duplication was confirmed by fluorescent in situ hybridization (FISH) in the patient's mother and an older sister. The mother has a history of anxiety disorder and depression. The sister had a history of delayed motor milestones. None of the three duplication carriers has any documented renal anomalies or other significant medical problems. This report demonstrates the clinical heterogeneity associated with microduplications of 22q11.2 and illustrates the difficulties related to providing prognostic information and accurate genetic counseling to families when this finding is detected. The described microduplication is the smallest in this genomic region reported to date and further implicates abnormal gene dosage of TBX1 in disorders resulting from 22q11.2 rearrangements. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

  11. A small multigene hydroxyproline-O-galactosyltransferase family functions in arabinogalactan-protein glycosylation, growth and development in Arabidopsis.

    PubMed

    Basu, Debarati; Tian, Lu; Wang, Wuda; Bobbs, Shauni; Herock, Hayley; Travers, Andrew; Showalter, Allan M

    2015-12-21

    Arabinogalactan-proteins (AGPs) are ubiquitous components of cell walls throughout the plant kingdom and are extensively post translationally modified by conversion of proline to hydroxyproline (Hyp) and by addition of arabinogalactan polysaccharides (AG) to Hyp residues. AGPs are implicated to function in various aspects of plant growth and development, but the functional contributions of AGP glycans remain to be elucidated. Hyp glycosylation is initiated by the action of a set of Hyp-O-galactosyltransferase (Hyp-O-GALT) enzymes that remain to be fully characterized. Three members of the GT31 family (GALT3-At3g06440, GALT4-At1g27120, and GALT6-At5g62620) were identified as Hyp-O-GALT genes by heterologous expression in tobacco leaf epidermal cells and examined along with two previously characterized Hyp-O-GALT genes, GALT2 and GALT5. Transcript profiling by real-time PCR of these five Hyp-O-GALTs revealed overlapping but distinct expression patterns. Transiently expressed GALT3, GALT4 and GALT6 fluorescent protein fusions were localized within Golgi vesicles. Biochemical analysis of knock-out mutants for the five Hyp-O-GALT genes revealed significant reductions in both AGP-specific Hyp-O-GALT activity and β-Gal-Yariv precipitable AGPs. Further phenotypic analysis of these mutants demonstrated reduced root hair growth, reduced seed coat mucilage, reduced seed set, and accelerated leaf senescence. The mutants also displayed several conditional phenotypes, including impaired root growth, and defective anisotropic growth of root tips under salt stress, as well as less sensitivity to the growth inhibitory effects of β-Gal-Yariv reagent in roots and pollen tubes. This study provides evidence that all five Hyp-O-GALT genes encode enzymes that catalyze the initial steps of AGP galactosylation and that AGP glycans play essential roles in both vegetative and reproductive plant growth.

  12. Alternative oxidase (AOX) constitutes a small family of proteins in Citrus clementina and Citrus sinensis L. Osb.

    PubMed

    Araújo Castro, Jacqueline; Gomes Ferreira, Monique Drielle; Santana Silva, Raner José; Andrade, Bruno Silva; Micheli, Fabienne

    2017-01-01

    The alternative oxidase (AOX) protein is present in plants, fungi, protozoa and some invertebrates. It is involved in the mitochondrial respiratory chain, providing an alternative route for the transport of electrons, leading to the reduction of oxygen to form water. The present study aimed to characterize the family of AOX genes in mandarin (Citrus clementina) and sweet orange (Citrus sinensis) at nucleotide and protein levels, including promoter analysis, phylogenetic analysis and C. sinensis gene expression. This study also aimed to do the homology modeling of one AOX isoform (CcAOXd). Moreover, the molecular docking of the CcAOXd protein with the ubiquinone (UQ) was performed. Four AOX genes were identified in each citrus species. These genes have an open reading frame (ORF) ranging from 852 bp to 1150 bp and a number of exons ranging from 4 to 9. The 1500 bp-upstream region of each AOX gene contained regulatory cis-elements related to internal and external response factors. CsAOX genes showed a differential expression in citrus tissues. All AOX proteins were predicted to be located in mitochondria. They contained the conserved motifs LET, NERMHL, LEEEA and RADE-H as well as several putative post-translational modification sites. The CcAOXd protein was modeled by homology to the AOX of Trypanosona brucei (45% of identity). The 3-D structure of CcAOXd showed the presence of two hydrophobic helices that could be involved in the anchoring of the protein in the inner mitochondrial membrane. The active site of the protein is located in a hydrophobic environment deep inside the AOX structure and contains a diiron center. The molecular docking of CcAOXd with UQ showed that the binding site is a recessed pocket formed by the helices and submerged in the membrane. These data are important for future functional studies of citrus AOX genes and/or proteins, as well as for biotechnological approaches leading to AOX inhibition using UQ homologs.

  13. Alternative oxidase (AOX) constitutes a small family of proteins in Citrus clementina and Citrus sinensis L. Osb

    PubMed Central

    Araújo Castro, Jacqueline; Gomes Ferreira, Monique Drielle; Santana Silva, Raner José; Andrade, Bruno Silva

    2017-01-01

    The alternative oxidase (AOX) protein is present in plants, fungi, protozoa and some invertebrates. It is involved in the mitochondrial respiratory chain, providing an alternative route for the transport of electrons, leading to the reduction of oxygen to form water. The present study aimed to characterize the family of AOX genes in mandarin (Citrus clementina) and sweet orange (Citrus sinensis) at nucleotide and protein levels, including promoter analysis, phylogenetic analysis and C. sinensis gene expression. This study also aimed to do the homology modeling of one AOX isoform (CcAOXd). Moreover, the molecular docking of the CcAOXd protein with the ubiquinone (UQ) was performed. Four AOX genes were identified in each citrus species. These genes have an open reading frame (ORF) ranging from 852 bp to 1150 bp and a number of exons ranging from 4 to 9. The 1500 bp-upstream region of each AOX gene contained regulatory cis-elements related to internal and external response factors. CsAOX genes showed a differential expression in citrus tissues. All AOX proteins were predicted to be located in mitochondria. They contained the conserved motifs LET, NERMHL, LEEEA and RADE-H as well as several putative post-translational modification sites. The CcAOXd protein was modeled by homology to the AOX of Trypanosona brucei (45% of identity). The 3-D structure of CcAOXd showed the presence of two hydrophobic helices that could be involved in the anchoring of the protein in the inner mitochondrial membrane. The active site of the protein is located in a hydrophobic environment deep inside the AOX structure and contains a diiron center. The molecular docking of CcAOXd with UQ showed that the binding site is a recessed pocket formed by the helices and submerged in the membrane. These data are important for future functional studies of citrus AOX genes and/or proteins, as well as for biotechnological approaches leading to AOX inhibition using UQ homologs. PMID:28459876

  14. Novel Deletion of SERPINF1 Causes Autosomal Recessive Osteogenesis Imperfecta Type VI in Two Brazilian Families

    PubMed Central

    Moldenhauer Minillo, Renata; Sobreira, Nara; de Fatima de Faria Soares, Maria; Jurgens, Julie; Ling, Hua; Hetrick, Kurt N.; Doheny, Kimberly F.; Valle, David; Brunoni, Decio; Alvarez Perez, Ana B.

    2014-01-01

    Autosomal recessive osteogenesis imperfecta (OI) accounts for 10% of all OI cases, and, currently, mutations in 10 genes (CRTAP, LEPRE1, PPIB, SERPINH1, FKBP10, SERPINF1, SP7, BMP1, TMEM38B, and WNT1) are known to be responsible for this form of the disease. PEDF is a secreted glycoprotein of the serpin superfamily that maintains bone homeostasis and regulates osteoid mineralization, and it is encoded by SERPINF1, currently associated with OI type VI (MIM 172860). Here, we report a consanguineous Brazilian family in which multiple individuals from at least 4 generations are affected with a severe form of OI, and we also report an unrelated individual from the same small city in Brazil with a similar but more severe phenotype. In both families the same homozygous SERPINF1 19-bp deletion was identified which is not known in the literature yet. We described intra- and interfamilial clinical and radiological phenotypic variability of OI type VI caused by the same homozygous SERPINF1 19-bp deletion and suggest a founder effect. Furthermore, the SERPINF1 genotypes/phenotypes reported so far in the literature are reviewed. PMID:25565926

  15. The VP3 factor from viruses of Birnaviridae family suppresses RNA silencing by binding both long and small RNA duplexes.

    PubMed

    Valli, Adrian; Busnadiego, Idoia; Maliogka, Varvara; Ferrero, Diego; Castón, José R; Rodríguez, José Francisco; García, Juan Antonio

    2012-01-01

    RNA silencing is directly involved in antiviral defense in a wide variety of eukaryotic organisms, including plants, fungi, invertebrates, and presumably vertebrate animals. The study of RNA silencing-mediated antiviral defences in vertebrates is hampered by the overlap with other antiviral mechanisms; thus, heterologous systems are often used to study the interplay between RNA silencing and vertebrate-infecting viruses. In this report we show that the VP3 protein of the avian birnavirus Infectious bursal disease virus (IBDV) displays, in addition to its capacity to bind long double-stranded RNA, the ability to interact with double-stranded small RNA molecules. We also demonstrate that IBDV VP3 prevents the silencing mediated degradation of a reporter mRNA, and that this silencing suppression activity depends on its RNA binding ability. Furthermore, we find that the anti-silencing activity of IBDV VP3 is shared with the homologous proteins expressed by both insect- and fish-infecting birnaviruses. Finally, we show that IBDV VP3 can functionally replace the well-characterized HCPro silencing suppressor of Plum pox virus, a potyvirus that is unable to infect plants in the absence of an active silencing suppressor. Altogether, our results support the idea that VP3 protects the viral genome from host sentinels, including those of the RNA silencing machinery.

  16. Rem2, a member of the RGK family of small GTPases, is enriched in nuclei of the basal ganglia

    PubMed Central

    Liput, Daniel J.; Lu, Van B.; Davis, Margaret I.; Puhl, Henry L.; Ikeda, Stephen R.

    2016-01-01

    Rem2 is a member of the RGK subfamily of RAS small GTPases. Rem2 inhibits high voltage activated calcium channels, is involved in synaptogenesis, and regulates dendritic morphology. Rem2 is the primary RGK protein expressed in the nervous system, but to date, the precise expression patterns of this protein are unknown. In this study, we characterized Rem2 expression in the mouse nervous system. In the CNS, Rem2 mRNA was detected in all regions examined, but was enriched in the striatum. An antibody specific for Rem2 was validated using a Rem2 knockout mouse model and used to show abundant expression in striatonigral and striatopallidal medium spiny neurons but not in several interneuron populations. In the PNS, Rem2 was abundant in a subpopulation of neurons in the trigeminal and dorsal root ganglia, but was absent in sympathetic neurons of superior cervical ganglia. Under basal conditions, Rem2 was subject to post-translational phosphorylation, likely at multiple residues. Further, Rem2 mRNA and protein expression peaked at postnatal week two, which corresponds to the period of robust neuronal maturation in rodents. This study will be useful for elucidating the functions of Rem2 in basal ganglia physiology. PMID:27118437

  17. The microRNA-200 family targets multiple non-small cell lung cancer prognostic markers in H1299 cells and BEAS-2B cells.

    PubMed

    Pacurari, Maricica; Addison, Joseph B; Bondalapati, Naveen; Wan, Ying-Wooi; Luo, Dajie; Qian, Yong; Castranova, Vincent; Ivanov, Alexey V; Guo, Nancy Lan

    2013-08-01

    Lung cancer remains the leading cause of cancer-related mortality for both men and women. Tumor recurrence and metastasis is the major cause of lung cancer treatment failure and death. The microRNA‑200 (miR-200) family is a powerful regulator of the epithelial-mesenchymal transition (EMT) process, which is essential in tumor metastasis. Nevertheless, miR-200 family target genes that promote metastasis in non-small cell lung cancer (NSCLC) remain largely unknown. Here, we sought to investigate whether the microRNA-200 family regulates our previously identified NSCLC prognostic marker genes associated with metastasis, as potential molecular targets. Novel miRNA targets were predicted using bioinformatics tools based on correlation analyses of miRNA and mRNA expression in 57 squamous cell lung cancer tumor samples. The predicted target genes were validated with quantitative RT-PCR assays and western blot analysis following re-expression of miR-200a, -200b and -200c in the metastatic NSCLC H1299 cell line. The results show that restoring miR-200a or miR-200c in H1299 cells induces downregulation of DLC1, ATRX and HFE. Reinforced miR-200b expression results in downregulation of DLC1, HNRNPA3 and HFE. Additionally, miR-200 family downregulates HNRNPR3, HFE and ATRX in BEAS-2B immortalized lung epithelial cells in quantitative RT-PCR and western blot assays. The miR-200 family and these potential targets are functionally involved in canonical pathways of immune response, molecular mechanisms of cancer, metastasis signaling, cell-cell communication, proliferation and DNA repair in Ingenuity pathway analysis (IPA). These results indicate that re-expression of miR-200 downregulates our previously identified NSCLC prognostic biomarkers in metastatic NSCLC cells. These results provide new insights into miR-200 regulation in lung cancer metastasis and consequent clinical outcome, and may provide a potential basis for innovative therapeutic approaches for the treatment of this

  18. Spondylo-meta-epiphyseal dysplasia (SMED), short limb-hand type: a congenital familial skeletal dysplasia with distinctive features and histopathology.

    PubMed

    Borochowitz, Z; Langer, L O; Gruber, H E; Lachman, R; Katznelson, M B; Rimoin, D L

    1993-02-01

    We report on a "new" severe short-limb bone dysplasia which can be labeled descriptively a spondylo-meta-epiphyseal dysplasia. The 3 patients were born to 2 unrelated Sepharadic Jewish families and a Puerto Rican family. Clinical abnormalities include small stature with short limbs including short hands, a short nose with wide nasal bridge and wide nostrils, a long philtrum, ocular hypertelorism, retro/micrognathia, and a narrow chest. Radiological abnormalities include platyspondyly, short tubular bones with very abnormal metaphyses and epiphyses beyond early infancy, short ribs, and a typical evolution of bony changes over time. Chondroosseous morphology and ultrastructure document sparse matrix and degenerating chondrocytes surrounded by dense amorphous material in the 1 patient studied. Consanguinity is present in 1 family. In addition to the described patient, 2 other short-limb sibs, who did not survive infancy, were born into this family. Even in the absence of any photographic or radiologic documentation of these other 2 infants, autosomal recessive mode of inheritance seems probable.

  19. The bldC Developmental Locus of Streptomyces coelicolor Encodes a Member of a Family of Small DNA-Binding Proteins Related to the DNA-Binding Domains of the MerR Family

    PubMed Central

    Hunt, Alison C.; Servín-González, Luis; Kelemen, Gabriella H.; Buttner, Mark J.

    2005-01-01

    The bldC locus, required for formation of aerial hyphae in Streptomyces coelicolor, was localized by map-based cloning to the overlap between cosmids D17 and D25 of a minimal ordered library. Subcloning and sequencing showed that bldC encodes a member of a previously unrecognized family of small (58- to 78-residue) DNA-binding proteins, related to the DNA-binding domains of the MerR family of transcriptional activators. BldC family members are found in a wide range of gram-positive and gram-negative bacteria. Constructed ΔbldC mutants were defective in differentiation and antibiotic production. They failed to form an aerial mycelium on minimal medium and showed severe delays in aerial mycelium formation on rich medium. In addition, they failed to produce the polyketide antibiotic actinorhodin, and bldC was shown to be required for normal and sustained transcription of the pathway-specific activator gene actII-orf4. Although ΔbldC mutants produced the tripyrrole antibiotic undecylprodigiosin, transcripts of the pathway-specific activator gene (redD) were reduced to almost undetectable levels after 48 h in the bldC mutant, in contrast to the bldC+ parent strain in which redD transcription continued during aerial mycelium formation and sporulation. This suggests that bldC may be required for maintenance of redD transcription during differentiation. bldC is expressed from a single promoter. S1 nuclease protection assays and immunoblotting showed that bldC is constitutively expressed and that transcription of bldC does not depend on any of the other known bld genes. The bldC18 mutation that originally defined the locus causes a Y49C substitution that results in instability of the protein. PMID:15629942

  20. The bldC developmental locus of Streptomyces coelicolor encodes a member of a family of small DNA-binding proteins related to the DNA-binding domains of the MerR family.

    PubMed

    Hunt, Alison C; Servín-González, Luis; Kelemen, Gabriella H; Buttner, Mark J

    2005-01-01

    The bldC locus, required for formation of aerial hyphae in Streptomyces coelicolor, was localized by map-based cloning to the overlap between cosmids D17 and D25 of a minimal ordered library. Subcloning and sequencing showed that bldC encodes a member of a previously unrecognized family of small (58- to 78-residue) DNA-binding proteins, related to the DNA-binding domains of the MerR family of transcriptional activators. BldC family members are found in a wide range of gram-positive and gram-negative bacteria. Constructed DeltabldC mutants were defective in differentiation and antibiotic production. They failed to form an aerial mycelium on minimal medium and showed severe delays in aerial mycelium formation on rich medium. In addition, they failed to produce the polyketide antibiotic actinorhodin, and bldC was shown to be required for normal and sustained transcription of the pathway-specific activator gene actII-orf4. Although DeltabldC mutants produced the tripyrrole antibiotic undecylprodigiosin, transcripts of the pathway-specific activator gene (redD) were reduced to almost undetectable levels after 48 h in the bldC mutant, in contrast to the bldC+ parent strain in which redD transcription continued during aerial mycelium formation and sporulation. This suggests that bldC may be required for maintenance of redD transcription during differentiation. bldC is expressed from a single promoter. S1 nuclease protection assays and immunoblotting showed that bldC is constitutively expressed and that transcription of bldC does not depend on any of the other known bld genes. The bldC18 mutation that originally defined the locus causes a Y49C substitution that results in instability of the protein.

  1. Retinal and choroidal ischemic syndrome, digestive tract and renal small vessel hyalinosis, intracerebral calcifications and phenotypic abnormalities: a new family syndrome.

    PubMed

    van Effenterre, G; Haut, J; Brezin, A; Le Mer, Y; Rambaud, J C; Galian, A; Touchard, G; Rothschild, E

    1989-01-01

    A new family syndrome is described that affected three of seven siblings and another patient who had been abandoned at birth but came from the same area of France. All four patients were young women with a very peculiar phenotype, poikiloderma and greying of the hair, and idiopathic non-arteriosclerotic cerebral calcifications. Pathological studies demonstrated small-vessel hyalinosis due to basal membrane thickening, mainly in the digestive tract, kidneys and calcified areas of the brain. The clinical and biological expressions of these vascular changes varied. Peripheral retinal ischemic syndrome and chorioretinal scars were found in the ocular fundi of three patients. Malabsorption and protein-losing enteropathy was the main problem in all four, and was the cause of one patient's death. A subarachnoid hemorrhage due to a right sylvian aneurysm also occurred in two of the three sisters and was lethal for one. Nephropathy with renal failure and systemic hypertension is the major problem of the two surviving patients.

  2. A novel SOX9 H169Q mutation in a family with overlapping phenotype of mild campomelic dysplasia and small patella syndrome.

    PubMed

    Matsushita, Masaki; Kitoh, Hiroshi; Kaneko, Hiroshi; Mishima, Kenichi; Kadono, Izumi; Ishiguro, Naoki; Nishimura, Gen

    2013-10-01

    The phenotypic similarities have been demonstrated between non-lethal campomelic dysplasia (CD) and small patella syndrome (SPS), in which different genetic defects have been identified. We report on a familial case of skeletal dysplasia with overlapping phenotype of mild CD and SPS, including defective ischio-pubic ossification, elongated femoral neck, hypoplastic patellae, and increased space between the first and the second toes (sandal gap). Direct sequencing analysis demonstrated a novel missense mutation (p.H169Q) within the coding region of the SOX9 gene and negative for TBX4 mutations. Functional analysis of the p.H169Q mutant revealed reduced but not fully abolished transactivation capacity of the mutated protein. Retained residual SOX9 function might contribute to an extremely mild CD phenotype in the present cases. © 2013 Wiley Periodicals, Inc. Copyright © 2013 Wiley Periodicals, Inc.

  3. Family with sequence similarity member 20C is the primary but not the only kinase for the small-integrin-binding ligand N-linked glycoproteins in bone.

    PubMed

    Yang, Xiudong; Yan, Wenjuan; Tian, Ye; Ma, Pan; Opperman, Lynne A; Wang, Xiaofang

    2016-01-01

    Recent studies have identified family with sequence similarity member 20C (FAM20C) as a kinase that phosphorylates the Ser in Ser-X-Glu/phospho-Ser (pSer) motifs in the small-integrin-binding ligand N-linked glycoproteins (SIBLINGs). There is no in vivo evidence that validates this finding, and it is unclear whether FAM20C is the only kinase for SIBLINGs. We extracted bone noncollagenous proteins (NCPs) from Fam20C-knockout (KO) mice and analyzed the phosphorylation levels. The total NCPs were separated into osteopontin-, bone sialoprotein-, and dentin matrix protein-1-enriched fractions by anion-exchange chromatography and analyzed by SDS-PAGE, native PAGE, and Western immunoblot analysis. The NCP phosphorylation level in the KO mice was lower than that in the wild-type (WT). On the native gel, the SIBLINGs from KO mice showed a lower migration rate (Mr) than those from the WT. Calf intestine phosphatase treatment shifted SIBLINGs from the WT mice to the level adjacent to the KO, but failed to shift the latter, suggesting a phosphorylation loss of SIBLINGs in the KO mice. Mass spectrometry identified less pSers in the SIBLINGs from the KO mice [including the region of the acidic Ser- and aspartate-rich motif (ASARM) peptides]. In an intriguing finding, several pSers in the Ser-X-Glu motifs in the KO mice maintained their phosphorylation, whereas several others in non-Ser-X-Glu motifs did not. Phospho-Tyrs and phospho-Thrs in the SIBLINGs did not appear to be associated with FAM20C. Our results indicate that FAM20C is the primary, but not the only, kinase for the SIBLINGs.-Yang, X., Yan, W., Tian, Y., Ma, P., Opperman, L. A., Wang, X. Family with sequence similarity member 20C is the primary but not the only kinase for the small-integrin-binding ligand N-linked glycoproteins in bone.

  4. Identification and biochemical characterization of Rap2C, a new member of the Rap family of small GTP-binding proteins.

    PubMed

    Paganini, Simona; Guidetti, Gianni Francesco; Catricalà, Silvia; Trionfini, Piera; Panelli, Simona; Balduini, Cesare; Torti, Mauro

    2006-01-01

    The Rap family of small GTP-binding proteins is composed by four different members: Rap1A, Rap1B, Rap2A and Rap2B. In this work we report the identification and characterization of a fifth member of this family of small GTPases. This new protein is highly homologous to Rap2A and Rap2B, binds labeled GTP on nitrocellulose, and is recognized by a specific anti-Rap2 antibody, but not by an anti-Rap1 antibody. The protein has thus been named Rap2C. Binding of GTP to recombinant purified Rap2C was Mg(2+)-dependent. However, accurate comparison of the kinetics of nucleotide binding and release revealed that Rap2C bound GTP less efficiently and possessed slower rate of GDP release compared to the highly homologous Rap2B. Moreover, in the presence of Mg(2+), the relative affinity of Rap2C for GTP was only about twofold higher than that for GDP, while, under the same conditions, Rap2B was able to bind GTP with about sevenfold higher affinity than GDP. When expressed in eukaryotic cells, Rap2C localized at the plasma membrane, as dictated by the presence of a CAAX motif at the C-terminus. We found that Rap2C represented the predominant Rap2 protein expressed in circulating mononuclear leukocytes, but was not present in platelets. Importantly, Rap2C was found to be expressed in human megakaryocytes, suggesting that the protein may be down-regulated during platelets generation. This work demonstrates that Rap2C is a new member of the Rap2 subfamily of proteins, able to bind guanine nucleotides with peculiar properties, and differently expressed by various hematopoietic subsets. This new protein may therefore contribute to the still poorly clarified cellular events regulated by this subfamily of GTP-binding proteins.

  5. Family-wide Analysis of the Inhibition of Arf Guanine Nucleotide Exchange Factors with Small Molecules: Evidence of Unique Inhibitory Profiles.

    PubMed

    Benabdi, Sarah; Peurois, François; Nawrotek, Agata; Chikireddy, Jahnavi; Cañeque, Tatiana; Yamori, Takao; Shiina, Isamu; Ohashi, Yoshimi; Dan, Shingo; Rodriguez, Raphaël; Cherfils, Jacqueline; Zeghouf, Mahel

    2017-09-13

    Arf GTPases and their guanine nucleotide exchange factors (ArfGEFs) are major regulators of membrane traffic and organelle structure in cells. They are associated with a variety of diseases and are thus attractive therapeutic targets for inhibition by small molecules. Several inhibitors of unrelated chemical structures have been discovered, which have shown their potential in dissecting molecular pathways and blocking disease-related functions. However, their specificity across the ArfGEF family has remained elusive. Importantly, inhibitory responses in the context of membranes, which are critical determinants of Arf and ArfGEF cellular functions, have not been investigated. Here, we compare the efficiency and specificity of four structurally distinct ArfGEF inhibitors, Brefeldin A, SecinH3, M-COPA, and NAV-2729, toward six ArfGEFs (human ARNO, EFA6, BIG1, and BRAG2 and Legionella and Rickettsia RalF). Inhibition was assessed by fluorescence kinetics using pure proteins, and its modulation by membranes was determined with lipidated GTPases in the presence of liposomes. Our analysis shows that despite the intra-ArfGEF family resemblance, each inhibitor has a specific inhibitory profile. Notably, M-COPA is a potent pan-ArfGEF inhibitor, and NAV-2729 inhibits all GEFs, the strongest effects being against BRAG2 and Arf1. Furthermore, the presence of the membrane-binding domain in Legionella RalF reveals a strong inhibitory effect of BFA that is not measured on its GEF domain alone. This study demonstrates the value of family-wide assays with incorporation of membranes, and it should enable accurate dissection of Arf pathways by these inhibitors to best guide their use and development as therapeutic agents.

  6. Medical History, Lifestyle, Family History, and Occupational Risk Factors for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: The InterLymph Non-Hodgkin Lymphoma Subtypes Project

    PubMed Central

    Benavente, Yolanda; Blair, Aaron; Vermeulen, Roel; Cerhan, James R.; Costantini, Adele Seniori; Monnereau, Alain; Nieters, Alexandra; Clavel, Jacqueline; Call, Timothy G.; Maynadié, Marc; Lan, Qing; Clarke, Christina A.; Lightfoot, Tracy; Norman, Aaron D.; Sampson, Joshua N.; Casabonne, Delphine; Cocco, Pierluigi; de Sanjosé, Silvia

    2014-01-01

    Background Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are two subtypes of non-Hodgkin lymphoma. A number of studies have evaluated associations between risk factors and CLL/SLL risk. However, these associations remain inconsistent or lacked confirmation. This may be due, in part, to the inadequate sample size of CLL/SLL cases. Methods We performed a pooled analysis of 2440 CLL/SLL cases and 15186 controls from 13 case-control studies from Europe, North America, and Australia. We evaluated associations of medical history, family history, lifestyle, and occupational risk factors with CLL/SLL risk. Multivariate logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Results We confirmed prior inverse associations with any atopic condition and recreational sun exposure. We also confirmed prior elevated associations with usual adult height, hepatitis C virus seropositivity, living or working on a farm, and family history of any hematological malignancy. Novel associations were identified with hairdresser occupation (OR = 1.77, 95% CI = 1.05 to 2.98) and blood transfusion history (OR = 0.79, 95% CI = 0.66 to 0.94). We also found smoking to have modest protective effect (OR = 0.9, 95% CI = 0.81 to 0.99). All exposures showed evidence of independent effects. Conclusions We have identified or confirmed several independent risk factors for CLL/SLL supporting a role for genetics (through family history), immune function (through allergy and sun), infection (through hepatitis C virus), and height, and other pathways of immune response. Given that CLL/SLL has more than 30 susceptibility loci identified to date, studies evaluating the interaction among genetic and nongenetic factors are warranted. PMID:25174025

  7. myc family oncogene amplification in tumor cell lines established from small cell lung cancer patients and its relationship to clinical status and course.

    PubMed Central

    Johnson, B E; Ihde, D C; Makuch, R W; Gazdar, A F; Carney, D N; Oie, H; Russell, E; Nau, M M; Minna, J D

    1987-01-01

    44 small cell lung cancer cell lines established from 227 patients were studied for myc family DNA amplification (c-myc, N-myc, and L-myc). Two of 19 lines (11%) established from untreated patients' tumors had DNA amplification (one N-myc and one L-myc), compared with 11 of 25 (5 c-myc, 3 N-myc, and 3 L-myc) cell lines (44%) established from relapsed patients' tumors (P = 0.04). The 19 patients who had tumor cell lines established before chemotherapy treatment survived a median of 14 wk compared with 48 wk for the 123 extensive stage patients who did not have cell lines established (P less than 0.001). Relapsed patients whose cell lines had c-myc DNA amplification survived a shorter period (median of 33 wk) than patients whose cell lines did not have c-myc amplification (median of 53 wk; P = 0.04). We conclude that myc family DNA amplification is more common in tumor cell lines established from treated than untreated patients' tumors, and c-myc amplification in treated patients' tumor cell lines is associated with shortened survival. Images PMID:3034978

  8. Familial occurrence of an association of multiple intestinal atresia and choanal atresia: a new syndrome?

    PubMed

    Ferrarini, Alessandra; Osterheld, Maria-Chiara; Vial, Yvan; de Viragh, Pierre A; Cotting, Jacques; Martinet, Danielle; Beckmann, Jacques S; Fellmann, Florence

    2009-12-01

    We report on two familial cases from a non-consanguineous marriage, presenting multiple intestinal and choanal atresia. Massive hydramnios and dilatation of the bowel were observed at 29 weeks of gestation during routine ultrasound scan of a healthy mother. The fetal karyotype was normal and cystic fibrosis screening was negative. Regular scans were performed throughout the pregnancy. The child was born at 34 weeks gestation. Choanal atresia was diagnosed at birth and abdominal investigations showed multiple atresia interesting both the small bowel and the colon. Further interventions were necessary because of recurrent obstructions. During the following pregnancy, a dilatation of the fetal intestinal tract was detected by ultrasonography at 27 weeks of gestation. Pregnancy was interrupted. Post-mortem examination of the fetus confirmed the stenosis of long segments of the small intestine associated with areas of colonic atresia. In both cases, histology and distribution were consistent with those reported in hereditary multiple intestinal atresia (HMIA). An association between multiple intestinal and choanal atresia has never been reported. We suggest it could correspond to a new autosomal recessive entity for which cytogenetic investigations and high-resolution array CGH revealed no visible anomalies.

  9. Rapidly expanding genetic diversity and host range of the Circoviridae viral family and other Rep encoding small circular ssDNA genomes.

    PubMed

    Delwart, Eric; Li, Linlin

    2012-03-01

    The genomes of numerous circoviruses and distantly related circular ssDNA viruses encoding a rolling circle replication initiator protein (Rep) have been characterized from the tissues of mammals, fish, insects, plants (geminivirus and nanovirus), in human and animal feces, in an algae cell, and in diverse environmental samples. We review the genome organization, phylogenetic relationships and initial prevalence studies of cycloviruses, a proposed new genus in the Circoviridae family. Viral fossil rep sequences were also recently identified integrated on the chromosomes of mammals, frogs, lancelets, crustaceans, mites, gastropods, roundworms, placozoans, hydrozoans, protozoans, land plants, fungi, algae, and phytoplasma bacterias and their plasmids, reflecting the very wide past host range of rep bearing viruses. An ancient origin for viruses with Rep-encoding small circular ssDNA genomes, predating the diversification of eukaryotes, is discussed. The cellular hosts and pathogenicity of many recently described rep-containing circular ssDNA genomes remain to be determined. Future studies of the virome of single cell and multi-cellular eukaryotes are likely to further extend the known diversity and host-range of small rep-containing circular ssDNA viral genomes. Copyright © 2011 Elsevier B.V. All rights reserved.

  10. Rapidly expanding genetic diversity and host range of the Circoviridae viral family and other Rep encoding small circular ssDNA genomes

    PubMed Central

    Delwart, Eric; Li, Linlin

    2011-01-01

    The genomes of numerous circoviruses and distantly related circular DNA viruses encoding a rolling circle replication initiator protein (Rep) have been characterized from the tissues of mammals, fish, insects, and plants (geminivirus and nanovirus), human and animal feces, in an algae cell, and in diverse environmental samples. We review the genome organization, phylogenetic relationships and initial prevalence studies of cycloviruses, a proposed new genus in the Circoviridae family. Viral fossil rep sequences were also identified integrated on the chromosomes of mammals, frogs, lancelets, crustaceans, mites, gastropods, roundworms, placozoans, hydrozoans, protozoans, land plants, fungi, algae, and phytoplasma bacterias and their plasmids, reflecting their past host range. An ancient origin for viruses with rep-encoding single stranded small circular genomes, predating the diversification of eukaryotes, is discussed. The cellular hosts and pathogenicity of many recently described rep-containing circular genomes remain to be determined. Future studies of the virome of single cell and multi-cellular eukaryotes are likely to further extend the known diversity and host-range of small rep-containing circular viral genomes. PMID:22155583

  11. Consanguinity and the sib-pair method: An approach using identity by descent between and within individuals

    SciTech Connect

    Genin, E.; Clerget-Darpoux, F.

    1996-11-01

    To test for linkage between a trait and a marker, one can consider identical marker alleles in related individuals, for instance, sibs. For recessive diseases, it has been shown that some information may be gained from the identity by descent (IBD) of the two alleles of an affected inbred individual at the marker locus. The aim of this paper is to extend the sib-pair method of linkage analysis to the situation of sib pairs sampled from consanguineous populations. This extension takes maximum advantage of the information provided by both the IBD pattern between sibs and allelic identity within each sib of the pair. This is possible through the use of the condensed identity coefficients. Here, we propose a new test of linkage based on a {Chi}{sup 2}. We compare the performance of this test with that of the classical {Chi}{sup 2} test based on the distribution of sib pairs sharing 0, 1, or 2 alleles IBD. For sib pairs from first-cousin matings, the proposed test can better detect the role of a disease-susceptibility (DS) locus. Its power is shown to be greater than that of the classical test, especially for models where the DS allele may be common and incompletely penetrant; that is to say for situations that may be encountered in multifactorial diseases. A study of the impact of inbreeding on the expected proportions of sib pairs sharing 0, 1, or 2 alleles IBD is also performed here. Ignoring inbreeding, when in fact inbreeding exists, increases the rate of type I errors in tests of linkage. 21 refs., 8 figs., 9 tabs.

  12. Genome-wide analysis identifies gain and loss/change of function within the small multigenic insecticidal Albumin 1 family of Medicago truncatula.

    PubMed

    Karaki, L; Da Silva, P; Rizk, F; Chouabe, C; Chantret, N; Eyraud, V; Gressent, F; Sivignon, C; Rahioui, I; Kahn, D; Brochier-Armanet, C; Rahbé, Y; Royer, C

    2016-03-10

    Albumin 1b peptides (A1b) are small disulfide-knotted insecticidal peptides produced by Fabaceae (also called Leguminosae). To date, their diversity among this plant family has been essentially investigated through biochemical and PCR-based approaches. The availability of high-quality genomic resources for several fabaceae species, among which the model species Medicago truncatula (Mtr), allowed for a genomic analysis of this protein family aimed at i) deciphering the evolutionary history of A1b proteins and their links with A1b-nodulins that are short non-insecticidal disulfide-bonded peptides involved in root nodule signaling and ii) exploring the functional diversity of A1b for novel bioactive molecules. Investigating the Mtr genome revealed a remarkable expansion, mainly through tandem duplications, of albumin1 (A1) genes, retaining nearly all of the same canonical structure at both gene and protein levels. Phylogenetic analysis revealed that the ancestral molecule was most probably insecticidal giving rise to, among others, A1b-nodulins. Expression meta-analysis revealed that many A1b coding genes are silent and a wide tissue distribution of the A1 transcripts/peptides within plant organs. Evolutionary rate analyses highlighted branches and sites with positive selection signatures, including two sites shown to be critical for insecticidal activity. Seven peptides were chemically synthesized and folded in vitro, then assayed for their biological activity. Among these, AG41 (aka MtrA1013 isoform, encoded by the orphan TA24778 contig.), showed an unexpectedly high insecticidal activity. The study highlights the unique burst of diversity of A1 peptides within the Medicago genus compared to the other taxa for which full-genomes are available: no A1 member in Lotus, or in red clover to date, while only a few are present in chick pea, soybean or pigeon pea genomes. The expansion of the A1 family in the Medicago genus is reminiscent of the situation described for

  13. Identification of expression signatures predictive of sensitivity to the Bcl-2 family member inhibitor ABT-263 in small cell lung carcinoma and leukemia/lymphoma cell lines.

    PubMed

    Tahir, Stephen K; Wass, John; Joseph, Mary K; Devanarayan, Viswanath; Hessler, Paul; Zhang, Haichao; Elmore, Steve W; Kroeger, Paul E; Tse, Christin; Rosenberg, Saul H; Anderson, Mark G

    2010-03-01

    ABT-263 inhibits the antiapoptotic proteins Bcl-2, Bcl-x(L), and Bcl-w and has single-agent efficacy in numerous small cell lung carcinoma (SCLC) and leukemia/lymphoma cell lines in vitro and in vivo. It is currently in clinical trials for treating patients with SCLC and various leukemia/lymphomas. Identification of predictive markers for response will benefit the clinical development of ABT-263. We identified the expression of Bcl-2 family genes that correlated best with sensitivity to ABT-263 in a panel of 36 SCLC and 31 leukemia/lymphoma cell lines. In cells sensitive to ABT-263, expression of Bcl-2 and Noxa is elevated, whereas expression of Mcl-1 is higher in resistant cells. We also examined global expression differences to identify gene signature sets that correlated with sensitivity to ABT-263 to generate optimal signature sets predictive of sensitivity to ABT-263. Independent cell lines were used to verify the predictive power of the gene sets and to refine the optimal gene signatures. When comparing normal lung tissue and SCLC primary tumors, the expression pattern of these genes in the tumor tissue is most similar to sensitive SCLC lines, whereas normal tissue is most similar to resistant SCLC lines. Most of the genes identified using global expression patterns are related to the apoptotic pathway; however, all but Bcl-rambo are distinct from the Bcl-2 family. This study leverages global expression data to identify key gene expression patterns for sensitivity to ABT-263 in SCLC and leukemia/lymphoma and may provide guidance in the selection of patients in future clinical trials.

  14. Palliative Care Intervention in Improving Symptom Control and Quality of Life in Patients With Stage II-IV Non-small Cell Lung Cancer and Their Family Caregivers

    ClinicalTrials.gov

    2016-10-13

    Caregiver; Psychological Impact of Cancer and Its Treatment; Recurrent Non-small Cell Lung Cancer; Stage IIA Non-small Cell Lung Cancer; Stage IIB Non-small Cell Lung Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer

  15. Suppression of Wnt signaling by the miR-29 family is mediated by demethylation of WIF-1 in non-small-cell lung cancer

    SciTech Connect

    Tan, Min; Wu, Junjie; Cai, Yong

    2013-09-06

    Highlights: •Dnmt3A and Dnmt3B are involved in the down-regulation of WIF-1 expression in non-small-cell lung cancer. •MiR-29 family members could restore WIF-1 expression through demethylation. •MiR-29s suppress Wnt/β-catenin signaling pathway and inhibit tumor growth. •The expression of miR-29a and miR-29b could be regulated partially in a positive feedback loop. -- Abstract: Wnt inhibitory factor-1 (WIF-1) silencing induced by promoter hypermethylation is a common mechanism of aberrant activation of the Wnt signaling pathway in non-small-cell lung cancer (NSCLC). However, the activity of regulators associated with the methylation of the WIF-1 gene remains unclear. Here, we investigated the role of three DNA methyltransferases (DNMT1, DNMT3A and DNMT3B) in the expression of WIF-1. The three DNMTs were up-regulated in NSCLC tumor tissues and suppression of DNMT3A and DNMT3B restored the expression of WIF-1 in NSCLC cells. The miR-29 family (miR-29a, -29b, and -29c), which negatively regulates DNMT3A and DNMT3B, was examined in association with the Wnt/β-catenin signaling pathway. A positive correlation between the expression of WIF-1 and that of MiR-29s was observed in NSCLC tissues. Methylation-specific PCR and Western blotting indicated that miR-29s positively regulate WIF-1 expression by inhibiting the methylation of its promoter. Furthermore, miR-29 overexpression downregulated β-catenin expression, inhibited cell proliferation and induced apoptosis. The expression of miR-29a and miR-29b was partially regulated by DNMT3A and DNMT3B in a positive feedback loop. Taken together, our findings show that miR-29s suppress the Wnt signaling pathway through demethylation of WIF-1 in NSCLC.

  16. A 5-year survey of biopsy proven kidney diseases in Lebanon: significant variation in prevalence of primary glomerular diseases by age, population structure and consanguinity

    PubMed Central

    Karnib, Hussein H.; Gharavi, Ali G.; Aftimos, Georges; Mahfoud, Ziyad; Saad, Reem; Gemayel, Elias; Masri, Badiaa; Assaad, Shafika; Badr, Kamal F.; Ziyadeh, Fuad N.

    2010-01-01

    Background. Differences in epidemiology of kidney disease across the Middle East may arise from variations in indication for biopsy, environmental exposure and socio-economic status. The Lebanese population is composed of different ethnicities, with distinct ancestry and religion, enabling comparison of their effect on the prevalence of kidney disease within a confined geographic setting and uniform practices. Here we report 5 years’ detailed epidemiology of renal diseases, based on histological diagnosis, in a sample from three large pathology centres in Lebanon. Methods. Records of renal biopsies analysed at the American University of Beirut Medical Center, Hotel Dieu de France Hospital and the Institut National de Pathologie from January 2003 till December 2007 were retrospectively examined. We recorded the following data for each patient: age, gender, indication for renal biopsy and histopathological diagnosis. Religious affiliation and parents’ consanguinity were recorded when feasible. Results. The mean age at renal biopsy was 36.76 ± 20 years (range 1–84). The most common diagnosis was mesangioproliferative glomerulonephritis (GN; 20%), followed by focal segmental glomerulosclerosis (13.2%). While there were no differences in age, gender or indications for biopsy among different religious affiliations, mesangioproliferative GN was significantly more frequent among Muslims (P = 0.039) and offspring of consanguineous unions (P = 0.036). On the other hand, focal segmental glomerulosclerosis was most prevalent in Christians (P < 0.001). Conclusions. Variation in the distribution of diagnoses between Muslim and Christian groups likely reflects differences in population structure and ancestry. In particular, the increased prevalence of mesangioproliferative GN among offspring of consanguineous unions in Muslims suggests a recessive genetic component to this disease which may be identified via homozygosity mapping. These findings have important

  17. The Small Noncoding RNA Processing Machinery of Two Living Fossil Species, Lungfish and Coelacanth, Gives New Insights into the Evolution of the Argonaute Protein Family

    PubMed Central

    Biscotti, Maria Assunta; Forconi, Mariko; Gerdol, Marco; Pallavicini, Alberto; Schartl, Manfred; Barucca, Marco

    2017-01-01

    Argonaute (AGO) family proteins play many roles in epigenetic programming, genome rearrangement, mRNA breakdown, inhibition of translation, and transposon silencing. Despite being a hotspot in current scientific research, their evolutionary history is still poorly understood and consequently the identification of evolutionary conserved structural features should also generate useful information for better understanding their functions. We report here for the first time the transcript sets of the two subfamilies, Ago and Piwi, in the West African lungfish Protopterus annectens and in the Indonesian coelacanth Latimeria menadoensis, two key species in the evolutionary lineage leading to tetrapods. The phylogenetic analysis of 142 inferred protein sequences in 22 fully sequenced species and the analysis of microsynteny performed in the major vertebrate lineages indicate an intricate pattern for the evolution of both subfamilies that has been shaped by whole genome duplications and lineage specific gains and losses. The argonaute subfamily was additionally expanded by local gene duplications at the base of the jawed vertebrate lineage. The subfamily of Piwi proteins is involved in several processes such as spermatogenesis, piRNA biogenesis, and transposon repression. Expression assessment of AGO genes and genes coding for proteins involved in small RNA biogenesis suggests a limited activity of the Piwi pathway in lungfish in agreement with the lungfish genome containing mainly old and inactive transposons. PMID:28206606

  18. Digestive tract and renal small vessel hyalinosis, idiopathic nonarteriosclerotic intracerebral calcifications, retinal ischemic syndrome, and phenotypic abnormalities. A new familial syndrome.

    PubMed

    Rambaud, J C; Galian, A; Touchard, G; Morel-Maroger, L; Mikol, J; Van Effenterre, G; Leclerc, J P; Le Charpentier, Y; Haut, J; Matuchansky, C

    1986-04-01

    A new familial syndrome that affected 3 of 7 siblings is described. All 3 patients were young women with a very peculiar phenotype, poikilodermia and hair greying, and idiopathic nonarteriosclerotic cerebral calcifications. Pathological studies demonstrated a marked and progressive hyalinosis involving capillaries and often arterioles and small veins of the digestive tract, kidneys, and calcified areas of the brain. Using electron microscopy, we found that the hyalin substance in the intestinal capillaries consisted of several concentric layers of basal membrane-like deposits within a finely granular fluffy material. Huge deposits of this material were present in the subepithelial and mesangial spaces of the kidneys. Endothelial cells and, in the kidneys, mesangial cells were markedly abnormal, and a true mesangiolysis pattern was present in 2 patients. The clinical and biologic expression of these vascular changes was variable. Diarrhea, rectal bleeding, malabsorption, and protein-losing enteropathy were the main and lethal clinical problems in the proband. Hypertension appeared in the early stage of a second pregnancy in 1 sister, and mild proteinuria was found in all 3 affected patients. Peripheral retinal ischemic syndrome and chorioretinal scars were found in the ocular fundi of both affected sisters of the proband. A subarachnoid hemorrhage, due to a right sylvian aneurism, also occurred in both sisters and was lethal in 1 sister. None of the known causes of distal vessel hyalinosis could be ascertained.

  19. Knockdown of Tubulin Polymerization Promoting Protein Family Member 3 Suppresses Proliferation and Induces Apoptosis in Non-Small-Cell Lung Cancer

    PubMed Central

    Li, Yintao; Xu, Yali; Ye, Kuanping; Wu, Nan; Li, Junfeng; Liu, Naijia; He, Min; Lu, Bin; Zhou, Wenbai; Hu, Renming

    2016-01-01

    Our previous studies demonstrated that depletion of tubulin polymerization promoting protein family member 3 (TPPP3) inhibits proliferation and induces apoptosis of HeLa cells. However, the expression and roles of TPPP3 in cancers remain largely unknown. In this study, we investigated the expression of TPPP3 in clinicopathological correlations in non-small-cell lung cancer (NSCLC) samples by immunohistochemistry. TPPP3 expression was significantly upregulated in NSCLC tissues, and high TPPP3 expression was positively associated with tumor size, lymph node metastasis, clinical stage, and poor survival. Furthermore, knockdown of TPPP3 by shRNA significantly inhibited cell proliferation and induced cell apoptosis and cell cycle arrest in vitro. In addition, depletion of TPPP3 inhibited lung cancer growth in vivo in the xenografts of H1299 cells; this effect was accompanied by the suppression of Ki67 expression. Our data suggested that TPPP3 might act as an oncogene in NSCLC. TPPP3 warrants consideration as a therapeutic candidate with anti-tumor potential. PMID:27390593

  20. Human endogenous retrovirus W family envelope gene activates the small conductance Ca2+-activated K+ channel in human neuroblastoma cells through CREB.

    PubMed

    Li, S; Liu, Z C; Yin, S J; Chen, Y T; Yu, H L; Zeng, J; Zhang, Q; Zhu, F

    2013-09-05

    Numerous studies have shown that human endogenous retrovirus W family (HERV-W) envelope gene (env) is related to various diseases but the underlying mechanism has remained poorly understood. Our previous study showed that there was abnormal expression of HERV-W env in sera of patients with schizophrenia. In this paper, we reported that overexpression of the HERV-W env elevated the levels of small conductance Ca(2+)-activated K(+) channel protein 3 (SK3) in human neuroblastoma cells. Using a luciferase reporter system and RNA interference method, we found that functional cAMP response element site was required for the expression of SK3 triggered by HERV-W env. In addition, it was also found that the SK3 channel was activated by HERV-W env. Further study indicated that cAMP response element-binding protein (CREB) was required for the activation of the SK3 channel. Thus, a novel signaling mechanism of how HERV-W env influences neuronal activity and contributes to mental illnesses such as schizophrenia was proposed.

  1. Src-Family Kinases Are Activated in Non-Small Cell Lung Cancer and Promote the Survival of Epidermal Growth Factor Receptor-Dependent Cell Lines

    PubMed Central

    Zhang, Jie; Kalyankrishna, Shailaja; Wislez, Marie; Thilaganathan, Nishan; Saigal, Babita; Wei, Wei; Ma, Long; Wistuba, Ignacio I.; Johnson, Faye M.; Kurie, Jonathan M.

    2007-01-01

    The role of Src-family kinases (SFKs) in non-small cell lung cancer (NSCLC) has not been fully defined. Here we addressed this question by examining SFK phosphorylation in NSCLC biopsy samples and using genetic and pharmacological approaches to inhibit SFK expression and activity in cultured NSCLC cells. Immunohistochemical analysis of NSCLC biopsy samples using a Tyr416 phosphorylation-specific, pan-SFK antibody revealed staining in 123 (33%) of 370 tumors. Because c-Src is known to be both an upstream activator and downstream mediator of epidermal growth factor receptor (EGFR), we next investigated SFK phosphorylation in a panel of NSCLC cell lines, including ones that depend on EGFR for survival. The EGFR-dependent NSCLC cell lines HCC827 and H3255 had increased phosphorylation of SFKs, and treatment of these cells with an SFK inhibitor (PP1 or SKI-606) induced apoptosis. PP1 decreased phosphorylation of EGFR, ErbB2, and ErbB3 and strikingly enhanced apoptosis by gefitinib, an EGFR inhibitor. HCC827 cells transfected with c-Src short hairpin RNA exhibited diminished phosphorylation of EGFR and ErbB2 and decreased sensitivity to apoptosis by PP1 or gefitinib. We conclude that SFKs are activated in NSCLC biopsy samples, promote the survival of EGFR-dependent NSCLC cells, and should be investigated as therapeutic targets in NSCLC patients. PMID:17200208

  2. Suppression of wingless-type MMTV integration site family, member 1 expression by small interfering RNA inhibits U251 glioma cell growth in vitro

    PubMed Central

    DONG, LUN; DUAN, XIAO-CHUN; HAN, CHONG-XU; ZHANG, HENGZHU; WU, YONGKANG

    2015-01-01

    A Wingless-type MMTV integration site family, member 1 (Wnt-1) RNA interference expression vector was constructed during the present study, which was used to transfect the glioma U251 cell line and investigate its effect on glioma. Two 21-base oligonucleotides complementary to the coding sequence that was flanking the loop sequence were designed to form a DNA hairpin template for the target small interfering RNA (siRNA). The siRNA templates were cloned into the siRNA expression vector, pGPU6/green fluorescent protein (GFP)/Neo and the sequence was confirmed by DNA sequencing. The pGPU6/GFP/Neo-short hairpin RNA (shRNA)-Wnt-1 vector was subsequently transfected into U251 cells, and reverse transcription polymerase chain reaction and western blot analysis were used to evaluate the Wnt-1 gene silencing effect on U251 cell growth by MTT assay and flow cytometry. The Wnt-1 protein expression was significantly reduced following transfection with the recombinant plasmid, as determined by western blot analysis of the transfected U251 cells. This transfection exhibited a significantly higher death rate, as shown by MTT. Thus, the present study demonstrated that the pGPU6/GFP/Neo-shRNA-Wnt-1 vector inhibited Wnt-1 protein expression. However, further investigations regarding the Wnt signaling pathway in glioma pathogenesis are required. PMID:25435937

  3. Deletion of the gene family of small chlorophyll-binding proteins (ScpABCDE) offsets C/N homeostasis in Synechocystis PCC 6803.

    PubMed

    Tibiletti, Tania; Hernández-Prieto, Miguel A; Matthijs, Hans C P; Niyogi, Krishna K; Funk, Christiane

    2016-04-01

    In the family of chlorophyll binding proteins, single helix small CAB-like proteins (SCPs) are found in all organisms performing oxygenic photosynthesis. Here, we investigated the function of these stress-inducible proteins in the cyanobacterium Synechocystis sp. PCC 6803. We compared physiological, proteome and transcriptome traits of a Photosystem I (PSI) deletion strain, which constitutively induces SCPs, and a PSI-less/ScpABCDE(-) without SCPs. The SCP mutant cells were larger in size, showed irregular thylakoid structure and differed in cell-surface morphology. Deletion of scp genes strongly affected the carbon (C) and nitrogen (N) balance, resulting in accumulation of carbohydrates and a decrease in N-rich compounds (proteins and chlorophyll). Data from transcriptomic and metabolomic experiments revealed a role of SCPs in the control of chlorophyll biosynthesis. Additionally, SCPs diminished formation of reactive oxygen species, thereby preventing damage within Photosystem II. We conclude that the lack of SCP-function to remove free chlorophyll under stress conditions has a large impact on the metabolism of the entire cell. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Asteroid families

    NASA Astrophysics Data System (ADS)

    Nesvorný, David; Bottke, William F.; Vokrouhlický, David; Morbidelli, Alessandro; Jedicke, Robert

    An asteroid family is a group of asteroids with similar orbits and spectra that was produced by a collisional breakup of a large parent body. To identify asteroid families, researchers look for clusters of asteroid positions in the space of proper orbital elements. These elements, being more constant over time than osculating orbital elements, provide a dynamical criterion of whether a group of bodies has a common ancestor. More than fifty asteroid families have been identified to date. Their analysis produced several important insights into the physics of large scale collisions, dynamical processes affecting small bodies in the Solar System, and surface and interior properties of asteroids.

  5. New Perspectives on the Rural Economy. Hearing on New Perspectives on the Rural Economy before the Subcommittee on Rural Economy and Family Farming of the Committee on Small Business. United States Senate, One Hundredth Congress, First Session.

    ERIC Educational Resources Information Center

    Congress of the U.S., Washington, DC. Senate Committee on Small Business.

    Testimony and prepared statements presented at a hearing before the Senate Subcommittee on Rural Economy and Family Farming focused on the concerns of rural small business. Witnesses included Senators from Montana, Illinois, New York, Oklahoma, South Dakota, Wisconsin, Minnesota, and Iowa, and nine representatives of business, state government,…

  6. Genome-wide identification and analysis of biotic and abiotic stress regulation of small heat shock protein (HSP20) family genes in bread wheat.

    PubMed

    Muthusamy, Senthilkumar K; Dalal, Monika; Chinnusamy, Viswanathan; Bansal, Kailash C

    2017-04-01

    Small Heat Shock Proteins (sHSPs)/HSP20 are molecular chaperones that protect plants by preventing protein aggregation during abiotic stress conditions, especially heat stress. Due to global climate change, high temperature is emerging as a major threat to wheat productivity. Thus, the identification of HSP20 and analysis of HSP transcriptional regulation under different abiotic stresses in wheat would help in understanding the role of these proteins in abiotic stress tolerance. We used sequences of known rice and Arabidopsis HSP20 HMM profiles as queries against publicly available wheat genome and wheat full length cDNA databases (TriFLDB) to identify the respective orthologues from wheat. 163 TaHSP20 (including 109 sHSP and 54 ACD) genes were identified and classified according to the sub-cellular localization and phylogenetic relationship with sequenced grass genomes (Oryza sativa, Sorghum bicolor, Zea mays, Brachypodium distachyon and Setaria italica). Spatio-temporal, biotic and abiotic stress-specific expression patterns in normalized RNA seq and wheat array datasets revealed constitutive as well as inductive responses of HSP20 in different tissues and developmental stages of wheat. Promoter analysis of TaHSP20 genes showed the presence of tissue-specific, biotic, abiotic, light-responsive, circadian and cell cycle-responsive cis-regulatory elements. 14 TaHSP20 family genes were under the regulation of 8 TamiRNA genes. The expression levels of twelve HSP20 genes were studied under abiotic stress conditions in the drought- and heat-tolerant wheat genotype C306. Of the 13 TaHSP20 genes, TaHSP16.9H-CI showed high constitutive expression with upregulation only under salt stress. Both heat and salt stresses upregulated the expression of TaHSP17.4-CI, TaHSP17.7A-CI, TaHSP19.1-CIII, TaACD20.0B-CII and TaACD20.6C-CIV, while TaHSP23.7-MTI was specifically induced only under heat stress. Our results showed that the identified TaHSP20 genes play an important role under

  7. Amelogenesis Imperfecta: 1 Family, 2 Phenotypes, and 2 Mutated Genes.

    PubMed

    Prasad, M K; Laouina, S; El Alloussi, M; Dollfus, H; Bloch-Zupan, A

    2016-12-01

    Amelogenesis imperfecta (AI) is a clinically and genetically heterogeneous group of diseases characterized by enamel defects. The authors have identified a large consanguineous Moroccan family segregating different clinical subtypes of hypoplastic and hypomineralized AI in different individuals within the family. Using targeted next-generation sequencing, the authors identified a novel heterozygous nonsense mutation in COL17A1 (c.1873C>T, p.R625*) segregating with hypoplastic AI and a novel homozygous 8-bp deletion in C4orf26 (c.39_46del, p.Cys14Glyfs*18) segregating with hypomineralized-hypoplastic AI in this family. This study highlights the phenotypic and genotypic heterogeneity of AI that can exist even within a single consanguineous family. Furthermore, the identification of novel mutations in COL17A1 and C4orf26 and their correlation with distinct AI phenotypes can contribute to a better understanding of the pathophysiology of AI and the contribution of these genes to amelogenesis.

  8. Phase I Study of Navitoclax (ABT-263), a Novel Bcl-2 Family Inhibitor, in Patients With Small-Cell Lung Cancer and Other Solid Tumors

    PubMed Central

    Gandhi, Leena; Camidge, D. Ross; Ribeiro de Oliveira, Moacyr; Bonomi, Philip; Gandara, David; Khaira, Divis; Hann, Christine L.; McKeegan, Evelyn M.; Litvinovich, Elizabeth; Hemken, Philip M.; Dive, Caroline; Enschede, Sari H.; Nolan, Cathy; Chiu, Yi-Lin; Busman, Todd; Xiong, Hao; Krivoshik, Andrew P.; Humerickhouse, Rod; Shapiro, Geoffrey I.; Rudin, Charles M.

    2011-01-01

    Purpose Resistance to chemotherapy-induced apoptosis represents a major obstacle to cancer control. Overexpression of Bcl-2 is seen in multiple tumor types and targeting Bcl-2 may provide therapeutic benefit. A phase I study of navitoclax, a novel inhibitor of Bcl-2 family proteins, was conducted to evaluate safety, pharmacokinetics, and preliminary efficacy in patients with solid tumors. Patients and Methods Patients enrolled to intermittent dosing cohorts received navitoclax on day −3, followed by dosing on days 1 to 14 of a 21-day cycle. Patients on continuous dosing received a 1-week lead-in dose of 150 mg followed by continuous daily administration. Blood samples were collected for pharmacokinetic analyses, biomarker analyses, and platelet monitoring. Results Forty-seven patients, including 29 with small-cell lung cancer (SCLC) or pulmonary carcinoid, were enrolled between 2007 and 2008, 35 on intermittent and 12 on continuous dosing cohorts. Primary toxicities included diarrhea (40%), nausea (34%), vomiting (36%), and fatigue (34%); most were grade 1 or 2. Dose- and schedule-dependent thrombocytopenia was seen in all patients. One patient with SCLC had a confirmed partial response lasting longer than 2 years, and eight patients with SCLC or carcinoid had stable disease (one remained on study for 13 months). Pro-gastrin releasing peptide (pro-GRP) was identified as a surrogate marker of Bcl-2 amplification and changes correlated with changes in tumor volume. Conclusion Navitoclax is safe and well tolerated, with dose-dependent thrombocytopenia as the major adverse effect. Preliminary efficacy data are encouraging in SCLC. Efficacy in SCLC and the utility of pro-GRP as a marker of treatment response will be further evaluated in phase II studies. PMID:21282543

  9. Rabconnectin-3, a novel protein that binds both GDP/GTP exchange protein and GTPase-activating protein for Rab3 small G protein family.

    PubMed

    Nagano, Fumiko; Kawabe, Hiroshi; Nakanishi, Hiroyuki; Shinohara, Masahiko; Deguchi-Tawarada, Maki; Takeuchi, Masakazu; Sasaki, Takuya; Takai, Yoshimi

    2002-03-22

    Rab3A, a member of the Rab3 small G protein family, regulates Ca(2+)-dependent exocytosis of neurotransmitter. The cyclical activation and inactivation of Rab3A are essential for the Rab3A action in exocytosis. GDP-Rab3A is activated to GTP-Rab3A by Rab3 GDP/GTP exchange protein (Rab3 GEP), and GTP-Rab3A is inactivated to GDP-Rab3A by Rab3 GTPase-activating protein (Rab3 GAP). It remains unknown how or in which step of the multiple exocytosis steps these regulators are activated and inactivated. We isolated here a novel protein that was co-immunoprecipitated with Rab3 GEP and GAP by their respective antibodies from the crude synaptic vesicle fraction of rat brain. The protein, named rabconnectin-3, bound both Rab3 GEP and GAP. The cDNA of rabconnectin-3 was cloned from a human cDNA library and its primary structure was determined. Human rabconnectin-3 consisted of 3,036 amino acids and showed a calculated M(r) of 339,753. It had 12 WD domains. Tissue and subcellular distribution analyses in rat indicated that rabconnectin-3 was abundantly expressed in the brain where it was enriched in the synaptic vesicle fraction. Immunofluorescence and immunoelectron microscopy revealed that rabconnectin-3 was concentrated on synaptic vesicles at synapses. These results indicate that rabconnectin-3 serves as a scaffold molecule for both Rab3 GEP and GAP on synaptic vesicles.

  10. Use of reverse transcriptase polymerase chain reaction for diagnosis and staging of alveolar rhabdomyosarcoma, Ewing sarcoma family of tumors, and desmoplastic small round cell tumor.

    PubMed

    Athale, U H; Shurtleff, S A; Jenkins, J J; Poquette, C A; Tan, M; Downing, J R; Pappo, A S

    2001-02-01

    To compare the use of reverse transcriptase polymerase chain reaction (RT-PCR) with that of morphology-based methods for diagnosis, staging, and detection of metastatic disease in pediatric alveolar rhabdomyosarcoma (ARMS), Ewing sarcoma family of tumors (ESFT), and desmoplastic small round cell tumors (DSRCT). RT-PCR assays for the EWS-FLII, EWS-ERG, PAX3-FKHR, PAX7-FKHR, and EWS-WTI fusion transcripts were performed on RNA extracted from the primary tumor tissue, bone marrow, and body fluids obtained at initial presentation and relapse. Molecular findings were compared with original histologic diagnoses and results of staging procedures. Eighty-eight samples from 47 patients with ARMS (n = 13), ESFT (n = 31), or DSRCT (n = 3) were analyzed. The detection rate of metastatic disease was significantly higher with RT-PCR (95%) as compared with the morphologic methods (70%) for the three pediatric sarcomas studied. In primary tumors with characteristic fusion transcript, RT-PCR was positive in all cases with morphologic evidence of metastatic disease. Moreover, in six patients (3 with ARMS, 2 with DSRCT, and 1 with ESFT) with metastatic disease, micrometastases in bone marrow (4) and other sites (2) were detected by RT-PCR alone. Importantly, none of the patients with localized disease diagnosed had micrometastases detected by RT-PCR in bone marrow. The high sensitivity and specificity of RT-PCR for the characteristic fusion transcripts of pediatric sarcomas make it an ideal method to aid in the routine staging of these patients. In addition, the 100% sensitivity of RT-PCR in detection of micrometastasis makes it useful for follow-up and detection of minimal residual disease. However, the clinical significance of molecularly-detectable disease remains unknown. Further studies should aim to elucidate the therapeutic and prognostic implications of micrometastases detected by RT-PCR alone.

  11. Microcephaly, dysmorphic features, corneal dystrophy, hairy nipples, underdeveloped labioscrotal folds, and small cerebellum in four patients.

    PubMed

    Kayserili, Hülya; Altunoglu, Umut; Yesil, Gozde; Rosti, Rasim Özgür

    2016-06-01

    Pontocerebellar hypoplasia (PCH) can occur as an isolated entity or part of a syndrome. PCH has been reported with facial dysmorphism, ocular anomalies, and genital anomalies, but the co-occurrence of all four has not been previously described. We report on four patients, born to two consanguineous families that are not related to one another, with distinctive facial features (short forehead, laterally extended, medially flared eyebrows), corneal dystrophy, underdevelopment of labioscrotal folds, and nonprogressive PCH. In addition, the patients show hair extruding from the lactiferous ducts, which to our knowledge has not been described before. The parental consanguinity, affected siblings of both genders, and absent manifestations in parents, indicate an autosomal recessive pattern of inheritance as most likely. © 2016 Wiley Periodicals, Inc.

  12. My Family.

    ERIC Educational Resources Information Center

    Alaska State-Operated Schools, Anchorage.

    This elementary reader is designed for use in a bilingual Inupiat-English program in Buckland and Deering, Alaska. It is the story of a small boy named Paul and his family. The Inupiat text and its English equivalent are never in opposition. The Inupiat text is presented on a picture page, with the English on the back. The illustrations, by J.…

  13. [Familial congenital hypomagnesemia revealed by neonatal convulsions].

    PubMed

    Ndiaye, M; Dehanin, T; Sow, A-D; Sène, M-S; Basse, A-M; Fall, A-L; Seck, L-B; Touré, K; Diop, A-G; Sow, H-D; Ndiaye, M-M

    2013-11-01

    Congenital hypomagnesemia is a rare disease, with an impact on cognitive and neurological development. We report on three familial cases of congenital hypomagnesemia, two boys and one girl who belong to the same consanguineous family. They all presented neonatal seizures and a psychomotor developmental delay. Cerebral computed tomography showed cerebral atrophy and calcifications in one case and magnetic resonance imaging found predominant cerebellar atrophy in the two other cases. All three patients also had hypocalcemia, hyperphosphoremia, and hypomagnesemia. The parathyroid hormone blood level was low in two cases and normal in the third. One 7-month old patient died. The others received a supplementation of calcium and magnesium, which normalized calcemia, phosphatemia but not magnesemia, which remained low despite high doses. They have both developed cognitive and behavioral impairments.

  14. A Comparison of Clinical and Immunologic Phenotypes in Familial and Sporadic Forms of Common Variable Immunodeficiency.

    PubMed

    Valizadeh, Amir; Yazdani, Reza; Azizi, Gholamreza; Abolhassani, Hassan; Aghamohammadi, Asghar

    2017-08-11

    Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency disease and its prevalence varies significantly among different population. Minority of CVID patients present a familial aggregation suggesting a higher probability of heritable genetic defects. A total of 235 registered CVID patients were evaluated in this cohort study. Familial and sporadic patients were stratified and demographic information, clinical records, laboratory and molecular data were compared among these two groups of patients. Multiple cases were identified in 12 families (30 patients) and sporadic presentation in 120 cases. The rate of parental consanguinity (83.3%) and clinical presentation of lymphoid malignancy (20.7%) were predominant in familial CVID patients, whereas significantly increased recurrent upper respiratory infections were recorded in sporadic patients (0.3 infections per year). Probands of familial group were presented with a higher severity score resulting in a profound mortality rate (41.7% after 30-years follow-up) comparing to the non-proband CVID patients in the same families with a lowered diagnostic delay. Familial CVID patients had a specific signature in clinical presentation and immunologic profile and a high consanguinity in this group of patients suggests a Mendelian trait with an autosomal recessive inheritance pattern. Diagnosis of an index patient within a multiple case families significantly improves the diagnostic process and outcomes of the yet asymptomatic patients. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  15. Under-Five Child Mortality and Morbidity Associated with Consanguineous Child Marriage in Pakistan: Retrospective Analysis using Pakistan Demographic and Health Surveys, 1990-91, 2006-07, 2012-13.

    PubMed

    Mustafa, Mudasir; Zakar, Rubeena; Zakar, Muhammad Zakria; Chaudhry, Ashraf; Nasrullah, Muazzam

    2017-05-01

    Objective To assess the combined effect of consanguineous and child marriages (CCM) on children health, which has not previously been explored, either globally or locally. Methods We analyzed secondary data from a series of cross-sectional, nationally representative Pakistan Demographic and Health Surveys 1990-91, 2006-07, and 2012-13. A total of 5406 mothers with 10,164 children were included in the analysis. Child health was assessed by variables such as history of diarrhea, acute respiratory infection (ARI), ARI with fever, Under-5 child mortality (U5CM) and small-size birth (SSB). Associations among variables were assessed by calculating unadjusted Odd Ratios (OR) and adjusted OR (AOR). Results A majority (n = 6,247, 61%) of the births were to mothers having CCM as compare to non-CCM (3917, 39%). There was a significant association between CCM and U5CM during 1990-91 (AOR 1.24, 95% CI 1.03-1.49) and 2006-07 (AOR 1.25, 95% CI 1.05-1.51), and infant mortality in 1990-91 (AOR 1.39, 95% CI 1.05-1.85) and 2006-07 (AOR 1.61, 95% CI 1.17-2.21). A significant association was also found between CCM and SSB infants in the period 2006-07 (AOR 1.19, 95% CI 1.01-1.42) and 2012-13 (AOR 1.22, 95% CI 1.02-1.46). We noted no effect of CCM on diarrhea, ARI, and ARI with fever. Conclusion CCM increases the likelihood of U5CM, infant mortality and SSB infants. Further quantitative and qualitative research should be conducted to assess the effects of environmental, congenital and genetic factors on the health of children born to mothers in CCM.

  16. Child Care: Promoting Quality in Family Child Care. Report to the Chairman, Subcommittee on Regulation, Business Opportunities, and Technology, Committee on Small Business, House of Representatives.

    ERIC Educational Resources Information Center

    General Accounting Office, Washington, DC. Health, Education, and Human Services Div.

    A recent study of family child care documented that a significant number of providers were giving inadequate care. As a result, this study sought to: (1) identify public and private initiatives to enhance the quality of family child care and determine how the initiatives are financed; (2) describe the federal role in supporting quality…

  17. Identification and Clinical Implications of Novel MYO15A Mutations in a Non-consanguineous Korean Family by Targeted Exome Sequencing

    PubMed Central

    Chang, Mun Young; Kim, Ah Reum; Kim, Nayoung K.D.; Lee, Chung; Lee, Kyoung Yeul; Jeon, Woo-Sung; Koo, Ja-Won; Oh, Seung Ha; Park, Woong-Yang; Kim, Dongsup; Choi, Byung Yoon

    2015-01-01

    Mutations of MYO15A are generally known to cause severe to profound hearing loss throughout all frequencies. Here, we found two novel MYO15A mutations, c.3871C>T (p.L1291F) and c.5835T>G (p.Y1945X) in an affected individual carrying congenital profound sensorineural hearing loss (SNHL) through targeted resequencing of 134 known deafness genes. The variant, p.L1291F and p.Y1945X, resided in the myosin motor and IQ2 domains, respectively. The p.L1291F variant was predicted to affect the structure of the actin-binding site from three-dimensional protein modeling, thereby interfering with the correct interaction between actin and myosin. From the literature analysis, mutations in the N-terminal domain were more frequently associated with residual hearing at low frequencies than mutations in the other regions of this gene. Therefore we suggest a hypothetical genotype-phenotype correlation whereby MYO15A mutations that affect domains other than the N-terminal domain, lead to profound SNHL throughout all frequencies and mutations that affect the N-terminal domain, result in residual hearing at low frequencies. This genotype-phenotype correlation suggests that preservation of residual hearing during auditory rehabilitation like cochlear implantation should be intended for those who carry mutations in the N-terminal domain and that individuals with mutations elsewhere in MYO15A require early cochlear implantation to timely initiate speech development. PMID:26242193

  18. A two fold risk of metabolic syndrome in a sample of patients with schizophrenia: do consanguinity and family history increase risk?

    PubMed

    Bener, Abdulbari; Al-Hamaq, Abdulla O A A; Dafeeah, Elnour E

    2014-01-01

    Patients with schizophrenia are at greater risk for metabolic syndrome (MetS) and other cardiovascular risk factors. The objective of the study was to examine the prevalence of metabolic syndrome (MetS) and its criteria among patients with schizophrenia (Sz) according to the revised criteria of NCEP ATP III and assess which component contributed to the increased risk of the MetS in schizophrenia patients. This was a matched case-control study. Outpatient clinics of the Psychiatry department and Primary Health Care (PHC) Centers of the Supreme Council of Health, State of Qatar. The study was carried out among patients with schizophrenia (SZ) and healthy subjects above 20 years old. The study based on matched by age and gender of 233 cases and 466 controls. The survey was conducted from June 2010 to May 2011. Face to face interviews were conducted using a structured questionnaire followed by laboratory tests. Metabolic syndrome was defined using the National Cholesterol Education Program - Third Adult Treatment Panel (ATP III). The prevalence of metabolic syndrome among schizophrenic patients (36.5%) were significantly higher than healthy subjects (18.7%) (p<0.001). The prevalence of MetS in schizophrenic subjects was reported to be two times higher than in the general population. The MetS components were higher among schizophrenic patients than healthy subjects. Among the components of MetS, central obesity (63.9%) was the most common criteria among patients compared to healthy subjects (45.7%) (p<0.001). Schizophrenic patients (27%) were significantly obese than the healthy subjects (13.1%). Female schizophrenia patients were more likely to have three or more metabolic abnormalities compared to men. The study indicated that metabolic syndrome was highly prevalent in patients with schizophrenia. The female gender was significantly associated with a higher prevalence of metabolic syndrome. The identification and clinical management of this high risk group is of great importance. Copyright © 2013 Diabetes India. Published by Elsevier Ltd. All rights reserved.

  19. Inbreeding coefficients for X-linked and autosomal genes in consanguineous marriages in Spanish populations: the case of Guipúzcoa (Basque Country).

    PubMed

    Calderón, R; Aresti, U; Ambrosio, B; González-Martín, A

    2009-03-01

    Inbreeding patterns over the past two centuries have been studied more extensively in Spain and Italy than anywhere else in Europe. Consanguinity studies in mainland Spain have shown that populations settled along the Cantabrian cornice share inbreeding patterns that distinguish them from other populations further south. A visual representation of spatial variations of two key inbreeding variables is presented here for the first time via contour maps. This paper also analyzes time trends of mean inbreeding coefficients for X-linked (F(x)) and autosomal genes (F) (1862-1995) together with variations in F(x)/F ratios in Guipúzcoa, the most autochthonous Spanish Basque province. Because close cousin marriages are a mark of identity of the study population, we evaluated the contribution of uncle-niece/aunt-nephew (M12) and first cousin (M22) marriages to F(x) and F values and compared the frequencies of M12 and M22 pedigree subtypes and their corresponding F(x)/F ratios to those found in other Spanish populations. The mean Fx and F inbreeding levels in Guipúzcoa for the 134-year period analyzed were 1.51 x 10(-3) and 1.04 x 10(-3), respectively, and the F(x)/F ratio was seen to be very stable over time. Our findings show that major similarities exist for close consanguineous marriage subtypes between Basque and non-Basque Spanish populations, despite significant geographic variability in terms of first cousin pedigrees. The distortion seems to be caused by Guipúzcoa. The F(x)/F ratios for first cousins in Spanish populations were higher than expected (1.25), with values ranging from 1.34 to 1.48. The findings of the present study may be useful for advancing knowledge on the effects of the interaction between biology and culture and for exploring associations between mating patterns and the prevalence of certain diseases.

  20. Whole-exome sequencing identifies novel homozygous mutation in NPAS2 in family with nonobstructive azoospermia

    PubMed Central

    Ramasamy, Ranjith; Bakircioğlu, M. Emre; Cengiz, Cenk; Karaca, Ender; Scovell, Jason; Jhangiani, Shalini N.; Akdemir, Zeynep C.; Bainbridge, Matthew; Yu, Yao; Huff, Chad; Gibbs, Richard A.; Lupski, James R.; Lamb, Dolores J.

    2015-01-01

    Objective To investigate the genetic cause of nonobstructive azoospermia (NOA) in a consanguineous Turkish family through homozygosity mapping followed by targeted exon/whole-exome sequencing to identify genetic variations. Design Whole-exome sequencing Setting Research laboratory Patient(s) We sequenced the exomes of two siblings in a consanguineous family with NOA. Intervention(s) All variants passing filter criteria were validated with Sanger sequencing to confirm familial segregation and absence in the control population. Main Outcome Measure Discovery of a mutation that could potentially cause NOA Results A novel non-synonymous mutation in neuronal PAS 2 domain (NPAS2) was identified in a consanguineous family from Turkey. This mutation in exon 14 (chr2: 101592000 C>G) of NPAS2 is likely a disease-causing mutation as it is predicted to be damaging, is a novel variant, and segregates with the disease. Family segregation of the variants showed the presence of homozygous mutation in the three brothers with NOA and heterozygous mutation in mother, one brother and one sister who were both fertile. The mutation is not found in the single nucleotide polymorphism (SNP) database, the 1000 Genomes Project, Baylor College of Medicine cohort of 500 Turkish patients (not a population specific polymorphism) or matching 50 fertile controls. Conclusions Using WES, we identified a novel homozygous mutation in NPAS2 as a likely disease-causing variant in a Turkish family diagnosed with NOA. Our data reinforce the clinical role of WES in the molecular diagnosis of highly heterogeneous genetic diseases which conventional genetic approaches have previously failed to conclude a molecular diagnosis. PMID:25956372

  1. Description of Eurystomatella sinica n. gen., n. sp., with establishment of a new family Eurystomatellidae n. fam. (Protista, Ciliophora, Scuticociliatia) and analyses of its phylogeny inferred from sequences of the small-subunit rRNA gene.

    PubMed

    Miao, Miao; Wang, Yangang; Song, Weibo; Clamp, John C; Al-Rasheid, Khaled A S

    2010-02-01

    Recently, an undescribed marine ciliate was isolated from China. Investigation of its morphology and infraciliature revealed it as an undescribed species representing a new genus, Eurystomatella n. gen., the type of the new family Eurystomatellidae n. fam. The new family is defined by close-set, apically positioned oral membranelles and a dominant buccal field that is surrounded by an almost completely circular paroral membrane. The new genus is defined by having a small oral membranelle 1 (M1), bipartite M2 and well-developed M3, a body surface faintly sculptured with a silverline system in a quadrangular, reticulate pattern and a cytostome located at the anterior third of a large buccal field. The type species of the new genus, Eurystomatella sinica n. sp., is a morphologically unique form that is defined mainly by the combination of a conspicuously flattened body, several caudal cilia, extremely long cilia associated with the buccal apparatus and a contractile vacuole located subcaudally. According to phylogenetic analyses of small-subunit (SSU) rRNA gene sequences, Eurystomatella clusters with the genus Cyclidium, as a sister group to the family Pleuronematidae. The great divergence in both buccal and somatic ciliature between Eurystomatella and all other known scuticociliates supports the establishment of a new family for Eurystomatella.

  2. Assessment of fertility and infertility in boron-exposed Turkish subpopulations: 3. Evaluation of fertility among sibs and in "borate families".

    PubMed

    Sayli, B S

    2001-09-01

    As a part of a work to reveal the health effects of boron and its compounds, fertility and infertility states of sibs of probands, contacted and interviewed in the field, and of their spouses were given. The purposes were to prevent duplications seemingly inevitable in a relatively small community with prevailing consanguinity while analyzing marriages over respective generations and to reveal if there occurred an aggregation of infertile couples. Any family without offspring after about the second year of marriage was considered primary infertile as adopted throughout the study and such families were ascertained through the individual pedigree charts set up according to the instructions of the proband, he (she) himself (herself) being excluded. The rates of childless families of this type were 0.0-3.4% among male and 0.9-3.8% among female sibs of the participant, and 2.3-10.0% among male and 0.0-5.6% among female sibs of his (her) spouse with averages of 2.3% of 1589, 2.6% of 1589, 4.0% of 1314, and 3.3% of 1436 instances, respectively. The differences were insignificant and the rates were not different from those concerning probands themselves and that of a comparable segment of the Turkish population. "Borate families/kindreds" with two or more members engaged in the borate industry were also assessed in order to detect if there was a significant clustering of infertiles within the kindred. Although it was difficult to compare with a matched group, few couples were examples of familial concentration of infertility. These results provided further support that boron exposure does not affect human reproduction primarily and most probably secondarily.

  3. From new genetics to everyday knowledge: Ideas about how genetic diseases are transmitted in two large Brazilian families

    NASA Astrophysics Data System (ADS)

    Santos, Silvana; Bizzo, Nelio

    2005-07-01

    This study focuses on everyday or lay understandings of inheritance. In the northeastern Brazil, 100 individuals were interviewed in order to describe how they explain the origin of genetic disorders affecting their relatives for several generations. There were involved 60 individuals from a large consanguineous family with many members affected with a neurodegenerative disorder, SPOAN syndrome (spastic paraplegia, optic atrophy and neuropathy), and 40 individuals of another family living with neurofibromatosis type 1 (NF1). The results indicate that families here studied have built narratives to explain the origin of genetic diseases, saying that an ancestor infected with syphilis gave rise to disorders and birthmarks transmitted to descendents.

  4. Exploring the genetic basis of 3MC syndrome: Findings in 12 further families.

    PubMed

    Urquhart, Jill; Roberts, Rebecca; de Silva, Deepthi; Shalev, Stavit; Chervinsky, Elena; Nampoothiri, Sheela; Sznajer, Yves; Revencu, Nicole; Gunasekera, Romesh; Suri, Mohnish; Ellingford, Jamie; Williams, Simon; Bhaskar, Sanjeev; Clayton-Smith, Jill

    2016-05-01

    The 3MC syndromes are a group of rare autosomal recessive disorders where the main clinical features are cleft lip and palate, hypertelorism, highly arched eyebrows, caudal appendage, postnatal growth deficiency, and genitourinary tract anomalies. Ophthalmological abnormalities, most notably anterior chamber defects may also be seen. We describe the clinical and molecular findings in 13 individuals with suspected 3MC syndrome from 12 previously unreported families. The exclusion of the MASP1 and COLEC11 Loci in two individuals from different consanguineous families and the absence of mutations in four further individuals sequenced for both genes raises the possibility that that there is further genetic heterogeneity of 3MC syndrome.

  5. Association between aggressive care and bereaved families' evaluation of end-of-life care for veterans with non-small cell lung cancer who died in Veterans Affairs facilities.

    PubMed

    Ersek, Mary; Miller, Susan C; Wagner, Todd H; Thorpe, Joshua M; Smith, Dawn; Levy, Cari R; Gidwani, Risha; Faricy-Anderson, Katherine; Lorenz, Karl A; Kinosian, Bruce; Mor, Vincent

    2017-08-15

    To the authors' knowledge, little is known regarding the relationship between patients' and families' satisfaction with aggressive end-of-life care. Herein, the authors examined the associations between episodes of aggressive care (ie, chemotherapy, mechanical ventilation, acute hospitalizations, and intensive care unit admissions) within the last 30 days of life and families' evaluations of end-of-life care among patients with non-small cell lung cancer (NSCLC). A total of 847 patients with NSCLC (34% of whom were aged <65 years) who died in a nursing home or intensive care, acute care, or hospice/palliative care (HPC) unit at 1 of 128 Veterans Affairs Medical Centers between 2010 and 2012 were examined. Data sources included Veterans Affairs administrative and clinical data, Medicare claims, and the Bereaved Family Survey. The response rate for the Bereaved Family Survey was 62%. Greater than 72% of veterans with advanced lung cancer who died in an inpatient setting had at least 1 episode of aggressive care and 31% received chemotherapy within the last 30 days of life. For all units except for HPC, when patients experienced at least 1 episode of aggressive care, bereaved families rated care lower compared with when patients did not receive any aggressive care. For patients dying in an HPC unit, the associations between overall ratings of care and ≥2 inpatient admissions or any episode of aggressive care were not found to be statistically significant. Rates of aggressive care were not associated with age, and family ratings of care were similar for younger and older patients. Aggressive care within the last month of life is common among patients with NSCLC and is associated with lower family evaluations of end-of-life care. Specialized care provided within an HPC unit may mitigate the negative effects of aggressive care on these outcomes. Cancer 2017;123:3186-94. © 2017 American Cancer Society. © 2017 American Cancer Society.

  6. Clinical and genetic investigation of a large Tunisian family with complete achromatopsia: identification of a new nonsense mutation in GNAT2 gene.

    PubMed

    Ouechtati, Farah; Merdassi, Ahlem; Bouyacoub, Yosra; Largueche, Leila; Derouiche, Kaouther; Ouragini, Houyem; Nouira, Sonia; Tiab, Leila; Baklouti, Karim; Rebai, Ahmed; Schorderet, Daniel F; Munier, Francis L; Zografos, Leonidas; Abdelhak, Sonia; El Matri, Leila

    2011-01-01

    Complete achromatopsia is a rare autosomal recessive disease associated with CNGA3, CNGB3, GNAT2 and PDE6C mutations. This retinal disorder is characterized by complete loss of color discrimination due to the absence or alteration of the cones function. The purpose of the present study was the clinical and the genetic characterization of achromatopsia in a large consanguineous Tunisian family. Ophthalmic evaluation included a full clinical examination, color vision testing and electroretinography. Linkage analysis using microsatellite markers flanking CNGA3, CNGB3, GNAT2 and PDE6C genes was performed. Mutations were screened by direct sequencing. A total of 12 individuals were diagnosed with congenital complete achromatopsia. They are members of six nuclear consanguineous families belonging to the same large consanguineous family. Linkage analysis revealed linkage to GNAT2. Mutational screening of GNAT2 revealed three intronic variations c.119-69G>C, c.161+66A>T and c.875-31G>C that co-segregated with a novel mutation p.R313X. An identical GNAT2 haplotype segregating with this mutation was identified, indicating a founder mutation. All patients were homozygous for the p.R313X mutation. This is the first report of the clinical and genetic investigation of complete achromatopsia in North Africa and the largest family with recessive achromatopsia involving GNAT2; thus, providing a unique opportunity for genotype-phenotype correlation for this extremely rare condition.

  7. Geographical Range of Rio Mamoré Virus (Family Bunyaviridae, Genus Hantavirus) in Association with the Small-Eared Pygmy Rice Rat (Oligoryzomys microtis)

    PubMed Central

    Richter, Martin H.; Hanson, John Delton; Cajimat, Maria N.; Milazzo, Mary Louise

    2010-01-01

    Abstract Hantavirus HTN·007 was originally isolated from a small-eared pygmy rice rat (Oligoryzomys microtis) captured in northeastern Peru. The results of analyses of nucleotide and amino acid sequence data in this study indicated that HTN·007 is a strain of Rio Mamoré virus (RIOMV) which is enzootic in small-eared pygmy rice rat populations in Bolivia. As such, the results of this study extend our knowledge of the geographical range of RIOMV and support the notion that the small-eared pygmy rice rat is the principal host of RIOMV. PMID:20687859

  8. A Novel Family in Medicago truncatula Consisting of More Than 300 Nodule-Specific Genes Coding for Small, Secreted Polypeptides with Conserved Cysteine Motifs1[w

    PubMed Central

    Mergaert, Peter; Nikovics, Krisztina; Kelemen, Zsolt; Maunoury, Nicolas; Vaubert, Danièle; Kondorosi, Adam; Kondorosi, Eva

    2003-01-01

    Transcriptome analysis of Medicago truncatula nodules has led to the discovery of a gene family named NCR (nodule-specific cysteine rich) with more than 300 members. The encoded polypeptides were short (60–90 amino acids), carried a conserved signal peptide, and, except for a conserved cysteine motif, displayed otherwise extensive sequence divergence. Family members were found in pea (Pisum sativum), broad bean (Vicia faba), white clover (Trifolium repens), and Galega orientalis but not in other plants, including other legumes, suggesting that the family might be specific for galegoid legumes forming indeterminate nodules. Gene expression of all family members was restricted to nodules except for two, also expressed in mycorrhizal roots. NCR genes exhibited distinct temporal and spatial expression patterns in nodules and, thus, were coupled to different stages of development. The signal peptide targeted the polypeptides in the secretory pathway, as shown by green fluorescent protein fusions expressed in onion (Allium cepa) epidermal cells. Coregulation of certain NCR genes with genes coding for a potentially secreted calmodulin-like protein and for a signal peptide peptidase suggests a concerted action in nodule development. Potential functions of the NCR polypeptides in cell-to-cell signaling and creation of a defense system are discussed. PMID:12746522

  9. Family welfare.

    PubMed

    Sinha, N K

    1992-01-01

    Between 1901-1921, India gained 12.9 million people because mortality remained high. The death rate fell between 1921-1951, but birth rates remained the same. Therefore 110 million people were added--2 times the population increase between 1891-1921. Between 1951-1981, the population increased to 324 million. Socioeconomic development was responsible for most of the downward trend in the birth rate during the 20th century. Even though large families were the norm in early India, religious leaders encouraged small family size. The 1st government family planning clinics in the world opened in Mysore and Bangalore in 1930. Right before Independence, the Bhore Committee made recommendations to reduce population growth such as increasing the age of marriage for girls. Since 1951 there has been a change in measures and policies geared towards population growth with each of the 7 5-Year Plans because policy makers applied what they learned from each previous plan. The 1st 5-Year Plan emphasized the need to understand what factors contribute to population growth. It also integrated family planning services into health services of hospitals and health centers. The government was over zealous in its implementation of the sterilization program (2nd 5-Year Plan, 1956-1961), however, which hurt family planning programs for many years. As of early 1992, sterilization, especially tubectomy, remained the most popular family planning method, however. The 7th 5-Year Plan changed its target of reaching a Net Reproductive Rate of 1 by 2001 to 2006-2011. It set a goal of 100% immunization coverage by 1990 but it did not occur. In 1986, the Ministry of Health and Family Welfare planned to make free contraceptives available in urban and rural areas and to involve voluntary organizations. The government needs to instill measures to increase women's status, women's literacy, and age of marriage as well as to eliminate poverty, ensure old age security, and ensure child survival and

  10. Novel mutations in abetalipoproteinaemia and homozygous familial hypobetalipoproteinaemia.

    PubMed

    Vongsuvanh, R; Hooper, A J; Coakley, J C; Macdessi, J S; O'Loughlin, E V; Burnett, J R; Gaskin, K J

    2007-11-01

    Abetalipoproteinaemia (ABL) and homozygous familial hypobetalipoproteinaemia (FHBL) are rare inherited disorders associated with low or undetectable levels of apolipoprotein B (apoB)-containing lipoproteins. Patients present with the symptoms and sequelae of fat malabsorption, including fat-soluble vitamin deficiencies. We describe two novel mutations: one an APOB gene mutation causing FHBL and the other a microsomal triglyceride transfer protein (MTP) gene mutation causing ABL. Two siblings of consanguineous parents were homozygous for an apoB mutation 4339delT causing an apoB-30.9 truncation. In another family, a boy born to consanguineous parents was homozygous for a 319 bp in-frame deletion of MTP exon 15 (c.2076-39_2303 + 52del319). All three children presented with malabsorption and liver dysfunction and had similar very low serum lipid, apoB, and fat-soluble vitamin levels. The FHBL parents had low serum lipid and apoB profiles distinguishing the disorder from the normal levels in ABL parents. Future patients presenting with FHBL or ABL should be genotyped to provide further insight into the varying clinical severity related to molecular heterogenicity in these two conditions.

  11. A Case of Nasu-Hakola Disease without Fractures or Consanguinity Diagnosed Using Exome Sequencing and Treated with Sodium Valproate

    PubMed Central

    Yamazaki, Kiyohiro; Yoshino, Yuta; Mori, Yoko; Ochi, Shinichiro; Yoshida, Taku; Ishimaru, Takashi; Ueno, Shu-ichi

    2015-01-01

    Nasu-Hakola disease (NHD) is a rare autosomal recessive neuropsychiatric disorder characterized by bone cysts, fractures, and cognitive impairment. Two genes are responsible for the development of NHD; TYROBP and TREM2. Although it presents with typical signs and symptoms, diagnosing this disease remains difficult. This case report describes a male with NHD with no family or past history of bone fractures who was diagnosed using exome sequencing. His frontal lobe psychiatric symptoms recovered partially following treatment with sodium valproate, but not with an antipsychotic. PMID:26598595

  12. Familial epilepsy in Algeria: Clinical features and inheritance profiles.

    PubMed

    Chentouf, Amina; Dahdouh, Aïcha; Guipponi, Michel; Oubaiche, Mohand Laïd; Chaouch, Malika; Hamamy, Hanan; Antonarakis, Stylianos E

    2015-09-01

    To document the clinical characteristics and inheritance pattern of epilepsy in multigeneration Algerian families. Affected members from extended families with familial epilepsy were assessed at the University Hospital of Oran in Algeria. Available medical records, neurological examination, electroencephalography and imaging data were reviewed. The epilepsy type was classified according to the criteria of the International League Against Epilepsy and modes of inheritance were deduced from pedigree analysis. The study population included 40 probands; 23 male (57.5%) and 17 female subjects (42.5%). The mean age of seizure onset was 9.5 ± 6.1 years. According to seizure onset, 16 patients (40%) had focal seizures and 20 (50%) had generalized seizures. Seizure control was achieved for two patients (5%) for 10 years, while 28 (70%) were seizure-free for 3 months. Eleven patients (27.5%) had prior febrile seizures, 12 were diagnosed with psychiatric disorders and four families had syndromic epilepsy. The consanguinity rate among parents of affected was 50% with phenotypic concordance observed in 25 families (62.5%). Pedigree analysis suggested autosomal dominant (AD) inheritance with or without reduced penetrance in 18 families (45%), probable autosomal recessive (AR) inheritance in 14 families (35%), and an X-linked recessive inheritance in one family. This study reveals large Algerian families with multigenerational inheritance of epilepsy. Molecular testing such as exome sequencing would clarify the genetic basis of epilepsy in some of our families. Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

  13. Women with family cancer history are at risk for poorer physical quality of life and lower self-efficacy: a longitudinal study among men and women with non-small cell lung cancer.

    PubMed

    Banik, Anna; Schwarzer, Ralf; Pawlowska, Izabela; Boberska, Monika; Cieslak, Roman; Luszczynska, Aleksandra

    2017-04-04

    We investigated the determinants of trajectories of physical symptoms related to lung cancer (a quality of life [QOL] aspect) and self-efficacy among patients with non-small cell lung cancer (NSCLC). It was hypothesized that gender and family cancer history in first-degree relatives would have synergistic effects on QOL-lung cancer specific symptoms and self-efficacy. Women with family cancer history were expected to be at risk of poorer adjustment. Quantitative, longitudinal design was applied. Participants provided their responses at 3-4 days after surgery, 1-month follow-up, and 4-month follow-up. We recruited 102 in-patients (men: 51%) with NSCLC who underwent surgery aimed at removing a lung tumor. Self-report data were collected with QLQ-LC13 and a scale for self-efficacy for managing illness. Mixed-models analysis indicated that trajectories of physical quality of life (symptoms of lung cancer) as well as self-efficacy were unfavorable among women with family cancer history. Among NSCLC patients, gender and family cancer history may be considered basic screening criteria for identifying groups of patients at risk for poorer physical QOL (higher level of physical symptoms related to lung cancer) and lower incline of self-efficacy after cancer surgery.

  14. Vorticella Linnaeus, 1767 (Ciliophora, Oligohymenophora, Peritrichia) is a grade not a clade: redefinition of Vorticella and the families Vorticellidae and Astylozoidae using molecular characters derived from the gene coding for small subunit ribosomal RNA.

    PubMed

    Sun, Ping; Clamp, John; Xu, Dapeng; Kusuoka, Yasushi; Miao, Wei

    2012-01-01

    Recent phylogenetic analyses of the peritrich genus Vorticella have suggested that it might be paraphyletic, with one Vorticella species - Vorticella microstoma grouping with the swimming peritrichs Astylozoon and Opisthonecta in a distant clade. These results were based on very limited taxon sampling and thus could not be accepted as conclusive evidence for revising the generic classification. We tested paraphyly of the genus Vorticella by making a new analysis with a broad range of samples from three continents that yielded 52 new sequences of the gene coding for small subunit rRNA. Our results, together with the available sequences in Genbank, form a comprehensive set of data for the genus Vorticella. Analyses of these data showed that Vorticella microstoma morphotypes, Astylozoon, and Opisthonecta form a well-supported, monophyletic clade, that is distinct from and basal to the family Vorticellidae containing other species of Vorticella. Paraphyly of the genus Vorticella and family Vorticellidae was strongly confirmed by these results. Furthermore, the two clades of Vorticella identified by the SSU rRNA gene are so genetically diverse whereas the genetic distances within the one containing Vorticella microstoma morphotypes, Astylozoon, and Opisthonecta were so slight, which marked it as a separate family that must be defined by molecular characters in the absence of unifying morphological and morphogenetic characters. An emended characterization and status of the genus Vorticella, the families Vorticellidae and Astylozoidae are presented and discussed.

  15. Association of PPARγ2 gene variant Pro12Ala polymorphism with hypertension and obesity in the aboriginal Qatari population known for being consanguineous.

    PubMed

    Bener, Abdulbari; Darwish, Sarah; Al-Hamaq, Abdulla Oaa; Mohammad, Ramzi M; Yousafzai, Mohammad T

    2013-01-01

    The aim of this study was to investigate the association of the Pro12Ala polymorphism of the human peroxisome proliferator-activated receptor gamma 2 (PPARγ2) gene with hypertension and obesity in a highly consanguineous aboriginal Qatari population. A cross-sectional survey conducted from January 2011-December 2012. Primary health care clinics. A random sample of 1,528 Qatari male and female population older than 20 years of age. Data on age, sex, income, level of education, occupation status, body mass index, and blood pressure and lipid profile were obtained. The Pro12Ala in the PPARγ2 gene was detected on the LightCycler® using two specific probes: (Sensor [G] 5'-CTC CTA TTG ACG CAG AAA GCG-FL and PPAR Anchor 5' LC Red 640- TCC TTC ACT GAT ACA CTG TCT GCA AAC ATA TC-PH). Univariate and multivariate logistic regression were performed. Out of a total 1,528 participants, 220 were diagnosed with essential hypertension, and 420 were obese. Participants with consanguinity were significantly higher among hypertensive than normotensive (41.9% versus 30.8%; P=0.001). Altogether, more than three-fourths (89%) of the participants had a wild genotype (Pro12Pro), 9.8% were heterozygous with Pro12Ala, and only 1.2% was homozygous with the Ala12Ala genotype. The frequency of the Pro allele was 94.5% in normotensive versus 90.5% in hypertensive, while the distribution of the Ala allele was 5.5% in normotensive versus 9.5% in the hypertensive group (P=0.001). The odds of hypertension were 1.7 times higher among the participants with the Ala allele as compared to those with the Pro, while adjusting for other potential confounders (adjusted odds ratio 1.69; 95% confidence interval 1.12-2.55; P=0.012). There was no association between the PPARγ2Ala allele and obesity (P=0.740). The current study revealed an association between the PPARγ2Ala allele and hypertension in Qatar's population. On the other hand, this study found no association between the Ala allele and obesity.

  16. Association of PPARγ2 gene variant Pro12Ala polymorphism with hypertension and obesity in the aboriginal Qatari population known for being consanguineous

    PubMed Central

    Bener, Abdulbari; Darwish, Sarah; Al-Hamaq, Abdulla OAA; Mohammad, Ramzi M; Yousafzai, Mohammad T

    2013-01-01

    Aim The aim of this study was to investigate the association of the Pro12Ala polymorphism of the human peroxisome proliferator-activated receptor gamma 2 (PPARγ2) gene with hypertension and obesity in a highly consanguineous aboriginal Qatari population. Design A cross-sectional survey conducted from January 2011–December 2012. Setting Primary health care clinics. Subjects A random sample of 1,528 Qatari male and female population older than 20 years of age. Materials and methods Data on age, sex, income, level of education, occupation status, body mass index, and blood pressure and lipid profile were obtained. The Pro12Ala in the PPARγ2 gene was detected on the LightCycler® using two specific probes: (Sensor [G] 5′-CTC CTA TTG ACG CAG AAA GCG-FL and PPAR Anchor 5′ LC Red 640- TCC TTC ACT GAT ACA CTG TCT GCA AAC ATA TC-PH). Univariate and multivariate logistic regression were performed. Result Out of a total 1,528 participants, 220 were diagnosed with essential hypertension, and 420 were obese. Participants with consanguinity were significantly higher among hypertensive than normotensive (41.9% versus 30.8%; P=0.001). Altogether, more than three-fourths (89%) of the participants had a wild genotype (Pro12Pro), 9.8% were heterozygous with Pro12Ala, and only 1.2% was homozygous with the Ala12Ala genotype. The frequency of the Pro allele was 94.5% in normotensive versus 90.5% in hypertensive, while the distribution of the Ala allele was 5.5% in normotensive versus 9.5% in the hypertensive group (P=0.001). The odds of hypertension were 1.7 times higher among the participants with the Ala allele as compared to those with the Pro, while adjusting for other potential confounders (adjusted odds ratio 1.69; 95% confidence interval 1.12–2.55; P=0.012). There was no association between the PPARγ2Ala allele and obesity (P=0.740). Conclusion The current study revealed an association between the PPARγ2Ala allele and hypertension in Qatar’s population. On the other

  17. Consanguinity Associated with Increased Prevalence and Severity of Bipolar Disorder in Pakistan: A Case Report Highlighting the Genetic Link.

    PubMed

    Aadil, Muhammad; Munir, Aitzaz; Arshad, Hasnain; Tariq, Feham; Anwar, Muhammad Jahanzaib; Amjad, Noman; Akhlaq, Anum

    2017-07-13

    This case report highlights the genetic link associated with bipolar disorder and rising prevalence of such cases in Pakistan due to the lack of knowledge and understanding of the disease. It also shows that a family history of bipolar disorder is associated with more aggressive episodes, early onset, and treatment relapse. Further studies are warranted to fully understand the pathophysiology of genetic linkages causing bipolar disorder so we can understand the natural course of illness and provide effective treatment. We report the case of a 25-year-old girl who presented to the hospital with severe mania and had around 20 episodes of acute mania in the last ten years. Her parents (first cousins) and brother all had a diagnosis of bipolar disorder.

  18. Co-existence of phenylketonuria either with maple syrup urine disease or Sandhoff disease in two patients from Iran: emphasizing the role of consanguinity.

    PubMed

    Abiri, Maryam; Talebi, Saeed; Uitto, Jouni; Youssefian, Leila; Vahidnezhad, Hassan; Shirzad, Tina; Salehpour, Shadab; Zeinali, Sirous

    2016-10-01

    Most inborn errors of metabolism (IEMs) are inherited in an autosomal recessive manner. IEMs are one of the major concerns in Iran due to its extensive consanguineous marriages. Herein, we report two patients with two co-existent IEMs: a girl affected by classic phenylketonuria (PKU) and maple syrup urine disease (MSUD) and a male patient affected with Sandhoff disease and PKU, where Sandhoff disease was suspected due to the presence of a cherry-red spot in the eyes at 6 months which is unrelated to PKU. Sequencing of candidate genes in the first patient revealed one novel and three recurrent compound heterozygous mutations of p.Ser231Pro and p.Ala300Ser in the PAH gene and p.Glu330Lys and p.Arg170Cys mutations in the BCKDHB gene. Genetic testing results in the second patient showed previously reported homozygous mutations of p.Arg261Gln in the PAH and p.Arg533Cys mutation in the HEXB gene. Genetic testing confirmed the clinical diagnosis of both diseases in both patients. To the best of our knowledge; this is the first report of the co-existence of two distinct genetic disorders in two individuals from Iran. Co-existent different IEMs in patients complicated the clinical diagnosis and management of the diseases.

  19. Small proline-rich protein 2 family is a cluster of genes induced by estrogenic compounds through nuclear estrogen receptors in the mouse uterus.

    PubMed

    Hong, Seok-Ho; Lee, Jae Eun; Jeong, Jin Ju; Hwang, Soo Jin; Bae, Se Na; Choi, Ji Young; Song, Haengseok

    2010-11-01

    We have investigated the potential actions of E(2) and endocrine disruptors (EDs) with estrogenic activity, such as bisphenol A, on the regulation of the Sprr2 family of genes in the mouse uterus using real-time RT-PCR, RT-PCR and Western blotting. Most members of Sprr2 genes that are induced by E(2), such as Sprr2a, 2b and 2e, showed E(2) dose-dependent increase at mRNA levels. Sprr2 expression was considerably reduced by pretreatment with ICI 182,780, an antagonist for nuclear estrogen receptors. Progesterone moderately dampened E(2)-induced Sprr2 expression. Furthermore, EDs comparably induced the expression of Sprr2 genes in a dose-dependent manner and EDs-induced Sprr2 expression was similarly modulated by ICI 182,780 and progesterone, strongly suggesting that they are, indeed, an estrogen-responsive gene family. Collectively, dose-dependent induction of Sprr2 genes by estrogen and EDs is primarily mediated via the genomic actions of estrogen signaling in the uterus, but not in other reproductive tracts, in mice. Copyright © 2010 Elsevier Inc. All rights reserved.

  20. Challenges and solutions for gene identification in the presence of familial locus heterogeneity

    PubMed Central

    Rehman, Atteeq U; Santos-Cortez, Regie Lyn P; Drummond, Meghan C; Shahzad, Mohsin; Lee, Kwanghyuk; Morell, Robert J; Ansar, Muhammad; Jan, Abid; Wang, Xin; Aziz, Abdul; Riazuddin, Saima; Smith, Joshua D; Wang, Gao T; Ahmed, Zubair M; Gul, Khitab; Shearer, A Eliot; Smith, Richard J H; Shendure, Jay; Bamshad, Michael J; Nickerson, Deborah A; Hinnant, John; Khan, Shaheen N; Fisher, Rachel A; Ahmad, Wasim; Friderici, Karen H; Riazuddin, Sheikh; Friedman, Thomas B; Wilch, Ellen S; Leal, Suzanne M

    2015-01-01

    Next-generation sequencing (NGS) of exomes and genomes has accelerated the identification of genes involved in Mendelian phenotypes. However, many NGS studies fall short of identifying causal variants, with estimates for success rates as low as 25% for uncovering the pathological variant underlying disease etiology. An important reason for such failures is familial locus heterogeneity, where within a single pedigree causal variants in two or more genes underlie Mendelian trait etiology. As examples of intra- and inter-sibship familial locus heterogeneity, we present 10 consanguineous Pakistani families segregating hearing impairment due to homozygous variants in two different hearing impairment genes and a European-American pedigree in which hearing impairment is caused by four variants in three different genes. We have identified 41 additional pedigrees with syndromic and nonsyndromic hearing impairment for which a single previously reported hearing impairment gene has been identified but only segregates with the phenotype in a subset of affected pedigree members. We estimate that locus heterogeneity occurs in 15.3% (95% confidence interval: 11.9%, 19.9%) of the families in our collection. We demonstrate novel approaches to apply linkage analysis and homozygosity mapping (for autosomal recessive consanguineous pedigrees), which can be used to detect locus heterogeneity using either NGS or SNP array data. Results from linkage analysis and homozygosity mapping can also be used to group sibships or individuals most likely to be segregating the same causal variants and thereby increase the success rate of gene identification. PMID:25491636

  1. Crystallization and preliminary X-ray diffraction analysis of XAC1151, a small heat-shock protein from Xanthomonas axonopodis pv. citri belonging to the α-crystallin family

    SciTech Connect

    Hilario, Eduardo; Teixeira, Elaine Cristina; Pedroso, Gisele Audrei; Bertolini, Maria Célia; Medrano, Francisco Javier

    2006-05-01

    XAC1151, a small heat-shock protein from X. axonopodis pv. citri belonging to the α-crystallin family, was crystallized using the sitting-drop vapour-diffusion method in the presence of ammonium phosphate. X-ray diffraction data were collected to 1.65 Å resolution using a synchrotron-radiation source. The hspA gene (XAC1151) from Xanthomonas axonopodis pv. citri encodes a protein of 158 amino acids that belongs to the small heat-shock protein (sHSP) family of proteins. These proteins function as molecular chaperones by preventing protein aggregation. The protein was crystallized using the sitting-drop vapour-diffusion method in the presence of ammonium phosphate. X-ray diffraction data were collected to 1.65 Å resolution using a synchrotron-radiation source. The crystal belongs to the rhombohedral space group R3, with unit-cell parameters a = b = 128.7, c = 55.3 Å. The crystal structure was solved by molecular-replacement methods. Structure refinement is in progress.

  2. Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11.

    PubMed

    zur Stadt, Udo; Schmidt, Susanne; Kasper, Brigitte; Beutel, Karin; Diler, A Sarper; Henter, Jan-Inge; Kabisch, Hartmut; Schneppenheim, Reinhard; Nürnberg, Peter; Janka, Gritta; Hennies, Hans Christian

    2005-03-15

    Familial hemophagocytic lymphohistiocytosis (FHL) is a rare autosomal recessive disorder characterized by hyperactive phagocytes and defects in natural killer cell function. It has been shown previously that mutations in the perforin 1 gene (PRF1) and in UNC13D are associated with FHL2 and FHL3, respectively, indicating genetic heterogeneity. We performed genome-wide homozygosity mapping in a large consanguineous Kurdish kindred with five children affected with FHL. Linkage to a 10 cM region on chromosome 6q24 between D6S1569 and D6S960 defined a novel FHL locus. By screening positional candidate genes, we identified a homozygous deletion of 5 bp in the syntaxin 11 gene (STX11) in this family. We could demonstrate that syntaxin 11 protein was absent in the mononuclear cell fraction of patients with the homozygous 5 bp deletion. In addition to this family, we found homozygous mutations in STX11 in five consanguineous Turkish/Kurdish FHL kindreds including two families with the 5 bp deletion, one family with a large 19.2 kb genomic deletion spanning the entire coding region of STX11 (exon 2) and two families with a nonsense mutation that leads to a premature stop codon in the C-terminal end of the protein. As both STX11 and UNC13D are involved in vesicle trafficking and membrane fusion, we conclude that, besides mutations in perforin 1, defects in the endocytotic or the exocytotic pathway may be a common mechanism in FHL.

  3. A DIDMOAD syndrome family with juvenile glaucoma and myopia findings.

    PubMed

    Bekir, N A; Güngör, K; Güran, S

    2000-08-01

    We present here two DIDMOAD syndrome cases (Diabetes Mellitus, Diabetes Insipidus, Optic Atrophy, Deafness) in a Turkish family. In the examination of the propositus who had consanguineous parents, diabetes mellitus, diabetes insipidus, optic atrophy, and deafness were observed in addition to myopia, juvenile glaucoma, posterior polar cataract, and dilatation of the urinary tract. Diabetes mellitus, diabetes inspidus, optic atrophy, deafness, myopia, and ventricular septal defect were observed in his elder brother. Juvenile onset diabetes mellitus, congenital glaucoma, deafness, and heart disease were the other remarkable findings observed in relatives to this family. Juvenile glaucoma, posterior polar cataract observed in our propositus, and myopia in both our DIDMOAD syndrome cases are the first ophthalmic manifestations described in the DIDMOAD syndrome.

  4. Familial Mediterranean fever (FMF) in Lebanon and Jordan: a population genetics study and report of three novel mutations.

    PubMed

    Medlej-Hashim, Myrna; Serre, Jean-Louis; Corbani, Sandra; Saab, Odile; Jalkh, Nadine; Delague, Valérie; Chouery, Eliane; Salem, Nabiha; Loiselet, Jacques; Lefranc, Gérard; Mégarbané, André

    2005-01-01

    Familial Mediterranean fever (FMF) is an autosomal recessive disease mostly frequent in Mediterranean populations. Over 50 mutations have been identified in the gene responsible for the disease, MEFV. The present study reports the frequencies of MEFV mutations in 558 Lebanese and 55 Jordanian FMF patients and points out the severity of the M694V frequently observed mutation among these patients. Three novel mutations, T177I, S108R and E474K were also identified in the Lebanese group. An excess of homozygotes and a deficit of heterozygotes were observed in both samples when compared to the expected number of observed genotypes under the Hardy-Weinberg hypothesis. Homozygotes for M694V and M694I were still in excess in the Lebanese group of patients, even after consanguinous homozygotes were removed, or population structure was considered. This excess is therefore neither due to consanguinity nor to subgroups in the Lebanese population, but rather to more remote consanguinity or to a selection bias favoring the census of these genotypes. The fact that FMF female patients were less censed than male patients may be due to the greater resistance of females to pain and to the possibility of confusing abdominal and gynecological pain. The phenotypic heterogeneity of the FMF could then originate both from genetic causes like allelic heterogeneity or modulating genes, and cultural background facing the physiological consequences of genotypes at risk.

  5. Structure, expression, and phylogenetic relationships of a family of ypt genes encoding small G-proteins in the green alga Volvox carteri.

    PubMed

    Fabry, S; Jacobsen, A; Huber, H; Palme, K; Schmitt, R

    1993-09-01

    In addition to the previously described gene yptV1 encoding a small G-protein we have now identified and sequenced four more ras-related ypt genes (yptV2-yptV5) from the green alga Volvox carteri. The four new genes encode polypeptides consisting of 203 to 217 amino-acid residues that contain the typical sequence elements (GTP-binding domains, effector domain) of the ypt/rab subgroup of the Ras superfamily. Comparison of the derived amino-acid sequences from the V. carteri ypt gene products and their Ypt homologs from other species revealed similarity values ranging from 60% to 85%, whereas intraspecies similarities were found to approach only 55%. The coding sequences are interrupted by 5-7 introns of variable size (70-1000 nucleotides) occupying different positions in the genes. Reverse-transcribed samples of stage-specific RNAs were PCR-amplified with primers specific to yptV1, yptV3, yptV4, and yptV5 to determine if yptV transcription might be restricted to either cell type or to a specific stage of the life cycle. These experiments demonstrated that each of these genes is expressed throughout the entire Volvox life cycle and in both the somatic and the reproductive cells of the alga. The transcription start sites of yptV1 and yptV5 were mapped by primer extension. Expression of recombinant yptV cDNA in E. coli yielded recombinant proteins that bound GTP specifically, demonstrating a property which is typical for small G-proteins. The derived YptV polypeptide sequences were used to group them into four distinct classes of Ras-like proteins. These are the first proteins of the Ras superfamily to be identified in a green alga. We discuss the possible role of the YptV-proteins in the intracellular vesicle transport of Volvox.

  6. Family Therapy

    MedlinePlus

    ... Family therapy is a type of psychological counseling (psychotherapy) that helps family members improve communication and resolve ... organizations? Do you have specialty training in family psychotherapy? What is your experience with my family's type ...

  7. The Genetic Causes of Nonsyndromic Congenital Retinal Detachment: A Genetic and Phenotypic Study of Pakistani Families

    PubMed Central

    Keser, Vafa; Khan, Ayesha; Siddiqui, Sorath; Lopez, Irma; Ren, Huanan; Qamar, Raheel; Nadaf, Javad; Majewski, Jacek; Chen, Rui; Koenekoop, Robert K.

    2017-01-01

    Purpose To evaluate consanguineous pedigrees from Pakistan with a clinical diagnosis of nonsyndromic congenital retinal nonattachment (NCRNA) and identify genes responsible for the disease as currently only one NCRNA gene is known (atonal basic helix-loop-helix transcription factor 7: ATOH7). Methods We implemented a three-step genotyping platform: single nucleotide polymorphism genotyping to identify loss of heterozygosity regions in patients, Retinal Information Network panel screening for mutations in currently known retinal genes. Negative patients were then subjected to whole exome sequencing. Results We evaluated 21 consanguineous NCRNA pedigrees and identified the causal mutations in known retinal genes in 13 out of our 21 families. We found mutations in ATOH7 in three families. Surprisingly, we then found mutations in familial exudative vitreoretinopathy (FEVR) genes; low-density lipoprotein receptor-related protein 5 mutations (six families), tetraspanin 12 mutations (two families), and NDP mutations (two families). Thus, 62% of the patients were successfully genotyped in our study with seven novel and six previously reported mutations in known retinal genes. Conclusions Although the clinical diagnosis of all children was NCRNA with severe congenital fibrotic retinal detachments, the molecular diagnosis determined that the disease process was in fact a very severe form of FEVR in 10 families. Because severe congenital retinal detachment has not been previously associated with all the FEVR genes, we have thus expanded the phenotypic spectrum of FEVR, a highly variable retinal detachment phenotype that has clinical overlap with NCRNA. We identified seven novel mutations. We also established for the first time genetic overlap between the Iranian and Pakistani populations. We identified eight NCRNA families that do not harbor mutations in any known retinal genes, suggesting novel causal genes in these families. PMID:28192794

  8. Homozygosity Mapping in Leber Congenital Amaurosis and Autosomal Recessive Retinitis Pigmentosa in South Indian Families.

    PubMed

    Srilekha, Sundaramurthy; Arokiasamy, Tharigopala; Srikrupa, Natarajan N; Umashankar, Vetrivel; Meenakshi, Swaminathan; Sen, Parveen; Kapur, Suman; Soumittra, Nagasamy

    2015-01-01

    Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP) are retinal degenerative diseases which cause severe retinal dystrophy affecting the photoreceptors. LCA is predominantly inherited as an autosomal recessive trait and contributes to 5% of all retinal dystrophies; whereas RP is inherited by all the Mendelian pattern of inheritance and both are leading causes of visual impairment in children and young adults. Homozygosity mapping is an efficient strategy for mapping both known and novel disease loci in recessive conditions, especially in a consanguineous mating, exploiting the fact that the regions adjacent to the disease locus will also be homozygous by descent in such inbred children. Here we have studied eleven consanguineous LCA and one autosomal recessive RP (arRP) south Indian families to know the prevalence of mutations in known genes and also to know the involvement of novel loci, if any. Complete ophthalmic examination was done for all the affected individuals including electroretinogram, fundus photograph, fundus autofluorescence, and optical coherence tomography. Homozygosity mapping using Affymetrix 250K HMA GeneChip on eleven LCA families followed by screening of candidate gene(s) in the homozygous block identified mutations in ten families; AIPL1 - 3 families, RPE65- 2 families, GUCY2D, CRB1, RDH12, IQCB1 and SPATA7 in one family each, respectively. Six of the ten (60%) mutations identified are novel. Homozygosity mapping using Affymetrix 10K HMA GeneChip on the arRP family identified a novel nonsense mutation in MERTK. The mutations segregated within the family and was absent in 200 control chromosomes screened. In one of the eleven LCA families, the causative gene/mutation was not identified but many homozygous blocks were noted indicating that a possible novel locus/gene might be involved. The genotype and phenotype features, especially the fundus changes for AIPL1, RPE65, CRB1, RDH12 genes were as reported earlier.

  9. Prevention of beta-thalassemia in a large Pakistani family through cascade testing.

    PubMed

    Baig, S M; Din, M A; Hassan, H; Azhar, A; Baig, J M; Aslam, M; Anjum, I; Farooq, M; Hussain, M S; Rasool, M; Nawaz, S; Qureshi, J A; Zaman, T

    2008-01-01

    We report cascade testing of a large Pakistani family for beta-thalassemia alleles. The family was still practicing consanguineous marriages and was at risk of having more affected births. The objective of this study was to show that identification of disease carriers in families with index cases in order to create awareness about disease and provide genetic counseling would result in reduction of the frequency of beta-thalassemia in Pakistan. In this large family with an index case, 27 available living members were tested for beta-thalassemia. Carriers of the disease were detected by measuring hemoglobin indices, and amplification refractory mutation system polymerase chain reaction was used for mutation analysis. Genetic counseling was provided to members of this family. There were already 3 marriages between the carrier members and 1 between a carrier and noncarrier in this large family; 12 (44.4%) members were found to carry the mutant gene, representing a very high carrier rate compared to the 5.4% carrier frequency of beta-thalassemia in the general population of Pakistan. The family was counseled for prevention of affected births. The initially reluctant family gradually became cooperative and seriously attended the genetic counseling sessions. Cascade testing is more practical than general population screening in a country with limited health facilities where consanguineous marriages are practiced. This report emphasizes the need of extensive testing within families with index cases to identify the carriers of beta-thalassemia in order to reduce disease occurrence through awareness and genetic counseling. (c) 2008 S. Karger AG, Basel

  10. Homozygosity Mapping in Leber Congenital Amaurosis and Autosomal Recessive Retinitis Pigmentosa in South Indian Families

    PubMed Central

    Srilekha, Sundaramurthy; Arokiasamy, Tharigopala; Srikrupa, Natarajan N.; Umashankar, Vetrivel; Meenakshi, Swaminathan; Sen, Parveen; Kapur, Suman; Soumittra, Nagasamy

    2015-01-01

    Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP) are retinal degenerative diseases which cause severe retinal dystrophy affecting the photoreceptors. LCA is predominantly inherited as an autosomal recessive trait and contributes to 5% of all retinal dystrophies; whereas RP is inherited by all the Mendelian pattern of inheritance and both are leading causes of visual impairment in children and young adults. Homozygosity mapping is an efficient strategy for mapping both known and novel disease loci in recessive conditions, especially in a consanguineous mating, exploiting the fact that the regions adjacent to the disease locus will also be homozygous by descent in such inbred children. Here we have studied eleven consanguineous LCA and one autosomal recessive RP (arRP) south Indian families to know the prevalence of mutations in known genes and also to know the involvement of novel loci, if any. Complete ophthalmic examination was done for all the affected individuals including electroretinogram, fundus photograph, fundus autofluorescence, and optical coherence tomography. Homozygosity mapping using Affymetrix 250K HMA GeneChip on eleven LCA families followed by screening of candidate gene(s) in the homozygous block identified mutations in ten families; AIPL1 – 3 families, RPE65- 2 families, GUCY2D, CRB1, RDH12, IQCB1 and SPATA7 in one family each, respectively. Six of the ten (60%) mutations identified are novel. Homozygosity mapping using Affymetrix 10K HMA GeneChip on the arRP family identified a novel nonsense mutation in MERTK. The mutations segregated within the family and was absent in 200 control chromosomes screened. In one of the eleven LCA families, the causative gene/mutation was not identified but many homozygous blocks were noted indicating that a possible novel locus/gene might be involved. The genotype and phenotype features, especially the fundus changes for AIPL1, RPE65, CRB1, RDH12 genes were as reported earlier. PMID:26147992

  11. Small endohedral metallofullerenes: exploration of the structure and growth mechanism in the Ti@C2n (2n = 26-50) family.

    PubMed

    Mulet-Gas, Marc; Abella, Laura; Dunk, Paul W; Rodríguez-Fortea, Antonio; Kroto, Harold W; Poblet, Josep M

    2015-01-01

    The formation of the smallest fullerene, C28, was recently reported using gas phase experiments combined with high-resolution FT-ICR mass spectrometry. An internally located group IV metal stabilizes the highly strained non-IPR C28 cage by charge transfer (IPR = isolated pentagon rule). Ti@C44 also appeared as a prominent peak in the mass spectra, and U@C28 was demonstrated to form by a bottom-up growth mechanism. We report here a computational analysis using standard DFT calculations and Car-Parrinello MD simulations for the family of the titled compounds, aiming to identify the optimal cage for each endohedral fullerene and to unravel key aspects of the intriguing growth mechanisms of fullerenes. We show that all the optimal isomers from C26 to C50 are linked by a simple C2 insertion, with the exception of a few carbon cages that require an additional C2 rearrangement. The ingestion of a C2 unit is always an exergonic/exothermic process that can occur through a rather simple mechanism, with the most energetically demanding step corresponding to the closure of the carbon cage. The large formation abundance observed in mass spectra for Ti@C28 and Ti@C44 can be explained by the special electronic properties of these cages and their higher relative stabilities with respect to C2 reactivity. We further verify that extrusion of C atoms from an already closed fullerene is much more energetically demanding than forming the fullerene by a bottom-up mechanism. Independent of the formation mechanism, the present investigations strongly support that, among all the possible isomers, the most stable, smaller non-IPR carbon cages are formed, a conclusion that is also valid for medium and large cages.

  12. Autosomal recessive peripheral sensory neuropathy in 3 non-Ashkenazi Jewish families.

    PubMed Central

    Tamari, I; Goodman, R M; Sarova, I; Hertz, M; Adar, R; Zvibach, T

    1980-01-01

    Three unrelated Oriental Jewish families with a total of eight subjects with progressive hereditary sensory neuropathy are reported. The parents were all unaffected and because of parental consanguinity in each of the three families it is postulated that this rare neurological disorder is transmitted in an autosomal recessive manner. In one family both parents showed an abnormal response to pain stimulation with normal motor and sensory nerve conduction velocity. This response may be an expression of the carrier state for this hereditary disease. Only five other families (non-Jewish) have been reported as having this form of peripheral hereditary sensory neuropathy. These observations suggest that one type, the progressive form, of peripheral hereditary sensory neuropathy may be more common in Oriental Jews. Images PMID:6937618

  13. A small GTPase of the Rab family is required for root hair formation and preinfection stages of the common bean-Rhizobium symbiotic association.

    PubMed

    Blanco, Flavio Antonio; Meschini, Eitel Peltzer; Zanetti, María Eugenia; Aguilar, O Mario

    2009-09-01

    Legume plants are able to establish a symbiotic relationship with soil bacteria from the genus Rhizobium, leading to the formation of nitrogen-fixing root nodules. Successful nodulation requires both the formation of infection threads (ITs) in the root epidermis and the activation of cell division in the cortex to form the nodule primordium. This study describes the characterization of RabA2, a common bean (Phaseolus vulgaris) cDNA previously isolated as differentially expressed in root hairs infected with Rhizobium etli, which encodes a protein highly similar to small GTPases of the RabA2 subfamily. This gene is expressed in roots, particularly in root hairs, where the protein was found to be associated with vesicles that move along the cell. The role of this gene during nodulation has been studied in common bean transgenic roots using a reverse genetic approach. Examination of root morphology in RabA2 RNA interference (RNAi) plants revealed that the number and length of the root hairs were severely reduced in these plants. Upon inoculation with R. etli, nodulation was completely impaired and no induction of early nodulation genes (ENODs), such as ERN1, ENOD40, and Hap5, was detected in silenced hairy roots. Moreover, RabA2 RNAi plants failed to induce root hair deformation and to initiate ITs, indicating that morphological changes that precede bacterial infection are compromised in these plants. We propose that RabA2 acts in polar growth of root hairs and is required for reorientation of the root hair growth axis during bacterial infection.

  14. Crystallization and preliminary X-ray diffraction analysis of XAC1151, a small heat-shock protein from Xanthomonas axonopodis pv. citri belonging to the α-crystallin family

    PubMed Central

    Hilario, Eduardo; Teixeira, Elaine Cristina; Pedroso, Gisele Audrei; Bertolini, Maria Célia; Medrano, Francisco Javier

    2006-01-01

    The hspA gene (XAC1151) from Xanthomonas axonopodis pv. citri encodes a protein of 158 amino acids that belongs to the small heat-shock protein (sHSP) family of proteins. These proteins function as molecular chaperones by preventing protein aggregation. The protein was crystallized using the sitting-drop vapour-diffusion method in the presence of ammonium phosphate. X-ray diffraction data were collected to 1.65 Å resolution using a synchrotron-radiation source. The crystal belongs to the rhombohedral space group R3, with unit-cell parameters a = b = 128.7, c = 55.3 Å. The crystal structure was solved by molecular-replacement methods. Structure refinement is in progress. PMID:16682772

  15. Crystallization and preliminary X-ray diffraction analysis of XAC1151, a small heat-shock protein from Xanthomonas axonopodis pv. citri belonging to the alpha-crystallin family.

    PubMed

    Hilario, Eduardo; Teixeira, Elaine Cristina; Pedroso, Gisele Audrei; Bertolini, Maria Célia; Medrano, Francisco Javier

    2006-05-01

    The hspA gene (XAC1151) from Xanthomonas axonopodis pv. citri encodes a protein of 158 amino acids that belongs to the small heat-shock protein (sHSP) family of proteins. These proteins function as molecular chaperones by preventing protein aggregation. The protein was crystallized using the sitting-drop vapour-diffusion method in the presence of ammonium phosphate. X-ray diffraction data were collected to 1.65 angstroms resolution using a synchrotron-radiation source. The crystal belongs to the rhombohedral space group R3, with unit-cell parameters a = b = 128.7, c = 55.3 angstroms. The crystal structure was solved by molecular-replacement methods. Structure refinement is in progress.

  16. Not Your Family Farm

    ERIC Educational Resources Information Center

    Tenopir, Carol; Baker, Gayle; Grogg, Jill E.

    2007-01-01

    The information industry continues to consolidate, just as agribusiness has consolidated and now dominates farming. Both the family farm and the small information company still exist but are becoming rarer in an age of mergers, acquisitions, and increased economies of scale. Small companies distinguish themselves by high quality, special themes,…

  17. Not Your Family Farm

    ERIC Educational Resources Information Center

    Tenopir, Carol; Baker, Gayle; Grogg, Jill E.

    2007-01-01

    The information industry continues to consolidate, just as agribusiness has consolidated and now dominates farming. Both the family farm and the small information company still exist but are becoming rarer in an age of mergers, acquisitions, and increased economies of scale. Small companies distinguish themselves by high quality, special themes,…

  18. MiR-30 Family Potentially Targeting PI3K-SIAH2 Predicted Interaction Network Represents a Novel Putative Theranostic Panel in Non-small Cell Lung Cancer

    PubMed Central

    Chan, Lawrence W. C.; Wang, Fengfeng; Meng, Fei; Wang, Lili; Wong, Sze Chuen Cesar; Au, Joseph S. K.; Yang, Sijun; Cho, William C. S.

    2017-01-01

    Non-small cell lung cancer (NSCLC) comprises about 84% of all lung cancers. Many treatment options are available but the survival rate is still very low due to drug resistance. It has been found that phosphoinositide-3-kinase (PI3K) affects sensitivity to tyrosine kinase inhibitors (TKIs), including gefitinib and erlotinib. Expression level of seven in absentia homolog 2 (SIAH2), an E3 ubiquitin-protein ligase, is upregulated in NSCLC and correlated with tumor grade. However, the relationship between PI3K and SIAH2 remains unclear and therefore it is not known whether they can act as treatment co-targets and theranostic dual markers for overcoming TKI resistance. It is worthy to note that PI3K and SIAH2 are potentially regulated by a common group of microRNAs in miR-30 family. Our bioinformatics analyses showed upregulated SIAH2 expression in NSCLC based on mass spectrometry data, explored its indirect interaction with PI3K and predicted their targeting microRNAs in common. We have also explored the potential role of miR-30 family in the modulation of PI3K-SIAH2 interaction in NSCLC. PMID:28210267

  19. Efficacy of afatinib, an irreversible ErbB family blocker, in the treatment of intracerebral metastases of non-small cell lung cancer in mice.

    PubMed

    Zhang, Shi-Rong; Zhu, Lu-Cheng; Jiang, Yan-Ping; Zhang, Jing; Xu, Ru-Jun; Xu, Ya-Si; Xia, Bing; Ma, Sheng-Lin

    2017-02-01

    Few effective therapeutic options are currently available for the treatment of non-small cell lung cancer (NSCLC) with brain metastases (BM). Recent evidence shows that NSCLC patients with BMs respond well to afatinib, but little is known about the underlying mechanisms. In this study, we evaluated the efficacy of afatinib in treatment of BMs in mice and investigated whether afatinib could actively penetrate the brain-blood barrier and bind to its target. NSCLC BM model was established in nude mice by intracerebral injection of PC-9.luc cells. The tumors were measured weekly using in vivo quantitative bioluminescence. The mice are administrated afatinib (15, 30 mg·kg(-1)·d(-1), ig) for 14 d. The antitumor efficacy of afatinib was determined by tumor growth inhibition (TGI), which was calculated as [1-(change of tumor volume in treatment group/control group)×100]. Pharmacokinetic characteristics were measure in mice receiving a single dose of afatinib (30 mg/kg, ig). Pharmacodynamics of afatinib was also assessed by detecting the expression of pEGFR (Tyr1068) in brain tumor foci using immunohistochemistry. Administration of afatinib (15, 30 mg·kg(-1)·d(-1)) dose-dependently inhibited PC-9 tumor growth in the brain with a TGI of 90.2% and 105%, respectively, on d 14. After administration of afatinib (30 mg/kg), the plasma concentration of afatinib was 91.4±31.2 nmol/L at 0.5 h, reached a peak (417.1±119.9 nmol/L) at 1 h, and was still detected after 24 h. The cerebrospinal fluid (CSF) concentrations followed a similar pattern. The T1/2 values of afatinib in plasma and CSF were 5.0 and 3.7 h, respectively. The AUC(0-24 h) values for plasma and CSF were 2375.5 and 29.1 nmol/h, respectively. The plasma and CSF concentrations were correlated (r=0.844, P<0.01). Pharmacodynamics study showed that the expression levels of pEGFR were reduced by 90% 1 h after afatinib administration. The Emax was 86.5%, and the EC50 was 0.26 nmol/L. A positive correlation between CSF

  20. Intra-Family Gamete Donation: A Solution to Concerns Regarding Gamete Donation in China?

    PubMed

    Liao, Juhong; Devolder, Katrien

    2016-09-01

    Gamete donation from third parties is controversial in China as it severs blood ties, which are considered of utmost importance in Confucian tradition. In recent years, infertile couples are increasingly demonstrating a preference for the use of gametes donated by family members to conceive children-known as "intra-family gamete donation." The main advantage of intra-family gamete donation is that it maintains blood ties between children and both parents. To date there is no practice of intra-family gamete donation in China. In this paper, we investigate intra-family adoption in China in order to illustrate that intra-family gamete donation is consistent with Confucian tradition regarding the importance of maintaining blood ties within the family. There are several specific ethical issues raised by intra-family gamete donation. It may, for example, result in consanguinity and the semblance of incest, lead to confused family relationships, and raise concerns about possible coercion of familial donors. Confucian tradition provides a new approach to understand and deal with these ethical issues in a way that Western tradition does not. As a result, we suggest intra-family gamete donation could be an acceptable solution to the problem of infertility in China. However, further discussion and open debates on the ethical issues raised by intra-family gamete donation are needed in China.

  1. Disease severity in familial cases of IBD.

    PubMed

    Andreu, M; Márquez, L; Domènech, E; Gisbert, J P; García, V; Marín-Jiménez, I; Peñalva, M; Gomollón, F; Calvet, X; Merino, O; Garcia-Planella, E; Vázquez-Romero, N; Esteve, M; Nos, P; Gutiérrez, A; Vera, I; Cabriada, J L; Martín, M D; Cañas-Ventura, A; Panés, J

    2014-03-01

    Phenotypic traits of familial IBD relative to sporadic cases are controversial, probably related to limited statistical power of published evidence. To know if there are phenotype differences between familial and sporadic IBD, evaluating the prospective Spanish registry (ENEIDA) with 11,983 cases. 5783 patients (48.3%) had ulcerative colitis (UC) and 6200 (51.7%) Crohn's disease (CD). Cases with one or more 1st, 2nd or 3rd degree relatives affected by UC/CD were defined as familial case. In UC and CD, familial cases compared with sporadic cases had an earlier disease onset (UC: 33 years [IQR 25-44] vs 37 years [IQR 27-49]; p<0.0001); (CD: 27 years [IQR 21-35] vs 29 years [IQR 22-40]; p<0.0001), higher prevalence of extraintestinal immune-related manifestations (EIMs) (UC: 17.2% vs 14%; p=0.04); (CD: 30.1% vs 23.6%; p<0.0001). Familial CD had higher percentage of ileocolic location (42.7% vs 51.8%; p=0.0001), penetrating behavior (21% vs 17.6%; p=0.01) and perianal disease (32% vs 27.1%; p=0.003). Differences are not influenced by degree of consanguinity. When a sufficiently powered cohort is evaluated, familial aggregation in IBD is associated to an earlier disease onset, more EIMs and more severe phenotype in CD. This feature should be taken into account at establishing predictors of disease course. © 2013.

  2. Efficacy of afatinib, an irreversible ErbB family blocker, in the treatment of intracerebral metastases of non-small cell lung cancer in mice

    PubMed Central

    Zhang, Shi-rong; Zhu, Lu-cheng; Jiang, Yan-ping; Zhang, Jing; Xu, Ru-jun; Xu, Ya-si; Xia, Bing; Ma, Sheng-lin

    2017-01-01

    Few effective therapeutic options are currently available for the treatment of non-small cell lung cancer (NSCLC) with brain metastases (BM). Recent evidence shows that NSCLC patients with BMs respond well to afatinib, but little is known about the underlying mechanisms. In this study, we evaluated the efficacy of afatinib in treatment of BMs in mice and investigated whether afatinib could actively penetrate the brain-blood barrier and bind to its target. NSCLC BM model was established in nude mice by intracerebral injection of PC-9.luc cells. The tumors were measured weekly using in vivo quantitative bioluminescence. The mice are administrated afatinib (15, 30 mg·kg−1·d−1, ig) for 14 d. The antitumor efficacy of afatinib was determined by tumor growth inhibition (TGI), which was calculated as [1−(change of tumor volume in treatment group/control group)×100]. Pharmacokinetic characteristics were measure in mice receiving a single dose of afatinib (30 mg/kg, ig). Pharmacodynamics of afatinib was also assessed by detecting the expression of pEGFR (Tyr1068) in brain tumor foci using immunohistochemistry. Administration of afatinib (15, 30 mg·kg−1·d−1) dose-dependently inhibited PC-9 tumor growth in the brain with a TGI of 90.2% and 105%, respectively, on d 14. After administration of afatinib (30 mg/kg), the plasma concentration of afatinib was 91.4±31.2 nmol/L at 0.5 h, reached a peak (417.1±119.9 nmol/L) at 1 h, and was still detected after 24 h. The cerebrospinal fluid (CSF) concentrations followed a similar pattern. The T1/2 values of afatinib in plasma and CSF were 5.0 and 3.7 h, respectively. The AUC(0–24 h) values for plasma and CSF were 2375.5 and 29.1 nmol/h, respectively. The plasma and CSF concentrations were correlated (r=0.844, P<0.01). Pharmacodynamics study showed that the expression levels of pEGFR were reduced by 90% 1 h after afatinib administration. The Emax was 86.5%, and the EC50 was 0.26 nmol/L. A positive correlation between

  3. Family genome browser: visualizing genomes with pedigree information.

    PubMed

    Juan, Liran; Liu, Yongzhuang; Wang, Yongtian; Teng, Mingxiang; Zang, Tianyi; Wang, Yadong

    2015-07-15

    Families with inherited diseases are widely used in Mendelian/complex disease studies. Owing to the advances in high-throughput sequencing technologies, family genome sequencing becomes more and more prevalent. Visualizing family genomes can greatly facilitate human genetics studies and personalized medicine. However, due to the complex genetic relationships and high similarities among genomes of consanguineous family members, family genomes are difficult to be visualized in traditional genome visualization framework. How to visualize the family genome variants and their functions with integrated pedigree information remains a critical challenge. We developed the Family Genome Browser (FGB) to provide comprehensive analysis and visualization for family genomes. The FGB can visualize family genomes in both individual level and variant level effectively, through integrating genome data with pedigree information. Family genome analysis, including determination of parental origin of the variants, detection of de novo mutations, identification of potential recombination events and identical-by-decent segments, etc., can be performed flexibly. Diverse annotations for the family genome variants, such as dbSNP memberships, linkage disequilibriums, genes, variant effects, potential phenotypes, etc., are illustrated as well. Moreover, the FGB can automatically search de novo mutations and compound heterozygous variants for a selected individual, and guide investigators to find high-risk genes with flexible navigation options. These features enable users to investigate and understand family genomes intuitively and systematically. The FGB is available at http://mlg.hit.edu.cn/FGB/. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  4. Familial dysautonomia.

    PubMed

    Axelrod, Felicia B

    2004-03-01

    Familial dysautonomia (FD) is a neurodevelopmental genetic disorder within the larger classification of hereditary sensory and autonomic neuropathies, each caused by a different genetic error. The FD gene has been identified as IKBKAP. Mutations result in tissue-specific expression of mutant IkappaB kinase-associated protein (IKAP). The genetic error probably affects development, as well as maintenance, of neurons because there is neuropathological and clinical progression. Pathological alterations consist of decreased unmyelinated and small-fiber neurons. Clinical features reflect widespread involvement of sensory and autonomic neurons. Sensory loss includes impaired pain and temperature appreciation. Autonomic features include dysphagia, vomiting crises, blood pressure lability, and sudomotor dysfunction. Central dysfunction includes emotional lability and ataxia. With supportive treatment, prognosis has improved greatly. About 40% of patients are over age 20 years. The cause of death is usually pulmonary failure, unexplained sudden deaths, or renal failure. With the discovery of the genetic defect, definitive treatments are anticipated.

  5. Family History

    MedlinePlus

    Your family history includes health information about you and your close relatives. Families have many factors in common, including their genes, ... as heart disease, stroke, and cancer. Having a family member with a disease raises your risk, but ...

  6. Family Folklore

    ERIC Educational Resources Information Center

    Kotkin, Amy J.; Baker, Holly C.

    1977-01-01

    Discusses the Family Folklore Program of the Smithsonian Institution's annual Festival of American Folklife, in which the whole family can be involved in tracing family history through story telling, photographs, etc. (MS)

  7. Family History

    MedlinePlus

    ... Aneurysms » Diagnosis » Family History A- A A+ Family History Familial intracranial aneurysms are generally defined as the ... patients with an Intracranial Aneurysm (IA) have a history of smoking at some time in their life. ...

  8. Family Folklore

    ERIC Educational Resources Information Center

    Kotkin, Amy J.; Baker, Holly C.

    1977-01-01

    Discusses the Family Folklore Program of the Smithsonian Institution's annual Festival of American Folklife, in which the whole family can be involved in tracing family history through story telling, photographs, etc. (MS)

  9. Efficiency of allogeneic hematopoietic SCT from HLA fully-matched non-sibling relatives: a new prospect of exploiting extended family search.

    PubMed

    Hamidieh, A A; Dehaghi, M Ostadali; Paragomi, P; Navaei, S; Jalali, A; Eslami, G Ghazizadeh; Behfar, M; Ghavamzadeh, A

    2015-04-01

    The best donors for hematopoietic SCT (HSCT) are fully-matched siblings. In patients without fully-matched siblings, HLA registries or cord blood banks are alternative strategies with some restrictions. Owing to the high rate of consanguineous marriage in our country, between 2006 and 2013, extended family searches were undertaken in Hematology-Oncology Research Center and Stem Cell Transplantation (HORCSCT), Tehran, Iran, in 523 HSCT candidates with parental consanguinity and no available HLA identical sibling. Fully-matched other-relative donors were found for 109 cases. We retrospectively studied the HSCT outcome in these patients. Median time to neutrophil engraftment was 13 days (range: 9-31days). In 83 patients, full chimerism and in 17 patients, mixed chimerism was achieved. Acute GvHD (aGvHD) grade II-IV appeared in 36 patients (33%). The frequency of aGvHD development in various familial subgroups was NS. Five patients expired before day+100. In the surviving 104 cases, chronic GvHD developed in 20 patients (19.2%). The distantly related subgroup had significantly a higher rate of cGvHD (P=0.04). The 2-year OS and disease-free survival (DFS) were 76.7±4.5% and 71.7±4.7%, respectively. No significant difference in OS (P=0.30) and DFS (P=0.80) was unraveled between various familial relationships. Our considerable rate of fully-matched non-sibling family members and the favorable outcome support the rationale for extended family search in regions where consanguineous marriage is widely practiced.

  10. Family Literacy

    ERIC Educational Resources Information Center

    Holloway, John H.

    2004-01-01

    Research indicates that family literacy programs can provide opportunities for educational success for parents and children. The benefits reaped by the children in family literacy workshops are presented.

  11. Byler-like familial cholestasis in an extended kindred.

    PubMed

    Bourke, B; Goggin, N; Walsh, D; Kennedy, S; Setchell, K D; Drumm, B

    1996-09-01

    Progressive familial intrahepatic cholestasis (PFIC) occurs in many communities and races. A form of PFIC in five children from two consanguineous marriages in an Irish kindred is described. In addition, a review of clinical information from the records of three deceased members of the kindred strongly implies that they also suffered from PFIC. The children had a history of neonatal diarrhoea, sepsis, and intermittent jaundice that ultimately became permanent. They suffered intractable pruritus and growth retardation. Despite evidence of severe cholestasis, serum gamma-glutamyl transferase and cholesterol were normal in these children. Sweat sodium concentration were raised in three children. Liver histology showed severe intrahepatic cholestasis and hepatocellular injury. Urinary bile acid analysis revealed a non-specific pattern consistent with chronic cholestasis. These children suffer from a form of PFIC remarkably similar to that occurring in members of the Byler kindred.

  12. Exome sequencing reveals a mutation in DMP1 in a family with familial sclerosing bone dysplasia.

    PubMed

    Gannagé-Yared, Marie-Hélène; Makrythanasis, Periklis; Chouery, Eliane; Sobacchi, Cristina; Mehawej, Cybel; Santoni, Federico A; Guipponi, Michel; Antonarakis, Stylianos E; Hamamy, Hanan; Mégarbané, André

    2014-11-01

    Hypophosphatemic rickets (HR) comprises a rare group of inherited diseases. Very recently, mutations in the dentin matrix protein 1 (DMP1) gene were identified in patients with an extremely rare autosomal recessive form of HR (ARHR). To date, very few cases of these mutations were reported. A Lebanese consanguineous family with 2 affected sisters was studied. Patients aged 45 and 47years old presented with short stature, severe genu varum, cranial hyperostosis and a very high bone density that led to a diagnosis of a familial sclerosing bone dysplasia. Molecular analysis of known genes involved in osteopetrosis showed normal results. A combination of genotyping and exome sequencing was performed in order to elucidate the genetic basis of this pathology. Biochemical analysis was consistent with normal serum calcium and 1-25(OH)2D levels, low to normal serum phosphorus and elevated PTH values. Serum c-terminal FGF-23 was elevated in one of the two patients. A homozygous mutation disrupting the initiation codon of the DMP1 gene (OMIM 600980), NM_001079911.2: c.1A>G, p.Met1Val, was identified by exome sequencing and confirmed by Sanger sequencing. We report here a family of ARHR secondary to a DMP1 mutation located in the first coding exon of the gene. Our cases show that some ARHR cases may develop with age an unaccountable increase in bone density and bone overgrowth. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. Clinical features and molecular genetics of two Tunisian families with abetalipoproteinemia.

    PubMed

    Hammer, Monia Benhamed; El Euch-Fayache, Ghada; Nehdi, Houda; Feki, Moncef; Maamouri-Hicheri, Wieme; Hentati, Fayçal; Amouri, Rim

    2014-02-01

    Abetalipoproteinemia (ABL) is a rare monogenic disease characterized by very low plasma levels of cholesterol and triglyceride and almost complete absence of apolipoprotein B (apoB)-containing lipoproteins. Typically, patients present with failure to thrive, acanthocytosis, pigmented retinopathy and neurological features. It has been shown that ABL results from mutations in the gene encoding the microsomal triglyceride transfer protein (MTTP). Sanger sequencing of MTTP was performed for two unrelated consanguineous Tunisian families with two affected individuals each, presenting a more severe ABL phenotype than previously reported in the literature. The patients were found to be homozygous for two novel mutations. In the first family, a nonsense mutation, c.2313T>A, leading to a truncated protein (p.Y771X) was identified. In the second family, a splice mutation, IVS 9+2T>G, was found. These mutations are believed to abolish the assembly and secretion of apoB-containing lipoproteins.

  14. Molecular study of 33 families with Fraser syndrome new data and mutation review.

    PubMed

    van Haelst, M M; Maiburg, M; Baujat, G; Jadeja, S; Monti, E; Bland, E; Pearce, K; Hennekam, R C; Scambler, P J

    2008-09-01

    Fraser syndrome (FS) is an autosomal recessive malformation disorder characterized by cryptophthalmos, syndactyly, and abnormalities of the respiratory and urogenital tract. FS is considered to be the human equivalent of the murine blebbing mutants: in the mouse mutations at five loci cause a phenotype that is comparable to FS in humans, and thus far mutations in two syntenic human genes, FRAS1 and FREM2, have been identified to cause FS. Here we present the molecular analysis of 48 FS patients from 18 consanguineous and 15 nonconsanguineous families. Linkage analysis in consanguineous families indicated possible linkage to FRAS1 and FREM2 in 60% of the cases. Mutation analysis identified 11 new mutations in FRAS1 and one FREM2 mutation. Manifestations of these patients and previously reported cases with an FRAS1 mutation were compared to cases without detectable FRAS1 mutations to study genotype-phenotype correlations. Although our data suggest that patients with an FRAS1 mutation have more frequently skull ossification defects and low insertion of the umbilical cord, these differences are not statistically significant. Mutations were identified in only 43% of the cases suggesting that other genes syntenic to murine genes causing blebbing may be responsible for FS as well.

  15. Identification of three novel ECEL1 mutations in three families with distal arthrogryposis type 5D.

    PubMed

    Shaheen, R; Al-Owain, M; Khan, A O; Zaki, M S; Hossni, H A A; Al-Tassan, R; Eyaid, W; Alkuraya, F S

    2014-06-01

    Arthrogryposis refers to congenital contracture in at least two different body parts. When distal joints are primarily involved, the term distal arthrogryposis (DA) is used. The recognition of clinically distinct subtypes of DA has proven very useful in mapping the disease genes for this genetically heterogeneous condition. DA5D is characterized by ocular involvement usually in the form of ptosis and incomitant strabismus, but extraocular manifestations have also been reported. In a multiplex consanguineous family with DA5D, we combined autozygosity mapping and exome sequencing to identify a novel mutation in ECEL1. This was followed by targeted sequencing of this gene in another two extended consanguineous family with the same phenotype, which revealed two additional novel homozygous mutations. Our results support the recent identification of mutations in ECEL1 as a disease gene in DA5D and expand the clinical and allelic spectrum of this condition. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. Mariage consanguin et morbi-mortalité, courte revue de la littérature à partir d'une association exceptionnelle: syndrome de Usher et Neurofibromatose de Von Recklinghausen

    PubMed Central

    Atipo-Tsiba, Pépin-Williams

    2016-01-01

    Le syndrome de Usher est défini par l'association d'une surdité de perception congénitale de sévérité variable évolutive ou non et d'une rétinopathie pigmentaire progressivement cécitante. La Neurofibromatose de Von Recklinghausen ou Neurofibromatose de type I est la principale forme clinique des neurofibromatoses avec environ 90% des cas. Ces deux maladies sont d'origine génétique avec des prévalences très basses. La probabilité pour qu'un seul et même individu souffre à la fois de ces maladies est exceptionnelle. Comme toutes les maladies génétiques, la consanguinité augmente de façon assez sensible la probabilité de leur apparition. Le mariage consanguin est encore largement répondu au Maghreb et dans certaines régions d'Afrique de l'Ouest. Cette observation rapporte un cas exceptionnel de cette association chez un homme de 40 ans originaire de la Mauritanie né d'une union consanguine. PMID:27231508

  17. Family Privilege

    ERIC Educational Resources Information Center

    Seita, John R.

    2014-01-01

    Family privilege is defined as "strengths and supports gained through primary caring relationships." A generation ago, the typical family included two parents and a bevy of kids living under one roof. Now, every variation of blended caregiving qualifies as family. But over the long arc of human history, a real family was a…

  18. Family Literacy.

    ERIC Educational Resources Information Center

    Washington, Charles W., Ed.

    1996-01-01

    This newsletter theme issue focuses on the impact of learning disabilities within families, specifically families with low literacy skills. It explores the effectiveness of family literacy programs, examines the connection between the field of family literacy and learning disabilities (LD), and offers suggestions on how to work with students with…

  19. Family Privilege

    ERIC Educational Resources Information Center

    Seita, John R.

    2014-01-01

    Family privilege is defined as "strengths and supports gained through primary caring relationships." A generation ago, the typical family included two parents and a bevy of kids living under one roof. Now, every variation of blended caregiving qualifies as family. But over the long arc of human history, a real family was a…

  20. Cancerous leptomeningitis and familial congenital hypopituitarism.

    PubMed

    Vujovic, S; Vujosevic, S; Kavaric, S; Sopta, J; Ivovic, M; Saveanu, A; Brue, T; Korbonits, M; Popovic, V

    2016-05-01

    People are at higher risk of cancer as they get older or have a strong family history of cancer. The potential influence of environmental and behavioral factors remains poorly understood. Earlier population and case control studies reported that upper quartile of circulating IGF-I is associated with a higher risk of developing cancer suggesting possible involvement of the growth hormone (GH)/IGF system in initiation or progression of cancer. Since GH therapy increases IGF-1 levels, there have been concerns that GH therapy in hypopituitarism might increase the risk of cancer. We report a 42-year-old female patient who presented with subacute onset of symptoms of meningitis and with the absence of fever which resulted in death 70 days after the onset of symptoms. The patient together with her younger brother was diagnosed at the age of 5 years with familial congenital hypopituitarism, due to homozygous mutation c.150delA in PROP1 gene. Due to evolving hypopituitarism, she was replaced with thyroxine (from age 5), hydrocortisone (from age 13), GH (from age 13 until 17), and sex steroids in adolescence and adulthood. Her consanguineous family has a prominent history of malignant diseases. Six close relatives had malignant disease including her late maternal aunt with breast cancer. BRCA 1 and BRCA 2 mutational analysis in the patient's mother was negative. Histology after autopsy disclosed advanced ovarian cancer with multiple metastases to the brain, leptomeninges, lungs, heart, and adrenals. Low circulating IGF-1 did not seem to protect this patient from cancer initiation and progression in the context of strong family history of malignancies.

  1. Family Violence and Family Physicians

    PubMed Central

    Herbert, Carol P.

    1991-01-01

    The acronym IDEALS summarizes family physicians' obligations when violence is suspected: to identify family violence; document injuries; educate families and ensure safety for victims; access resources and coordinate care; co-operate in the legal process; and provide support for families. Failure to respond reflects personal and professional experience and attitudes, fear of legal involvement, and lack of knowledge. Risks of intervention include physician burnout, physician overfunctioning, escalation of violence, and family disruption. PMID:21228987

  2. Genetic analysis of Indian families with autosomal recessive retinitis pigmentosa by homozygosity screening.

    PubMed

    Singh, Hardeep Pal; Jalali, Subhadra; Narayanan, Raja; Kannabiran, Chitra

    2009-09-01

    To identify the disease-causing genes in families with autosomal recessive RP (ARRP). Families were screened for homozygosity at candidate gene loci followed by screening of the selected gene for pathogenic mutations if homozygosity was present at a given locus. A total of 34 families were included, of which 24 were consanguineous. Twenty-three genes were selected for screening. The presence of homozygosity was assessed by genotyping flanking microsatellite markers at each locus in affected individuals. Mutations were detected by sequencing of coding regions of genes. Sequence changes were tested for presence in 100 or more unrelated normal control subjects and for cosegregation in family members. Homozygosity was detected at one or more loci in affected individuals of 10 of 34 families. Homozygous disease cosegregating sequence changes (two frame-shift, two missense, and one nonsense; four novel) were found in the TULP1, RLBP1, ABCA4, RPE65, and RP1 genes in 5 of 10 families. These changes were absent in 100 normal control subjects. In addition, several polymorphisms and novel variants were found. All the putative pathogenic changes were associated with severe forms of RP with onset in childhood. Associated macular degeneration was found in three families with mutations in TULP1, ABCA4, and RP1 genes. Novel mutations were found in different ARRP genes. Mutations were detected in approximately 15% (5/34) of ARRP families tested, suggesting involvement of other genes in the remaining families.

  3. Family Life

    MedlinePlus

    ... Family and Friends Talking About Cancer Family Life Parenting While Living With Cancer How A Child Understands ... Learn more about how to get support for parenting while living with cancer . The importance of communication ...

  4. Family Violence

    MedlinePlus

    ... help. About Military OneSource Benefits Home and Family Finances Legal Issues Personal Financial Management and Taxes Taxes ... Surveys Site Map Categories Confidential Help Family & Relationships Finance & Legal Health & Wellness Education & Employment On & Off-Base ...

  5. Familial gigantism

    PubMed Central

    de Herder, Wouter W.

    2012-01-01

    Familial GH-secreting tumors are seen in association with three separate hereditary clinical syndromes: multiple endocrine neoplasia type 1, Carney complex, and familial isolated pituitary adenomas. PMID:22584702

  6. Family Support.

    ERIC Educational Resources Information Center

    Wieck, Colleen, Ed.; McBride, Marijo, Ed.

    1990-01-01

    This "Feature Issue" of the quarterly journal "Impact" presents 19 brief articles on family support systems in the United States for persons with developmental disabilities and their families. Emphasis is on provisions of Public Law 99-457. Articles include: "Family Support in the United States: Setting a Course for the…

  7. Family Matters.

    ERIC Educational Resources Information Center

    Featherstone, Joseph

    1979-01-01

    Emphasizing the family as the center of political/policy debates is the result of the tradition of romanticizing family virtues and a set of events ("the sixities"). Author sees the family emerging as a symbol in communal social policy development. Warns of dangers inherent in seeking private solutions to collective problems. (Author/CSS)

  8. Family Involvement.

    ERIC Educational Resources Information Center

    Liontos, Lynn Balster

    1992-01-01

    Family involvement in schools will work only when perceived as an enlarged concept focusing on all children, including those from at-risk families. Each publication reviewed here is specifically concerned with family involvement strategies concerned with all children or targeted at primarily high risk students. Susan McAllister Swap looks at three…

  9. Novel splice site mutation in CNNM4 gene in a family with Jalili syndrome.

    PubMed

    Cherkaoui Jaouad, Imane; Lyahyai, Jaber; Guaoua, Soukaina; El Alloussi, Mustapha; Zrhidri, Abdelali; Doubaj, Yassamine; Boulanouar, Abdelkrim; Sefiani, Abdelaziz

    2017-05-01

    Jalili syndrome is a rare autosomal recessive genetic disease characterized by the association of amelogenesis imperfecta and cone-rod retinal dystrophy. This syndrome is caused by mutations in the CNNM4 gene. Different types of CNNM4 mutations have been reported; missense, nonsense, large deletions, single base insertion, and duplication. We used Sanger sequencing to analyze a large consanguineous family with three siblings affected with Jalili syndrome, suspected clinically after dental and ophthalmological examination. These patients are carrying a novel homozygous mutation in the splice site acceptor of intron 3 (c.1682-1G > C) in the CNNM4 gene. We compare the findings of the present family to those from literature, in order to further delineate Jalili syndrome. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  10. A second family with autosomal recessive spondylometaphyseal dysplasia and early death.

    PubMed

    Mégarbané, André; Mehawej, Cybel; El Zahr, Amir; Haddad, Soha; Cormier-Daire, Valérie

    2014-04-01

    We report on a consanguineous Lebanese family in which two sibs had pre- and post-natal growth retardation, developmental delay, large anterior fontanel, prominent forehead, low-set ears, depressed nasal bridge, short nose, anteverted nares, increased nasal width, prominent abdomen, and short limbs. Radiographs disclosed the presence of wormian bones, platyspondyly, decreased interpedicular distance at the lumbar vertebrae, square iliac bones, horizontal acetabula, trident acetabula, hypoplastic ischia, partial agenesis of the sacrum, ribs with cupped ends, short long bones with abnormal modeling, slight widening of the distal femoral metaphyses, and delayed epiphyseal ossification. Both sibs had a severe cardiomegaly and died at around 24 months from a heart failure. Differential diagnosis suggests that this is a second family presenting a newly described early lethal chondrodysplasia first reported by [Mégarbané et al. (2008); Am J Med Genet Part A 146A:2916-2919].

  11. A functional interplay between the small GTPase Rab11a and mitochondria-shaping proteins regulates mitochondrial positioning and polarization of the actin cytoskeleton downstream of Src family kinases.

    PubMed

    Landry, Marie-Claude; Champagne, Claudia; Boulanger, Marie-Chloé; Jetté, Alexandra; Fuchs, Margit; Dziengelewski, Claire; Lavoie, Josée N

    2014-01-24

    It is believed that mitochondrial dynamics is coordinated with endosomal traffic rates during cytoskeletal remodeling, but the mechanisms involved are largely unknown. The adenovirus early region 4 ORF4 protein (E4orf4) subverts signaling by Src family kinases (SFK) to perturb cellular morphology, membrane traffic, and organellar dynamics and to trigger cell death. Using E4orf4 as a model, we uncovered a functional connection between mitochondria-shaping proteins and the small GTPase Rab11a, a key regulator of polarized transport via recycling endosomes. We found that E4orf4 induced dramatic changes in the morphology of mitochondria along with their mobilization at the vicinity of a polarized actin network typifying E4orf4 action, in a manner