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Migdal Ha‘Emeq, Israel

Romi H.,Ben - Gurion University of the Negev | Cohen I.,Ben - Gurion University of the Negev | Landau D.,Soroka Medical Center | Alkrinawi S.,Soroka Medical Center | And 8 more authors.
American Journal of Human Genetics

Meconium ileus, intestinal obstruction in the newborn, is caused in most cases by CFTR mutations modulated by yet-unidentified modifier genes. We now show that in two unrelated consanguineous Bedouin kindreds, an autosomal-recessive phenotype of meconium ileus that is not associated with cystic fibrosis (CF) is caused by different homozygous mutations in GUCY2C, leading to a dramatic reduction or fully abrogating the enzymatic activity of the encoded guanlyl cyclase 2C. GUCY2C is a transmembrane receptor whose extracellular domain is activated by either the endogenous ligands, guanylin and related peptide uroguanylin, or by an external ligand, Escherichia coli (E. coli) heat-stable enterotoxin STa. GUCY2C is expressed in the human intestine, and the encoded protein activates the CFTR protein through local generation of cGMP. Thus, GUCY2C is a likely candidate modifier of the meconium ileus phenotype in CF. Because GUCY2C heterozygous and homozygous mutant mice are resistant to E. coli STa enterotoxin-induced diarrhea, it is plausible that GUCY2C mutations in the desert-dwelling Bedouin kindred are of selective advantage. © 2012 by The American Society of Human Genetics. All rights reserved. Source

Nevet M.J.,Technion - Israel Institute of Technology | Shalev S.A.,Genetics Institute | Zlotogora J.,Hebrew University of Jerusalem | Mazzawi N.,ek Medical Center | Ben-Yosef T.,Technion - Israel Institute of Technology
Journal of Medical Genetics

Background: Retinitis pigmentosa (RP) is the most common form of hereditary retinal degeneration. At least 32 genes and loci have been implicated in non-syndromic autosomal recessive RP. Progressive rodecone degeneration is a canine form of autosomal recessive retinal degeneration, which serves as an animal model for human RP, and is caused by a missense mutation of the PRCD gene. The same homozygous PRCD mutation has been previously identified in a single human RP patient from Bangladesh. To date, this is the only RP-causing mutation of PRCD reported in humans. Methods: The cause of the high incidence rate of autosomal recessive RP in an isolated Muslim Arab village in Northern Israel was investigated by haplotype analysis in affected families. The underlying mutation was detected by direct sequencing of the causative gene, and its prevalence in affected and unaffected individuals from the village was determined. Patients who were homozygotes for this mutation underwent ophthalmic evaluation, including funduscopy and electroretinography. Results and conclusions: The identification of a novel pathogenic nonsense mutation of PRCD is reported. This founder mutation was found in a homozygous state in 18 patients from nine families, and its carrier frequency in the investigated village is 10%. The mutation is associated with a typical RP phenotype, including bone spicule-type pigment deposits and non-recordable electroretinograms. Additional findings include signs of macular degeneration and cataract. The identification of a second pathogenic mutation of PRCD in multiple RP patients confirms the role of PRCD in the aetiology of RP in humans. Source

Markus B.,Ben - Gurion University of the Negev | Narkis G.,Ben - Gurion University of the Negev | Landau D.,Ben - Gurion University of the Negev | Landau D.,Soroka Medical Center | And 4 more authors.
Human Mutation

Autosomal recessive lethal congenital contractural syndrome (LCCS) is a severe form of neuromuscular arthrogryposis. We previously showed that this phenotype is caused in two unrelated inbred Bedouin tribes by different defects in the phosphatidylinositol pathway. However, the molecular basis of the same phenotype in other tribes remained elusive. Whole exome sequencing identified a novel LCCS founder mutation within a minimal shared homozygosity locus of approximately 1Mb in two affected individuals of different tribes: a homozygous premature stop producing mutation in MYBPC1, encoding myosin-binding protein C, slow type. A dominant missense mutation in MYBPC1 was previously shown to cause mild distal arthrogryposis. We now show that a recessive mutation abrogating all functional domains in the same gene leads to LCCS. © 2012 Wiley Periodicals, Inc. Source

Dvir L.,Rappaport Family Institute for Research in the Medical science | Dvir L.,Technion - Israel Institute of Technology | Srour G.,Clalit | Abu-Ras R.,Clalit | And 6 more authors.
American Journal of Human Genetics

Retinitis pigmentosa (RP) is the most common form of hereditary retinal degeneration, with a worldwide prevalence of 1 in 4000. Over 30 genes and loci have been implicated in nonsyndromic autosomal-recessive (ar) RP. Genome-wide homozygosity mapping was conducted in two sibships from an extended consanguineous Muslim Arab Israeli family segregating ar severe early-onset RP. A shared homozygous region on chromosome 17q25.3 was identified in both sibships, with an overlap of 4.7 Mb. One of the genes located in this interval is PDE6G, encoding for the inhibitory γ subunit of rod photoreceptor cyclic GMP-phosphodiesterase. Mutations in the genes encoding for the catalytic subunits of this holoenzyme, PDE6A and PDE6B, cause arRP. Sequencing of all coding exons, including exon-intron boundaries, revealed a homozygous single base change (c.187+1G>T) located in the conserved intron 3 donor splice site of PDE6G. This mutation cosegregated with the disease in the extended family. We used an in vitro splicing assay to demonstrate that this mutation leads to incorrect splicing. Affected individuals had markedly constricted visual fields. Both scotopic and photopic electroretinograms were severely reduced or completely extinct. Funduscopy showed typical bone spicule-type pigment deposits spread mainly at the midperiphery, as well as pallor of the optic disk. Macular involvement was indicated by the lack of foveal reflex and typical cystoid macular edema, proved by optical coherence tomography. These findings demonstrate the positive role of the γ subunit in maintaining phosphodiesterase activity and confirm the contribution of PDE6G to the etiology of RP in humans. © 2010 The American Society of Human Genetics. Source

Sagi-Dain L.,Carmel Medical Center | Sagi-Dain L.,Genetics Institute | Sagi S.,Bnai Zion Medical Center
Obstetrical and Gynecological Survey

Importance: Shoulder dystocia is an obstetric emergency with potential catastrophic outcomes. Objective: To perform a systematic literature review examining the effectiveness of episiotomy in the prevention and management of shoulder dystocia during vaginal birth. Evidence Acquisition: Search was conducted by a research librarian in MEDLINE, Web of Science, Cochrane Library, and SCOPUS databases using the terms "episiotomy" and "shoulder dystocia," with no language or time restrictions. Two investigators independently selected original researches examining the effects of episiotomy on shoulder dystocia and its neonatal andmaternal outcomes. Relevant articles were accessed in full text, including manual search of the references. We contacted authors of studies with insufficient or unclear data. Because of clinical and methodological diversity of the studies, meta-analysis was not performed. Results: Fourteen articles met the inclusion criteria, encompassing a total of 9769 shoulder dystocia cases. Only 1 study effectively evaluated the role of episiotomy in shoulder dystocia prevention, yielding a nonsignificant result. Three articles assessed neonatal consequences of shoulder dystocia, one of them linking episiotomy to higher risk of neonatal injury. Two of the 3 studies evaluating maternal outcomes showed that episiotomy is related to increased risk of advanced perineal tears. Overall quality of evidence was rated as very low. Conclusions and Relevance: Our systematic review found no evidence supporting the use of episiotomy in the prevention and management of shoulder dystocia. This observation carries major clinical and legal implications for the obstetricians. Higher-quality studies are needed to evaluate this important issue. Target Audience: Obstetricians and gynecologists, family physicians Learning Objectives: After completion of this educational activity, the reader will be better able to analyze the paucity of existing literature examining the role of episiotomy in the prevention and management of shoulder dystocia, discuss the crucial issues in exploring the subject including uniform definition of shoulder dystocia and the report of episiotomy timing, and assess the knowledge needed to determine whether to perform episiotomy in deliveries with increased risk of shoulder dystocia, such as in cases of macrosomic fetus. © 2015 Wolters Kluwer Health, Inc. Source

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