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A Common Ancestral Mutation in CRYBB3 Identified in Multiple Consanguineous Families with Congenital Cataracts
PURPOSE: This study was performed to investigate the genetic determinants of autosomal recessive congenital cataracts in large consanguineous families. METHODS: Affected individuals underwent a detailed ophthalmological examination and slit-lamp photographs of the cataractous lenses were obtained. A...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4915718/ https://www.ncbi.nlm.nih.gov/pubmed/27326458 http://dx.doi.org/10.1371/journal.pone.0157005 |
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author | Jiao, Xiaodong Kabir, Firoz Irum, Bushra Khan, Arif O. Wang, Qiwei Li, David Khan, Asma A. Husnain, Tayyab Akram, Javed Riazuddin, Sheikh Hejtmancik, J. Fielding Riazuddin, S. Amer |
author_facet | Jiao, Xiaodong Kabir, Firoz Irum, Bushra Khan, Arif O. Wang, Qiwei Li, David Khan, Asma A. Husnain, Tayyab Akram, Javed Riazuddin, Sheikh Hejtmancik, J. Fielding Riazuddin, S. Amer |
author_sort | Jiao, Xiaodong |
collection | PubMed |
description | PURPOSE: This study was performed to investigate the genetic determinants of autosomal recessive congenital cataracts in large consanguineous families. METHODS: Affected individuals underwent a detailed ophthalmological examination and slit-lamp photographs of the cataractous lenses were obtained. An aliquot of blood was collected from all participating family members and genomic DNA was extracted from white blood cells. Initially, a genome-wide scan was performed with genomic DNAs of family PKCC025 followed by exclusion analysis of our familial cohort of congenital cataracts. Protein-coding exons of CRYBB1, CRYBB2, CRYBB3, and CRYBA4 were sequenced bidirectionally. A haplotype was constructed with SNPs flanking the causal mutation for affected individuals in all four families, while the probability that the four familial cases have a common founder was estimated using EM and CHM-based algorithms. The expression of Crybb3 in the developing murine lens was investigated using TaqMan assays. RESULTS: The clinical and ophthalmological examinations suggested that all affected individuals had nuclear cataracts. Genome-wide linkage analysis localized the causal phenotype in family PKCC025 to chromosome 22q with statistically significant two-point logarithm of odds (LOD) scores. Subsequently, we localized three additional families, PKCC063, PKCC131, and PKCC168 to chromosome 22q. Bidirectional Sanger sequencing identified a missense variation: c.493G>C (p.Gly165Arg) in CRYBB3 that segregated with the disease phenotype in all four familial cases. This variation was not found in ethnically matched control chromosomes, the NHLBI exome variant server, or the 1000 Genomes or dbSNP databases. Interestingly, all four families harbor a unique disease haplotype that strongly suggests a common founder of the causal mutation (p<1.64E-10). We observed expression of Crybb3 in the mouse lens as early as embryonic day 15 (E15), and expression remained relatively steady throughout development. CONCLUSION: Here, we report a common ancestral mutation in CRYBB3 associated with autosomal recessive congenital cataracts identified in four familial cases of Pakistani origin. |
format | Online Article Text |
id | pubmed-4915718 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-49157182016-07-06 A Common Ancestral Mutation in CRYBB3 Identified in Multiple Consanguineous Families with Congenital Cataracts Jiao, Xiaodong Kabir, Firoz Irum, Bushra Khan, Arif O. Wang, Qiwei Li, David Khan, Asma A. Husnain, Tayyab Akram, Javed Riazuddin, Sheikh Hejtmancik, J. Fielding Riazuddin, S. Amer PLoS One Research Article PURPOSE: This study was performed to investigate the genetic determinants of autosomal recessive congenital cataracts in large consanguineous families. METHODS: Affected individuals underwent a detailed ophthalmological examination and slit-lamp photographs of the cataractous lenses were obtained. An aliquot of blood was collected from all participating family members and genomic DNA was extracted from white blood cells. Initially, a genome-wide scan was performed with genomic DNAs of family PKCC025 followed by exclusion analysis of our familial cohort of congenital cataracts. Protein-coding exons of CRYBB1, CRYBB2, CRYBB3, and CRYBA4 were sequenced bidirectionally. A haplotype was constructed with SNPs flanking the causal mutation for affected individuals in all four families, while the probability that the four familial cases have a common founder was estimated using EM and CHM-based algorithms. The expression of Crybb3 in the developing murine lens was investigated using TaqMan assays. RESULTS: The clinical and ophthalmological examinations suggested that all affected individuals had nuclear cataracts. Genome-wide linkage analysis localized the causal phenotype in family PKCC025 to chromosome 22q with statistically significant two-point logarithm of odds (LOD) scores. Subsequently, we localized three additional families, PKCC063, PKCC131, and PKCC168 to chromosome 22q. Bidirectional Sanger sequencing identified a missense variation: c.493G>C (p.Gly165Arg) in CRYBB3 that segregated with the disease phenotype in all four familial cases. This variation was not found in ethnically matched control chromosomes, the NHLBI exome variant server, or the 1000 Genomes or dbSNP databases. Interestingly, all four families harbor a unique disease haplotype that strongly suggests a common founder of the causal mutation (p<1.64E-10). We observed expression of Crybb3 in the mouse lens as early as embryonic day 15 (E15), and expression remained relatively steady throughout development. CONCLUSION: Here, we report a common ancestral mutation in CRYBB3 associated with autosomal recessive congenital cataracts identified in four familial cases of Pakistani origin. Public Library of Science 2016-06-21 /pmc/articles/PMC4915718/ /pubmed/27326458 http://dx.doi.org/10.1371/journal.pone.0157005 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication. |
spellingShingle | Research Article Jiao, Xiaodong Kabir, Firoz Irum, Bushra Khan, Arif O. Wang, Qiwei Li, David Khan, Asma A. Husnain, Tayyab Akram, Javed Riazuddin, Sheikh Hejtmancik, J. Fielding Riazuddin, S. Amer A Common Ancestral Mutation in CRYBB3 Identified in Multiple Consanguineous Families with Congenital Cataracts |
title | A Common Ancestral Mutation in CRYBB3 Identified in Multiple Consanguineous Families with Congenital Cataracts |
title_full | A Common Ancestral Mutation in CRYBB3 Identified in Multiple Consanguineous Families with Congenital Cataracts |
title_fullStr | A Common Ancestral Mutation in CRYBB3 Identified in Multiple Consanguineous Families with Congenital Cataracts |
title_full_unstemmed | A Common Ancestral Mutation in CRYBB3 Identified in Multiple Consanguineous Families with Congenital Cataracts |
title_short | A Common Ancestral Mutation in CRYBB3 Identified in Multiple Consanguineous Families with Congenital Cataracts |
title_sort | common ancestral mutation in crybb3 identified in multiple consanguineous families with congenital cataracts |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4915718/ https://www.ncbi.nlm.nih.gov/pubmed/27326458 http://dx.doi.org/10.1371/journal.pone.0157005 |
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