| [PMID]: | 27326458 |
| [Au] Autor: | Jiao X; Kabir F; Irum B; Khan AO; Wang Q; Li D; Khan AA; Husnain T; Akram J; Riazuddin S; Hejtmancik JF; Riazuddin SA |
| [Ad] Endereço: | Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, United States of America. |
| [Ti] Título: | A Common Ancestral Mutation in CRYBB3 Identified in Multiple Consanguineous Families with Congenital Cataracts. |
| [So] Source: | PLoS One;11(6):e0157005, 2016. |
| [Is] ISSN: | 1932-6203 |
| [Cp] País de publicação: | United States |
| [La] Idioma: | eng |
| [Ab] Resumo: | 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. |
| [Mh] Termos MeSH primário: |
Catarata/congênito
Catarata/genética
Consanguinidade
Mutação/genética
Cadeia B de beta-Cristalina/genética
|
| [Mh] Termos MeSH secundário: |
Animais
Sequência de Bases
Cromossomos Humanos Par 22/genética
Família
Feminino
Perfilação da Expressão Gênica
Marcadores Genéticos
Haplótipos/genética
Seres Humanos
Cristalino/embriologia
Cristalino/metabolismo
Escore Lod
Masculino
Camundongos
Repetições de Microssatélites/genética
Linhagem
Polimorfismo de Nucleotídeo Único/genética
Lâmpada de Fenda
|
| [Pt] Tipo de publicação: | JOURNAL ARTICLE |
[Nm] Nome de substância:
| 0 (CRYBB3 protein, human); 0 (Genetic Markers); 0 (beta-Crystallin B Chain) |
| [Em] Mês de entrada: | 1707 |
| [Cu] Atualização por classe: | 170719 |
[Lr] Data última revisão:
| 170719 |
| [Sb] Subgrupo de revista: | IM |
| [Da] Data de entrada para processamento: | 160622 |
| [St] Status: | MEDLINE |
| [do] DOI: | 10.1371/journal.pone.0157005 |
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