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A splice site mutation in CRYBA1/A3 causing autosomal dominant posterior polar cataract in a Chinese pedigree.

ABSTRACT: PURPOSE: To identify the mutant gene for autosomal dominant posterior polar congenital cataract in a four-generation Chinese pedigree. METHODS: The clinical data of patients from the family were recorded by slit-lamp photography. Genomic DNA samples from peripheral blood of the pedigree members were then isolated to map the relevant gene, using microsatellite markers for two-point linkage analysis. Genotype and haplotypes of the pedigree were constructed using Cyrillic software to locate the relevant region. Direct sequencing was performed to screen out the disease-causing mutation. RESULTS: The congenital cataract phenotype of the pedigree was labeled as the posterior polar type by using slit-lamp photography. Linkage analysis results indicated a maximum logarithm of odds LOD score of (Z(max)) 2.02 at D17S1800 (theta(max)=0.00). Haplotyping identified a 26-cM region flanked by D17S921 and D17S800 on 17p12-21.2, namely at the betaA1/A3-crystallin (CRYBA1/A3) gene locus. Sequencing revealed a splice site mutation, G-->A, at the first base of intron 3 of CRYBA1/A3, which co-segregated with the affected individuals in the pedigree but which was not found in the unaffected members of the family or in the 50 unrelated controls. CONCLUSIONS: Our results demonstrated that a splice site mutation of CRYBA1/A3 was responsible for the autosomal dominant posterior polar congenital cataract in a four-generation Chinese pedigree. The same mutation in this gene had previously been reported to be associated with other phenotype cataracts. This study is the first report relating a mutation of CRYBA1/A3 to posterior polar cataract.

SUBMITTER: Gu Z

PROVIDER: S-EPMC2817011 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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A splice site mutation in CRYBA1/A3 causing autosomal dominant posterior polar cataract in a Chinese pedigree.

Gu Zhensheng Z Ji Baohu B Wan Chunling C He Guang G Zhang Juan J Zhang Ming M Feng Guoyin G He Lin L Gao Linghan L

Molecular vision 20100205

<h4>Purpose</h4>To identify the mutant gene for autosomal dominant posterior polar congenital cataract in a four-generation Chinese pedigree.<h4>Methods</h4>The clinical data of patients from the family were recorded by slit-lamp photography. Genomic DNA samples from peripheral blood of the pedigree members were then isolated to map the relevant gene, using microsatellite markers for two-point linkage analysis. Genotype and haplotypes of the pedigree were constructed using Cyrillic software to l ...[more]

PMID: 20142846

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Project description:PURPOSE: To identify the underlying genetic defect in a north Indian family with seven members in three-generations affected with bilateral congenital cataract. METHODS: Detailed family history and clinical data were recorded. Linkage analysis using fluorescently labeled microsatellite markers for the already known candidate gene loci was performed in combination with mutation screening by bidirectional sequencing. RESULTS: Affected individuals had bilateral congenital cataract. Cataract was of opalescent type with the central nuclear region denser than the periphery. Linkage was excluded for the known cataract candidate gene loci at 1p34-36, 1q21-25 (gap junction protein, alpha 8 [GJA8]), 2q33-36 (crystallin, gamma A [CRYGA], crystallin, gamma B [CRYGB], crystallin, gamma C [CRYGC], crystallin, gamma D [CRYGD], crystallin, beta A2 [CRYBA2]), 3q21-22 (beaded filament structural protein 2, phakinin [BFSP2]), 12q12-14 (aquaporin 0 [AQP0]), 13q11-13 (gap junction protein, alpha 3 [GJA3]), 15q21-22, 16q22-23 (v-maf musculoaponeurotic fibrosarcoma oncogene homolog [MAF], heat shock transcription factor 4 [HSF4]), 17q11-12 (crystallin, beta A1 [CRYBA1]), 17q24, 21q22.3 (crystallin, alpha A [CRYAA]), and 22q11.2 (crystallin, beta B1 [CRYBB1], crystallin, beta B2 [CRYBB2], crystallin, beta B3 [CRYBB3], crystallin, beta A4 [CRYBA4]). Crystallin, alpha B (CRYAB) at chromosome 11q23-24 was excluded by sequence analysis. However, sequencing the candidate gene, crystallin, gamma S (CRYGS), at chromosome 3q26.3-qter showed a heterozygous c.176G-->A change that resulted in the replacement of a structurally highly conserved valine by methionine at codon 42 (p.V42M). This sequence change was not observed in unaffected family members or in the 100 ethnically matched controls. CONCLUSIONS: We report a novel missense mutation, p.V42M, in CRYGS associated with bilateral congenital cataract in a family of Indian origin. This is the third report of a mutation in this exceptional member of the beta-/gamma-crystallin superfamily and further substantiates the genetic and clinical heterogeneity of autosomal dominant cataract.

Dataset Information

A splice site mutation in CRYBA1/A3 causing autosomal dominant posterior polar cataract in a Chinese pedigree.

Publications

A splice site mutation in CRYBA1/A3 causing autosomal dominant posterior polar cataract in a Chinese pedigree.

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