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Initiation codon mutation in betaB1-crystallin (CRYBB1) associated with autosomal recessive nuclear pulverulent cataract.

ABSTRACT: PURPOSE:To identify the molecular basis for autosomal recessively inherited congenital non-syndromic pulverulent cataracts in a consanguineous family with four affected children. METHODS:An autozygosity mapping strategy using high density SNP microarrays and microsatellite markers was employed to detect regions of homozygosity. Subsequently good candidate genes were screened for mutations by direct sequencing. RESULTS:The SNP microarray data demonstrated a 24.96 Mb region of homozygosity at 22q11.21-22q13.2 which was confirmed by microsatellite marker analysis. The candidate target region contained the beta-crystallin gene cluster and direct sequencing in affected family members revealed a novel mutation in CRYBB1 (c.2T>A; p.Met1Lys). CONCLUSIONS:To our knowledge this is the first case of an initiation codon mutation in a human crystallin gene, and only the second report of a CRYBB1 mutation associated with autosomal recessive congenital cataracts. In addition, although a number of genetic causes of autosomal dominant pulverulent cataracts have been identified (including CRYBB1) this is the first gene to have been implicated in autosomal recessive nuclear pulverulent cataract.

SUBMITTER: Meyer E

PROVIDER: S-EPMC2684559 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Initiation codon mutation in betaB1-crystallin (CRYBB1) associated with autosomal recessive nuclear pulverulent cataract.

Meyer Esther E Rahman Fatimah F Owens Jessica J Pasha Shanaz S Morgan Neil V NV Trembath Richard C RC Stone Edwin M EM Moore Anthony T AT Maher Eamonn R ER

Molecular vision 20090518

<h4>Purpose</h4>To identify the molecular basis for autosomal recessively inherited congenital non-syndromic pulverulent cataracts in a consanguineous family with four affected children.<h4>Methods</h4>An autozygosity mapping strategy using high density SNP microarrays and microsatellite markers was employed to detect regions of homozygosity. Subsequently good candidate genes were screened for mutations by direct sequencing.<h4>Results</h4>The SNP microarray data demonstrated a 24.96 Mb region o ...[more]

PMID: 19461930

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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

Initiation codon mutation in betaB1-crystallin (CRYBB1) associated with autosomal recessive nuclear pulverulent cataract.

Publications

Initiation codon mutation in betaB1-crystallin (CRYBB1) associated with autosomal recessive nuclear pulverulent cataract.

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