A common ancestral mutation in CRYBB3 identified in multiple consanguineous pedigrees with congenital cataracts

Abstract

Purpose: To investigate the genetic basis of autosomal recessive congenital cataracts in four large consanguineous pedigrees.

Methods: Affected individuals underwent a detailed ophthalmological and clinical examination and slit-lamp photographs were ascertained from the affected individuals if the cataractous lens was not operated upon yet. Blood samples were collected and genomic DNA was extracted. A genome wide scan was performed with short tandem repeat (STR) microsatellite markers and logarithm of odds (LOD) scores were calculated. Protein coding exons and exon-intron boundaries of CRYBB1, CRYBB2, CRYB3 and CRYBA4 were sequenced, bidirectionally, and expression of Crybb1, Crybb2, and Crybb3 in embryonic and postnatal mouse lens was investigated with Taqman probes. The disease haplotype was constructed with SNPs flanking the causal mutation.

Results: The clinical and ophthalmological examinations suggested that all affected individuals have nuclear cataracts. Genome-wide linkage analyses suggested a potential region on chromosome 22 harboring a cluster of four crystalline genes. DNA sequencing identified a missense variation: c.493G>C (p.G165R) in CRYBB3 that segregated with disease phenotype in the family. Subsequent interrogation of our entire cohort of familial cases identified three additional families localized to chromosome 22q harboring the c.493G>C (p.G165R) mutation. Interestingly, all four families harbor a common SNP haplotype that suggests individuals in these four families inherited the causal variant from a common ancestor.

Conclusions: Here, we report a common ancestral mutation in CRYBB3 associated with autosomal recessive congenital cataracts identified in four familial cases of Pakistani origin.