Abstract
Congenital cataract is a clinically and genetically heterogeneous disease. The present study was undertaken to find the genetic cause of congenital cataract families. DNA samples of a large consanguineous Pakistani family were genotyped with a high resolution single nucleotide polymorphism Illumina microarray. Homozygosity mapping identified a homozygous region of 4.4 Mb encompassing the gene GJA3. Sanger sequence analysis of the GJA3 gene revealed a novel homozygous variant c.950dup p.(His318ProfsX8) segregating in an autosomal recessive (AR) manner. The previously known mode of inheritance for GJA3 gene mutations in cataract was autosomal dominant (AD) only. The screening of additional probands (n = 41) of cataract families revealed a previously known mutation c.56C>T p.(Thr19Met) in GJA3 gene. In addition, sequencing of the exon-intron boundaries of the GJA8 gene in 41 cataract probands revealed two additional mutations: a novel c.53C>T p.(Ser18Phe) and a known c.175C>G p.(Pro59Ala) mutation, both co-segregating with the disease phenotype in an AD manner. All these mutations are predicted to be pathogenic by in silico analysis and were absent in the control databases. In conclusion, results of the current study enhance our understanding of the genetic basis of cataract, and identified the involvement of the GJA3 in the disease etiology in both AR and AD manners.
Highlights
Congenital cataract is the leading cause of visual impairment and blindness worldwide during infancy and early childhood
Multiple genes have been implicated in cataract [13]
We have focused on gap junction alpha 3 (GJA3) and GJA8 underlying human cataract frequent mutations in these genes explaining about 25%
Summary
Congenital cataract is the leading cause of visual impairment and blindness worldwide during infancy and early childhood. Worldwide estimates show that approximately 200,000 children every year are affected by lifelong vision impairment due to cataract [2]. Early diagnosis is very important to treat the disease by surgically removing the visually significant cataracts and to achieve good vision. In the homozygous region encompassing gap junction alpha 3 (GJA3) gene in a Pakistani family with a recessively inherited congenital cataract. Sequencing of GJA3 and GJA8 genes in 41 congenital cataract probands revealed one known mutation in GJA3 gene inherited dominantly and two mutations in GJA8 gene (one novel and one known) segregating in an autosomal dominant fashion in cataract families
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