A Novel GJB Mutation Causes Progressive Autosomal Dominant Congenital Cataracts in an Iranian Family

Abstract

Abstract: : Purpose: To determine the molecular basis of the cataract phenotype in a four generation pedigree with autosomal dominant progressive congenital nuclear cataracts. Methods: Forty-one family members (14 affected and 27 unaffected) had a full ocular assessment. The affected status (presence of cataracts) was determined prior to the genetic analysis. A panel of candidate loci was selected for preliminary linkage analysis. PCR-based genotyping of microsatellite markers was performed on a Pharmacia automated sequencer. Two-point linkage analysis used the MLINK program of the LINKAGE package v5.2.Results: Nuclear cataracts were present at birth and progressed to cause visual impairment in the second decade. Participants had cataract surgery because of a dense nuclear (fetal/ embryonal) cataract. Postoperatively, good visual function was obtained, with absence of nystagmus or amblyopia. By haplotype analysis using markers on chromosome 1, a 9cM region segregated with the disease phenotype. Linkage analysis gave a maximum two-point LOD score of 2.62 for marker D1S514 (theta = 0.05) . This was the region of GJB8, a gene encoding connexin 50 (Cx50). Direct sequencing of the coding sequence Cx50 in two affected and one unaffected individuals showed a heterozygous 68G to C change resulting in an arginine (R) to threonine (T) amino acid substitution. The non-conservative R23T mutation replaces a basic polar charged amino acid by an uncharged polar one at position 23 immediately adjacent to the initial amino acid of the first transmembrane domain. The sequence alteration segregated with the phenotype of all family members and was not seen in 100 control individuals of mixed ethnicity and 52 ethnically matched controls.Conclusions: Three heterozygous missense Cx50 mutations Cx50 (P88S, E48K and 247) have previously been described in three geographically distinct families with zonular pulverulent or zonular nuclear congenital cataracts. Here we report a novel heterozygous R23T mutation in the GJB8 gene encoding connexin 50 (Cx50) in an Iranian family causing a progresssive autosomal dominant congenital nuclear cataract.

Keywords: cataract • genetics • mutations