A novel GJA8 mutation in an Iranian family with progressive autosomal dominant congenital nuclear cataract

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THE AUTHORS DESCRIBE THE MOLECULAR CHARACTERization of an Iranian family with an autosomal dominant progressive congenital nuclear cataract. Affected members were found to have a novel heterozygous missense mutation R23T in the GJA8 gene encoding connexin 50 (Cx50). This sequence change segregated with the disease phenotype in the family and was not found in 152 control individuals, including 52 ethnically matched controls. This non-conservative mutation replaces an evolutionary conserved basic polar charged amino acid by an uncharged polar amino acid at position 23 in the amino-terminus of Cx50. The R32T mutation may result in failure to forma normal gap junctions (loss of function mutation) or alter the function of endogenous wild-type connexins (dominant negative mutation). In this family, there was a novel progressive phenotype mimicking an early onset age related nuclear cataract. Three heterozygous missense Cx50 mutations (P88S, E48K, and 1247M) have been described in three geographically distinct families with zonular pulverulent or zonular nuclear congenital cataracts. The mutational screening of a population of patients with congenital cataract (n = 37) and another with age related cataract (n = 44) failed to show any contribution of the four known Cx50 mutations.—Hans E. Grossniklaus