A novel "pearl box" cataract associated with a mutation in the connexin 46 (GJA3) gene

PURPOSE: To undertake mutation screening in the connexin 46 (GJA3) gene in seven congenital cataract families of Indian origin. METHODS: Seven Indian families with congenital cataract were analyzed by detailed family history and clinical evaluation. Each family had two to five affected members. Mutation screening was carried out in the candidate gene, connexin 46 (GJA3), using bidirectional sequencing of amplified products. Segregation of the observed change with the disease phenotype was further tested by restriction fragment length polymorphism (RFLP). RESULTS: Sequencing of the coding region of GJA3 showed the presence of a novel, heterozygous C260T change in one family (CC-472) who had two affected members. The cataract phenotype gave the appearance like a "pearl box" in these two affected individuals of this family. The observed C260T substitution created a novel restriction enzyme site for NlaIII and resulted in substitution of highly conserved threonine at position 87 by methionine (T87M). NlaIII restriction digestion analysis revealed this nucleotide change was not in unaffected members of this family or in 100 unrelated control subjects (200 chromosomes) with the same ethnic background. CONCLUSIONS: This is a novel mutation identified in the second transmembrane domain of the connexin 46. These findings thus expand the mutation spectrum of the GJA3 in association with congenital cataract.