Purpose: The aim of the study was to resolve the genetic etiology in families having inherited cataracts.
Methods: Families afflicted with congenital/childhood cataracts were registered in Chennai and Orissa (India). Blood samples were collected from the probands and available family members. Selected functional candidate genes were amplified by polymerase chain reaction (PCR) and characterized by direct sequencing. Putative mutations were confirmed in healthy controls.
Results: We observed interesting new polymorphisms of ethnic specificity, some of frequent nature, such as a 3-bp deletion in intron 3 of CRYBB2 (encoding βB2-crystallin) and IVS1+9 c>t variation in HSF4 (encoding heat-shock factor 4). Some rare single nucleotide polymorphisms (SNPs) co-segregate with the respective phenotype such as IVS3+120c>a of CRYBB2, while M44V of CRYGD (encoding γD-crystallin), although found in association with blue dot opacity was seen in a few healthy controls too. We identified two new mutations co-segregating along with the respective cataract phenotype within the families that were not seen in healthy controls from India or Germany. These include two missense mutations; one in GJA3 (encoding gap junction protein α3, which is also referred to as connexin 46); the mutation affects codon 19 (T19M), and the corresponding phenotype is a posterior-polar cataract. The other missense mutation affects CRYBB2 (W59C; total cataract). Additionally, a cDNA variation (G54A) identified in a zonular cataract affects a highly conserved splice site of CRYBB2. This mutation, however, showed reduced penetrance in the family, which might be explained by different molecular consequences in the affected family members: nonsense-mediated decay of the mutated mRNA might have no clinical phenotype in heterozygotes, whereas the translation of the mutated mRNA is predicted to lead to a small hybrid protein (consisting of 16 amino acids of the βB2-crystallin and 18 new amino-acids), which might have a dominant-negative function in the lens.
Conclusions: This report identifies in families with childhood cataract some new alleles, which may be considered as causative for cataracts. Furthermore, we report some geographically restricted rare polymorphic sites, whose significance might be considered in some context as modifiers or alleles in sensitizing ocular lens toward cataractogenesis.