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Mutation Analysis of Congenital Cataracts in Indian Families: Identification of SNPs and a New Causative Allele in CRYBB2 Gene

¹From the Dr. ALM Postgraduate Institute of Basic Medical Sciences, Department of Genetics, University of Madras, Taramani, Chennai, India; ²Center for BioTechnology, Anna University, Chennai, India; ⁴Aravind Eye Hospital and Postgraduate Institute of Ophthalmology, Madurai, India; and Institutes of ⁵Experimental and ⁶Developmental Genetics, GSF-National Research Center for Environment and Health, Neuherberg, Germany.

PURPOSE. To study some functional candidate genes in cataract families of Indian descent.

METHODS. Nine Indian families, clinically documented to have congenital/childhood cataracts, were screened for mutations in candidate genes such as CRYG (AD), CRYBB2, and GJA8 by PCR analyses and sequencing. Genomic DNA samples of either probands or any representative affected member of each family were PCR amplified and sequenced commercially. Documentation of single nucleotide polymorphisms (SNPs) and candidate mutations was done through BLAST SEARCH (http://www.ncbi.nlm.nih.gov/blast/Blast.cgi?).

RESULTS. Several single nucleotide polymorphisms in CRYG, CRYBB2, and GJA8 genes were observed. Because they do not co-segregate with the phenotype, they were excluded as candidates for the cataract formation in these patients. However, a substitution (W151C in exon 6 of CRYBB2) was identified as the most likely causative mutation underlying the phenotype of central nuclear cataract in all affected members of family C176. Protein structural interpretations demonstrated that no major structural alterations could be predicted and that even the hydrogen bonds to the neighboring Leu166 were unchanged. Surprisingly, hydropathy analysis of the mutant ßB2-crystallin featuring the amino acids at position 147 to 155, further increased the hydrophobicity, which might impair the solubility of the mutant protein. Finally, the Cys residue at position 151 might possibly be involved in intramolecular disulphide bridges with other cysteines during translation, possibly leading to dramatic structural changes.

CONCLUSIONS. Exon 6 of CRYBB2 appears to be a critical region susceptible for mutations leading to lens opacity.

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