A substitution of arginine to lysine at the COOH-terminus of MIP caused a different binocular phenotype in a congenital cataract family.

PURPOSE: To detect the cataractogenetic mutation for a six-generation family of Chinese origin with autosomal dominant binocular polymorphic cataracts.

METHODS

A genome wide scan was performed using 382 fluorescent-labeled microsatellite markers. Multiple polymerase chain reaction (PCR) was performed according to the protocols previously described. Two-point linkage analysis was performed with the FASTLINK version of the MLINK in Linkage Program Package. The candidate gene was screened by direct sequencing.

RESULTS

The disease locus was mapped to a 61 cM region on chromosome 12 defined by D12S310 and D12S351 near the major intrinsic protein gene (MIP). The maximum two-point lod score of 5.44 was obtained at marker D12S83 at theta=0.00. Direct sequencing of the encoding region of the candidate gene revealed a novel missense mutation G>A in exon 4 at nucleotide 702, which caused the replacement of arginine to lysine at codon 233 (p.R233K).

CONCLUSIONS

The change located in the alpha-helix domain of the COOH-terminus of MIP was determined to be associated with the binocular polymorphic cataract in this study. It suggests that arginine in this domain plays a crucial role in the function of the carboxyl-end of this protein and provides a helpful clue to further studies on completely understanding the physiological significance of MIP and its role in the formation of cataract.