3 MURINE CATARACT MUTANTS (CAT2) ARE DEFECTIVE IN DIFFERENT GAMMA-CRYSTALLIN GENES

A number of murine cataract mutations have been localized to chromosom e 1 close to the gamma-crystallin gene cluster (Cryg) (Everett ct at., 1994, Genomics 20: 429-434; Loster et al., 1994, Genomics 23: 240-242 ). Based on the size of the mapping or allelism tests they have not be en shown to be genetically distinct and have been assigned to locus sy mbol Cat2. Here we assign three mutations to the respective gamma-crys tallin gene. Using a systematic candidate gene approach Do analyze the entire Cryg cluster, an A --> G transition was found in exon 2 of Cry ga for the ENU-436 mutation and is designated Cryga(1Neu). The mutant allele Crygb(nop) (formerly Cat2(nop)) is caused by a replacement of 1 1 bp by 4 bp in the third exon of Crygb, while a C --> G transversion in exon 3 of Cryge has been found for the Cryge(t) (formerly Cat2(t)) mutation. For the mutation Cryga(1Neu), an Asp --> Gly exchange is ded uced, whereas the mutations Crygb(nop) and Cryge(t) lead to the format ion of in-frame stop codons and give rise to truncated proteins of 144 and 143 amino acids, respectively. The effects of the mutations upon gamma-crystallin structure are likely to be quite different. The Cryga (1Neu) mutation is expected to affect the link between Greek-key motif s 2 and 3, whereas both Crygb(nop) and Cryge(t) mutations are supposed to truncate the fourth Greek-key motif. All three mutations are predi cted to alter protein folding of the gamma-crystallins and result in l ens cataract, but the phenotype for each is quite distinctive. (C) 199 8 Academic Press.