A 76-bp deletion in the Mip gene causes autosomal dominant cataract in Hfi mice.

Hfi is a dominant cataract mutation where heterozygotes show hydropic lens fibers and homozygotes show total lens opacity. The Hfi locus was mapped to the distal part of mouse chromosome 10 close to the major intrinsic protein (Mip), which is expressed only in cell membranes of lens fibers. Molecular analysis of Mip revealed a 76-bp deletion that resulted in exon 2 skipping in Mip mRNA. In Hfi/Hfi this deletion resulted in a complete absence of the wildtype Mip. In contrast, Hfi/+ animals had the same amount of wildtype Mip as +/+. Results from pulse-chase expression studies excluded hetero-oligomerization of wildtype and mutant Mip as a possible mechanism for cataract formation in the Hfi/+. We propose that the cataract phenotype in the Hfi heterozygote mutant is due to a detrimental gain of function by the mutant Mip resulting in either cytotoxicity or disruption in processing of other proteins important for the lens. Cataract formation in the Hfi/Hfi mouse is probably a combined result of both the complete loss of wildtype Mip and a gain of function of the mutant Mip.

Mapping of the autosomal dominant cataract mutation (Coc) on mouse chromosome 16.

PURPOSE: To characterize the mouse cataract mutation Coc. METHODS: Coc is an X-radiation-induced autosomal dominant cataract mutation maintained on a murine C3H inbred strain. The affected heterozygotes were outcrossed to C57BL/6, and (C3H Coc/+ x C57BL/6) mice that were Coc/+ were then backcrossed to C57BL/6 to generate a panel of 103 progeny for mapping. For linkage analysis, microsatellites from each autosome were selected. The maximum distance between markers was 30 centimorgans (cM). RESULTS: The initial genome-wide screen of 14 backcrossed progeny indicated that the Coc locus resides on chromosome 16. Further mapping with additional markers from chromosome 16 for all 103 backcrossed progeny positioned Coc between markers D16Mit134 and D16Mit63. This region is syntenic to human chromosome 3. CONCLUSIONS: Mapping of the Coc locus to mouse chromosome 16 provides the positional information necessary to identify the candidate gene responsible for the Coc phenotype. The molecular characterization of the gene disrupted in the Coc mutation will provide insight into the mechanisms involved in cataract formation.

Stickler's syndrome in the Cleft Palate Clinic.

Stickler's syndrome is a much underdiagnosed entity in the ophthalmic population. It is a dominantly inherited disease of connective tissue whose ocular findings include moderate to severe myopia, vitreoretinal degeneration, retinal detachments, cataracts, and glaucoma. Non-ophthalmologic findings include cleft palate, midfacial hypoplasia, radiographic changes of spondyloepiphyseal dysplasia, narrow pelvis, and broad femoral neck. Twenty percent of patients with Stickler's syndrome will have a cleft palate. We undertook a study to determine the incidence of Stickler's syndrome in patients with an isolated cleft palate, and to see if this screening process would be useful in making an early diagnosis of the syndrome and in genetic counseling. It is important to distinguish this syndrome from that of isolated cleft palate in order to: 1) insure early detection of myopia and monitor for signs of retinal detachment, cataract, and glaucoma; and 2) provide definitive recurrence counseling for families (50% vs 2.3%).