A 76-bp deletion in the Mip gene causes autosomal dominant cataract in Hfimice

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 protei n (Mip), which is expressed only in cell membranes of lens fibers. Molecula r analysis of Mip revealed a 76-bp deletion that resulted in exon 2 skippin g in Mip mRNA, In Hfi/Hfi this deletion resulted in a complete absence of t he wildtype Mip. In contrast, Hfi/+ animals had the same amount of wildtype Mip as +/+. Results from pulse-chase expression studies excluded hetero-ol igomerization of wildtype and mutant Mip as a possible mechanism for catara ct formation in the Hfi/+. We propose that the cataract phenotype in the Hf i heterozygote mutant is due to a detrimental gain of function by the mutan t Mip resulting in either cytotoxicity or disruption in processing of other proteins important for the lens. Cataract formation in the Hfi/Hfi mouse i s probably a combined result of both the complete loss of wildtype Mip and a gain of function of the mutant Mip. (C) 2001 Academic Press.