Mutations in the Founder of the MIP Gene Family Underlie Cataract Development in the Mouse
| Title: | Mutations in the Founder of the MIP Gene Family Underlie Cataract Development in the Mouse |
|---|---|
| Authors: | Shiels, Alan; Bassnett, Steven |
| Publisher: | Nature Genetics |
| Date Published: | February 01, 1996 |
| Reference Number: | 35 |
The major intrinsic protein (MIP) of the vertebrate eye lens is the first identified member of a sequence-related family of cell-membrane proteins that appears to have evolved by gene duplication. Several members of the MIP family transport water (aquaporins), glycerol and other small molecules in microbial, plant and animal cells. Mutations in two aquaporin homologues of MIP underlie an autosomal recessive form of nephrogenic diabetes insipidus and absence of the Colton blood group antigens in humans, whereas, mutation of a third MIP-like gene underlies 'big brain' development in Drosophila. Here we show that distinct mutations in the murine Mip gene underlie one form of autosomal dominant cataract in the mouse. The cataract Fraser mutation is a transposon-induced splicing error that substitutes a long terminal repeat sequence for the carboxy-terminus of MIP. The lens opacity mutation is an amino-acid substitution that inhibits targeting of MIP to the cell-membrane. These allelic cataract mutations provide the first direct evidence that MIP plays a crucial role in the development of a transparent eye lens.
This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)
The authors worked with two forms of mutations in the MIP: The cataract Fraser mutation (Cat Fr) and the lens opacity mutation (Lop). These mutations interfere with optimum MIP functioning in a similar way: by substituting inappropriate information sequences in the MIP genetic coding. However, Cat Fr and Lop each substitute information that is different from each other. The Lop mutation is a missense mutation, a variety of mutation that involves alteration of one or more codons (a specific sequence of three consecutive genetic compounds that form the basic structural units of RNA and DNA). The authors hypothesize that the Lop mutation may inhibit the ability of MIP to get where it is supposed to go. The Cat Fr mutation is a splicing mutation which encodes a rogue genetic sequence that was not detectable by MIP antibodies.
Apparently, both mutations effectively inhibit MIP function at the cellular level, which has serious consequences since MIP is central to functional eye lens formation. It is possible that Cat Fr and Lop are loss-of-function mutations in the MIP gene. If so, their presence can reduce MIP below a critical threshold level in the lens, and this may be sufficient to trigger cataract development. But it could as well be that Cat Fr and Lop are deleterious gain-of-function mutations in the MIP gene that cause proteins to be misformed.
The authors conclude by noting that whatever the true pathogenic mechanism, both Cat Fr and Lop mutations in the mouse indicate the MIP gene could prove useful in genetic therapy for types of human cataracts.
The lay reader interested in NDI research may rightfully ask what this article holds forth for possible advances in NDI research. Several members of MIP (the major intrinsic protein) family transport water and other small molecules across membranes in cells. Mutations in two types of MIP underlie the recessive form of NDI. As researchers discover more about one of the members of the MIP family, their work is likely to help other researchers discover more about other MIP family members.