TY - JOUR
T1 - A 76-bp deletion in the Mip gene causes autosomal dominant cataract in Hfi mice
AU - Sidjanin, D. J.
AU - Parker-Wilson, Devonne M.
AU - Neuhäuser-Klaus, Angelika
AU - Pretsch, Walter
AU - Favor, Jack
AU - Deen, Peter M.T.
AU - Ohtaka-Maruyama, Chiaki
AU - Lu, Yun
AU - Bragin, Alvina
AU - Skach, William R.
AU - Chepelinsky, Ana B.
AU - Grimes, Patricia A.
AU - Stambolian, Dwight E.
N1 - Funding Information:
This research was supported in part by the National Institutes of Health, Bethesda, Maryland (Grants EY10321, GM53457, and 5T32EY07131), and by a grant from the Knights Templar Eye Foundation, Inc., Springfield, Illinois.
PY - 2001/6/15
Y1 - 2001/6/15
N2 - 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.
AB - 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.
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U2 - 10.1006/geno.2001.6509
DO - 10.1006/geno.2001.6509
M3 - Article
C2 - 11414759
AN - SCOPUS:0035874985
SN - 0888-7543
VL - 74
SP - 313
EP - 319
JO - Genomics
JF - Genomics
IS - 3
ER -