Document Detail

A 5-bp insertion in Mip causes recessive congenital cataract in KFRS4/Kyo rats.
MedLine Citation:
PMID:  23226368     Owner:  NLM     Status:  MEDLINE    
We discovered a new cataract mutation, kfrs4, in the Kyoto Fancy Rat Stock (KFRS) background. Within 1 month of birth, all kfrs4/kfrs4 homozygotes developed cataracts, with severe opacity in the nuclei of the lens. In contrast, no opacity was observed in the kfrs4/+ heterozygotes. We continued to observe these rats until they reached 1 year of age and found that cataractogenesis did not occur in kfrs4/+ rats. To define the histological defects in the lenses of kfrs4 rats, sections of the eyes of these rats were prepared. Although the lenses of kfrs4/kfrs4 homozygotes showed severely disorganised fibres and vacuolation, the lenses of kfrs4/+ heterozygotes appeared normal and similar to those of wild-type rats. We used positional cloning to identify the kfrs4 mutation. The mutation was mapped to an approximately 9.7-Mb region on chromosome 7, which contains the Mip gene. This gene is responsible for a dominant form of cataract in humans and mice. Sequence analysis of the mutant-derived Mip gene identified a 5-bp insertion. This insertion is predicted to inactivate the MIP protein, as it produces a frameshift that results in the synthesis of 6 novel amino acid residues and a truncated protein that lacks 136 amino acids in the C-terminal region, and no MIP immunoreactivity was observed in the lens fibre cells of kfrs4/kfrs4 homozygous rats using an antibody that recognises the C- and N-terminus of MIP. In addition, the kfrs4/+ heterozygotes showed reduced expression of Mip mRNA and MIP protein and the kfrs4/kfrs4 homozygotes showed no expression in the lens. These results indicate that the kfrs4 mutation conveys a loss-of-function, which leads to functional inactivation though the degradation of Mip mRNA by an mRNA decay mechanism. Therefore, the kfrs4 rat represents the first characterised rat model with a recessive mutation in the Mip gene.
Kei Watanabe; Kenta Wada; Tomoko Ohashi; Saki Okubo; Kensuke Takekuma; Ryoichi Hashizume; Jun-Ichi Hayashi; Tadao Serikawa; Takashi Kuramoto; Yoshiaki Kikkawa
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-11-30
Journal Detail:
Title:  PloS one     Volume:  7     ISSN:  1932-6203     ISO Abbreviation:  PLoS ONE     Publication Date:  2012  
Date Detail:
Created Date:  2012-12-11     Completed Date:  2013-05-23     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  101285081     Medline TA:  PLoS One     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e50737     Citation Subset:  IM    
Mammalian Genetics Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
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MeSH Terms
Amino Acid Sequence
Aquaporins / chemistry,  genetics*
Cataract / genetics*
Eye Proteins / chemistry,  genetics*
Gene Expression Regulation
Genes, Recessive / genetics*
Molecular Sequence Data
Mutagenesis, Insertional*
RNA, Messenger / genetics,  metabolism
Reg. No./Substance:
0/Aquaporins; 0/Eye Proteins; 0/RNA, Messenger; 0/aquaporin 0

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