RRC ID 27733
Author Watanabe K, Wada K, Ohashi T, Okubo S, Takekuma K, Hashizume R, Hayashi J, Serikawa T, Kuramoto T, Kikkawa Y.
Title A 5-bp insertion in Mip causes recessive congenital cataract in KFRS4/Kyo rats.
Journal PLoS One
Abstract 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.
Volume 7(11)
Pages e50737
Published 2012
DOI 10.1371/journal.pone.0050737
PII PONE-D-12-26424
PMID 23226368
PMC PMC3511373
MeSH Alleles Amino Acid Sequence Animals Aquaporins / chemistry Aquaporins / genetics* Cataract / genetics* Eye Proteins / chemistry Eye Proteins / genetics* Gene Expression Regulation Genes, Recessive / genetics* Molecular Sequence Data Mutagenesis, Insertional* Phenotype RNA, Messenger / genetics RNA, Messenger / metabolism Rats
IF 2.776
Times Cited 13
WOS Category BIOCHEMISTRY & MOLECULAR BIOLOGY
Resource
Rats KFRS4/Kyo(strainID=919) DOB/Oda(strainID=582)