RRC ID |
27733
|
著者 |
Watanabe K, Wada K, Ohashi T, Okubo S, Takekuma K, Hashizume R, Hayashi J, Serikawa T, Kuramoto T, Kikkawa Y.
|
タイトル |
A 5-bp insertion in Mip causes recessive congenital cataract in KFRS4/Kyo rats.
|
ジャーナル |
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.
|
巻・号 |
7(11)
|
ページ |
e50737
|
公開日 |
2012-1-1
|
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 |
2.74
|
引用数 |
13
|
WOS 分野
|
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
リソース情報 |
ラット |
KFRS4/Kyo(strainID=919)
DOB/Oda(strainID=582) |