| RRC ID |
69290
|
| Author |
Zhou B, Wei FY, Kanai N, Fujimura A, Kaitsuka T, Tomizawa K.
|
| Title |
Identification of a splicing variant that regulates type 2 diabetes risk factor CDKAL1 level by a coding-independent mechanism in human.
|
| Journal |
Hum Mol Genet
|
| Abstract |
Single-nucleotide polymorphisms (SNPs) in CDKAL1 have been associated with the development of type 2 diabetes (T2D). CDKAL1 catalyzes 2-methylthio modification of adenosine at position 37 of tRNA(Lys)(UUU). A deficit of this modification causes aberrant protein synthesis, and is associated with impairment of insulin secretion in both mouse model and human. However, it is unknown whether the T2D-associated SNPs in CDKAL1 are associated with downregulation of CDKAL1 by regulating the gene expression. Here, we report a specific splicing variant of CDKAL1 termed CDKAL1-v1 that is markedly lower in individuals carrying risk SNPs of CDKAL1. Interestingly, CDKAL1-v1 is a non-coding transcript, which regulates the CDKAL1 level by competitive binding to a CDKAL1-targeting miRNA. By direct editing of the genome, we further show that the nucleotides around the SNP regions are critical for the alternative splicing of CDKAL1-v1. These findings reveal that the T2D-associated SNPs in CDKAL1 reduce CDKAL1-v1 levels by impairing splicing, which in turn increases miRNA-mediated suppression of CDKAL1. Our results suggest that CDKAL1-v1-mediated suppression of CDKAL1 might underlie the pathogenesis of T2D in individuals carrying the risk SNPs.
|
| Volume |
23(17)
|
| Pages |
4639-50
|
| Published |
2014-9-1
|
| DOI |
10.1093/hmg/ddu184
|
| PII |
ddu184
|
| PMID |
24760768
|
| MeSH |
Alleles
Alternative Splicing / genetics*
Animals
Base Sequence
Cyclin-Dependent Kinase 5 / genetics*
Cyclin-Dependent Kinase 5 / metabolism
Diabetes Mellitus, Type 2 / genetics*
Genetic Predisposition to Disease*
HEK293 Cells
HeLa Cells
Humans
Insulin / metabolism
Insulin Secretion
Mice
MicroRNAs / metabolism
Molecular Sequence Data
Open Reading Frames / genetics*
Polymorphism, Single Nucleotide / genetics
RNA, Messenger / genetics
RNA, Messenger / metabolism
RNA, Untranslated / genetics
RNA, Untranslated / metabolism
Risk Factors
tRNA Methyltransferases
|
| IF |
5.101
|
| Resource |
| Human and Animal Cells |
293(RCB1637) |
