Identification of a splicing variant that regulates type 2 diabetes risk factor CDKAL1 level by a coding-independent mechanism in human

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.