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

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 tRNALys(UUU). Adeficit 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 SNPregions are critical for the alternative splicing of CDKAL1-v1. These findings reveal that the T2D-associated SNPs inCDKAL1 reduce CDKAL1-v1 levels by impairing splicing, which in turn increasesmiRNA-mediated suppression ofCDKAL1. Our results suggest that CDKAL1-v1-mediated suppression ofCDKAL1 might underlie the pathogenesis of T2D in individuals carrying the risk SNPs. © The Author 2014. Published by Oxford University Press. All rights reserved.