Functional loss of Cdkal1, a novel tRNA modification enzyme, causes the development of type 2 diabetes [Review]

Abstract

Abstract.A number of whole-genome association studies show the cdk5 regulatory associated protein 1-like 1 (cdkal1) gene to be one of the most reproducible risk genes in type 2 diabetes (T2D). Variations in the gene are associated with impaired insulin secretion but not insulin resistance or obesity. Although the physiological functions of Cdkal1 had been unclear, recent studies show that it is a tRNA modification enzyme, a mammalian methylthiotransferase that biosynthesizes 2-methylthio- A modification in tRNA Lys (UUU) is important for preventing the misreading of its cognate codons, especially when the rate of translation is relatively high. In both general and pancreatic β-cell-specific cdkal1-deficient mice, impaired mitochondrial ATP generation and first-phase insulin secretion are observed. Moreover, the β-cell-specific knockout mice show pancreatic islet hypertrophy and impaired blood glucose control. The mice are also hypersensitive to high-fat diet-induced endoplasmic reticulum (ER) stress. In this review, we provide an overview of the physiological functions of Cdkal1 and the molecular pathogenesis of T2D in patients carrying cdkal1 risk alleles.

Genetic variants on chromosome 6p21.1 and 6p22.3 are associated with type 2 diabetes risk: a case–control study in Han Chinese

“…Beta cellspecific CDKAL1 knockout mice models suggested that functional loss of CDKAL1 affects the accuracy of protein translation, causing the synthesis of abnormal insulin, which triggers estrogen receptor stress in beta cells. 30,31 The significant association between the SNP rs9472138 (about 73 kb to the transcription start site of VEGFA) and T2D was firstly replicated among Chinese population. Zeggini et al first reported in Caucasian that rs9472138 was associated with T2D in GWAS scan and the first stage validation, but achieved a borderline significant association (P¼0.095) in the second stage validation.…”

10 Years of GWAS Discovery: Biology, Function, and Translation

“…85 90,91 or data from animal models (CDKAL1 [MIM: 611259]). 92 Finally, the accumulation of data on coding variants (via exome sequencing and/or exome array genotyping) has highlighted several instances where GWAS signals previously attributed to non-coding variants can be reassigned to causal coding variants (e.g., TM6SF2 [MIM: 606563] 74 ). For others, such as RREB1 (MIM: 602209), identification of T2D-associated coding variants, statistically independent of the original GWAS signal, flags the likely effector transcripts.…”

Protein folding and tRNA biology

“…Their alterations result in severe consequences during translation, such as misreading, frame shifts, translation shifted to another distant site, as well as diverse pleiotropic cellular effects, including pathological states (Wei and Tomizawa 2011;Delaunay et al 2016). The three cases are clear examples of the links between tRNA modification and the cellular metabolic state.…”