title: Functional loss of Cdkal1, a novel tRNA modification enzyme, causes the development of type 2 diabetes.
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-N(6)-threonylcarbamoyladenosine (ms(2)t(6)A) at position 37 of tRNA(Lys)(UUU).  The ms(2)t(6)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 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.
authors: Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors: Fan-Yan
authors: FY
authors: Wei
authors: Kazuhito
authors: K
authors: Tomizawa
mesh_terms: D000818:Animals; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics* / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D050417:Insulin-Secreting Cells / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011384:Proinsulin / Q000235:genetics / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D012343:RNA, Transfer / Q000737:chemistry / Q000378:metabolism; D012359:tRNA Methyltransferases
chemical_list: D009419:Nerve Tissue Proteins; D012343:RNA, Transfer; D011384:Proinsulin; D012359:tRNA Methyltransferases; D051360:Cyclin-Dependent Kinase 5; C525110:CDKAL1 protein, human; C559068:CDKAL1 protein, mouse