tRNA Methyltransferase Homolog Gene TRMT10A Mutation in Young Onset Diabetes and Primary Microcephaly in Humans

摘要: We describe a new syndrome of young onset diabetes, short stature and microcephaly with intellectual disability in large consanguineous family three affected children. Linkage analysis whole exome sequencing were used to identify the causal nonsense mutation, which changed an arginine codon into stop at position 127 tRNA methyltransferase homolog gene TRMT10A (also called RG9MTD2). mRNA protein absent lymphoblasts from siblings. is ubiquitously expressed but enriched brain pancreatic islets, consistent tissues this syndrome. In situ hybridization studies showed that human embryonic fetal brain. mammalian ortholog S. cerevisiae TRM10, previously shown catalyze methylation guanine 9 (m1G9) several tRNAs. Consistent putative function, silico topology prediction indicated has predominant nuclear localization, we experimentally confirmed by immunofluorescence confocal microscopy. localizes nucleolus β- non-β-cells, where modifications occur. silencing induces rat β-cell apoptosis. Taken together, propose deficiency negatively affects mass pool neurons developing This first study describing impact mammals, highlighting role pathogenesis early diabetes. light recent report type 2 diabetes candidate CDKAL1 methylthiotransferase, findings suggest broader relevance methyltransferases