Abstract
We describe a new syndrome of young onset diabetes, short stature and microcephaly with intellectual disability in a large consanguineous family with three affected children. Linkage analysis and whole exome sequencing were used to identify the causal nonsense mutation, which changed an arginine codon into a stop at position 127 of the tRNA methyltransferase homolog gene TRMT10A (also called RG9MTD2). TRMT10A mRNA and protein were absent in lymphoblasts from the affected siblings. TRMT10A is ubiquitously expressed but enriched in brain and pancreatic islets, consistent with the tissues affected in this syndrome. In situ hybridization studies showed that TRMT10A is expressed in human embryonic and fetal brain. TRMT10A is the mammalian ortholog of S. cerevisiae TRM10, previously shown to catalyze the methylation of guanine 9 (m1G9) in several tRNAs. Consistent with this putative function, in silico topology prediction indicated that TRMT10A has predominant nuclear localization, which we experimentally confirmed by immunofluorescence and confocal microscopy. TRMT10A localizes to the nucleolus of β- and non-β-cells, where tRNA modifications occur. TRMT10A silencing induces rat and human β-cell apoptosis. Taken together, we propose that TRMT10A deficiency negatively affects β-cell mass and the pool of neurons in the developing brain. This is the first study describing the impact of TRMT10A deficiency in mammals, highlighting a role in the pathogenesis of microcephaly and early onset diabetes. In light of the recent report that the type 2 diabetes candidate gene CDKAL1 is a tRNA methylthiotransferase, the findings in this family suggest broader relevance of tRNA methyltransferases in the pathogenesis of type 2 diabetes.
Highlights
Type 2 diabetes (T2D) is a heterogeneous polygenic disease with dramatically increasing worldwide incidence as a consequence of the obesity epidemic [1]
The inherited predisposition to type 2 diabetes is attributed to common variants in over 60 loci
We describe a new syndrome of young onset diabetes, short stature and microcephaly with intellectual disability in a large consanguineous family
Summary
Type 2 diabetes (T2D) is a heterogeneous polygenic disease with dramatically increasing worldwide incidence as a consequence of the obesity epidemic [1]. T2D develops when b-cells fail to compensate for peripheral insulin resistance by increasing insulin secretion [4,5] as a consequence of b-cell dysfunction and reduced b-cell mass. Genome-wide association studies have identified a number of loci where genetic polymorphisms associate with T2D [6]. Inherited mutations in genes at some of these loci have been shown to cause monogenic forms of diabetes, indicating that genetic variants of different severity can generate a spectrum of monogenic and polygenic forms of diabetes [7]. An example of a T2D risk gene is CDK5 regulatory associated protein 1-like 1 (CDKAL1). Polymorphisms in this gene have been associated with T2D across ethnic populations [8]. Cdkal1-deficient b-cells have impaired glucose-induced insulin secretion, and Cdkal knockout mice develop glucose intolerance due to aberrant insulin synthesis [9]
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