title: TRMT10A dysfunction is associated with abnormalities in glucose homeostasis, short stature and microcephaly.
abstract: BACKGROUND
  Trm10 is a tRNA m(1)G9 methyltransferase, which in yeast modifies 12 different tRNA species, yet is considered non-essential for viability under standard growth conditions. In humans, there are three Trm10 orthologs, one mitochondrial and two presumed cytoplasmic. A nonsense mutation in one of the cytoplasmic orthologs (TRMT10A) has recently been associated with microcephaly, intellectual disability, short stature and adolescent onset diabetes.
  
  
  RESULTS
  The subjects were three patients who suffered from microcephaly, intellectual disability, short stature, delayed puberty, seizures and disturbed glucose metabolism, mainly hyperinsulinaemic hypoglycaemia. A homozygous Gly206Arg (G206R) mutation in the TRMT10A gene was identified using whole exome sequencing. The mutation segregated in the family and was absent from large control cohorts. Determination of the methylation activity of the expressed wild-type (WT) and variant TRMT10A enzymes with transcripts of (32)P -tRNA(Gly) GCC as a substrate revealed a striking defect (<0.1% of WT activity) for the variant enzyme. The binding affinity of the G206R variant enzyme to tRNA, determined by fluorescence anisotropy, was similar to that of the WT enzyme.
  
  
  CONCLUSIONS
  The completely abolished m(1)G9 methyltransferase activity of the mutant enzyme is likely due to significant defects in its ability to bind the methyl donor S-adenosyl methionine. We propose that TRMT10A deficiency accounts for abnormalities in glucose homeostasis initially manifesting both ketotic and non-ketotic hypoglycaemic events with transition to diabetes in adolescence, perhaps as a consequence of accelerated β cell apoptosis. The seizure disorder and intellectual disability are probably secondary to mutant gene expression in neuronal tissue.
authors: Department of Pediatrics, Hadassah-Hebrew University Medical Center, Ein-Kerem, Jerusalem, Israel.
authors: David
authors: D
authors: Gillis
authors: Department of Chemistry and Biochemistry, Ohio State Biochemistry Program and Center for RNA Biology, The Ohio State University, Columbus, Ohio, USA.
authors: Aiswarya
authors: A
authors: Krishnamohan
authors: Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors: Barak
authors: B
authors: Yaacov
authors: Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors: Avraham
authors: A
authors: Shaag
authors: Department of Chemistry and Biochemistry, Ohio State Biochemistry Program and Center for RNA Biology, The Ohio State University, Columbus, Ohio, USA.
authors: Jane E
authors: JE
authors: Jackman
authors: Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors: Orly
authors: O
authors: Elpeleg
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D001483:Base Sequence; D059472:Exome / Q000235:genetics; D005260:Female; D005454:Fluorescence Polarization; D044882:Glucose Metabolism Disorders / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D007585:Jews / Q000235:genetics; D008297:Male; D008780:Methyltransferases / Q000235:genetics*; D008831:Microcephaly / Q000235:genetics*; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014610:Uzbekistan
chemical_list: D008780:Methyltransferases; C000595175:TRMT10A protein, human
keywords: Endocrinology