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tRNA methyltransferase homolog gene TRMT10A mutation in young onset diabetes and primary microcephaly in humans.

Igoillo-Esteve M, Genin A, Lambert N, Désir J, Pirson I, Abdulkarim B, Simonis N, Drielsma A, Marselli L, Marchetti P, Vanderhaeghen P, Eizirik DL, Wuyts W, Julier C, Chakera AJ, Ellard S, Hattersley AT, Abramowicz M, Cnop M - PLoS Genet. (2013)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Experimental Medicine, Université Libre de Bruxelles, Brussels, Belgium.

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 (m(1)G9) 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.

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TRMT10A expression profile in fetal telencephalon at 11 GW.(A) TRMT10A antisense (AS) probe and (B) TRMT10A sense (S) probe as a negative control. Scale bar: 1 mm. (C) TRMT10A is expressed throughout the thickness of the dorsal telencephalon at 11 GW, with higher expression in the ventricular zone (VZ, red arrow) and marginal zone (MZ, black arrow). Scale bar: 100 µm. (D) Cresyl Violet staining on adjacent section. (E) Higher resolution of MZ (black arrow) and VZ (red arrow).
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pgen-1003888-g004: TRMT10A expression profile in fetal telencephalon at 11 GW.(A) TRMT10A antisense (AS) probe and (B) TRMT10A sense (S) probe as a negative control. Scale bar: 1 mm. (C) TRMT10A is expressed throughout the thickness of the dorsal telencephalon at 11 GW, with higher expression in the ventricular zone (VZ, red arrow) and marginal zone (MZ, black arrow). Scale bar: 100 µm. (D) Cresyl Violet staining on adjacent section. (E) Higher resolution of MZ (black arrow) and VZ (red arrow).

Mentions: In situ hybridization studies were performed in human embryonic brain samples at 8, 11, 17 and 19 gestational weeks (GW). TRMT10A was expressed throughout the whole thickness of the dorsal telencephalon (presumptive cerebral cortex) at 8 and 11 GW, with higher expression in the ventricular zone and marginal zone (Figure 4). The ventricular zone contains most neural progenitors at early stages of corticogenesis, while the marginal zone is the region where the first post-mitotic neurons migrate. At later stages TRMT10A expression was not detected in the dorsal telencephalon but was found in the cerebellar cortex and cerebellar nuclei (Figure S3 and data not shown).


tRNA methyltransferase homolog gene TRMT10A mutation in young onset diabetes and primary microcephaly in humans.

Igoillo-Esteve M, Genin A, Lambert N, Désir J, Pirson I, Abdulkarim B, Simonis N, Drielsma A, Marselli L, Marchetti P, Vanderhaeghen P, Eizirik DL, Wuyts W, Julier C, Chakera AJ, Ellard S, Hattersley AT, Abramowicz M, Cnop M - PLoS Genet. (2013)

TRMT10A expression profile in fetal telencephalon at 11 GW.(A) TRMT10A antisense (AS) probe and (B) TRMT10A sense (S) probe as a negative control. Scale bar: 1 mm. (C) TRMT10A is expressed throughout the thickness of the dorsal telencephalon at 11 GW, with higher expression in the ventricular zone (VZ, red arrow) and marginal zone (MZ, black arrow). Scale bar: 100 µm. (D) Cresyl Violet staining on adjacent section. (E) Higher resolution of MZ (black arrow) and VZ (red arrow).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3814312&req=5

pgen-1003888-g004: TRMT10A expression profile in fetal telencephalon at 11 GW.(A) TRMT10A antisense (AS) probe and (B) TRMT10A sense (S) probe as a negative control. Scale bar: 1 mm. (C) TRMT10A is expressed throughout the thickness of the dorsal telencephalon at 11 GW, with higher expression in the ventricular zone (VZ, red arrow) and marginal zone (MZ, black arrow). Scale bar: 100 µm. (D) Cresyl Violet staining on adjacent section. (E) Higher resolution of MZ (black arrow) and VZ (red arrow).
Mentions: In situ hybridization studies were performed in human embryonic brain samples at 8, 11, 17 and 19 gestational weeks (GW). TRMT10A was expressed throughout the whole thickness of the dorsal telencephalon (presumptive cerebral cortex) at 8 and 11 GW, with higher expression in the ventricular zone and marginal zone (Figure 4). The ventricular zone contains most neural progenitors at early stages of corticogenesis, while the marginal zone is the region where the first post-mitotic neurons migrate. At later stages TRMT10A expression was not detected in the dorsal telencephalon but was found in the cerebellar cortex and cerebellar nuclei (Figure S3 and data not shown).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Experimental Medicine, Université Libre de Bruxelles, Brussels, Belgium.

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 (m(1)G9) 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.

Show MeSH
Related in: MedlinePlus