Alternative titles; symbols
HGNC Approved Gene Symbol: TRMT10C
SNOMEDCT: 1172841001;
Cytogenetic location: 3q12.3 Genomic coordinates (GRCh38): 3:101,561,868-101,566,446 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q12.3 | Combined oxidative phosphorylation deficiency 30 | 616974 | Autosomal recessive | 3 |
Ribonuclease (RNase) P (EC 3.1.26.5) functions in tRNA maturation by removing extra nucleotides from the 5-prime end of tRNA precursors. TRMT10C is a subunit of the mitochondrial RNase P complex. Unlike nuclear RNase P (see 608513), mitochondrial RNase P has no RNA component (Holzmann et al., 2008).
By database analysis to identify HeLa cell mitochondrial proteins that copurified with RNase P activity, followed by RT-PCR of HeLa cell total RNA, Holzmann et al. (2008) cloned TRMT10C, which they called RG9MTD1 or MRPP1.
Holzmann et al. (2008) found that a mixture of recombinant human RG9MTD1, HSD17B10 (300256), and KIAA0391 (609947) showed Mg(2+)-dependent tRNA-specific endonuclease activity and removed 5-prime extensions from several substrate tRNA precursors, cleaving the phosphate at the 5-prime end of the tRNA. The RNase P activity exhibited by these proteins was indistinguishable from that of endogenous HeLa cell mitochondrial RNase P. All 3 proteins were required for the activity in vitro, and knockdown of any component in HeLa cells reduced endogenous mitochondrial RNase P activity. Treatment with RNase had no effect on RNase P activity, and addition of RNA either inhibited or had no effect on RNase P activity, depending on the RNA concentration. These results suggested that, unlike nuclear RNase P or orthologs from lower organisms, mitochondrial RNase P does not require RNA for tRNA precursor 5-prime trimming. Holzmann et al. (2008) noted that RG9MTD1 is an ortholog of yeast Trm10, a tRNA m(1)G methyltransferase, and that HSD17B10 is a multifunctional member of the short-chain dehydrogenase/reductase family. They proposed that either RG9MTD1 or both RG9MTD1 and HSD17B10 function in tRNA binding. Holzmann et al. (2008) suggested that KIAA0291, which contains a putative metallonuclease domain, may be responsible for the nuclease activity of the complex.
Brzezniak et al. (2011) found that silencing the MRPP1 gene in HeLa cells resulted in accumulation of tRNA precursors with unprocessed 5-prime and 3-prime ends. In contrast, knockdown of the 3-prime tRNA-processing enzyme, RNase Z (ELAC2; 605367), resulted in accumulation of tRNA precursors with unprocessed 3-prime ends only. Brzezniak et al. (2011) concluded that RNase Z preferentially acts after RNase P and can only process RNA already cleaved at the tRNA 5-prime end.
Safra et al. (2017) developed an approach that allows the transcriptomewide mapping of N1-methyladenosine (m1A) at single-nucleotide resolution. Within the cytosol, m1A is present in a low number of mRNAs, typically at low stoichiometries, and almost invariably in tRNA T-loop-like structures, where it is introduced by the TRMT6/TRMT61A complex. Safra et al. (2017) identify a single m1A site in the mitochondrial ND5 (MTND5; 516005) mRNA, catalyzed by TRMT10C, with methylation levels that are highly tissue-specific and tightly developmentally controlled. m1A leads to translational repression, probably through a mechanism involving ribosomal scanning or translation. Safra et al. (2017) concluded that their findings suggested that m1A on mRNA, probably because of its disruptive impact on basepairing, leads to translational repression, and is generally avoided by cells, while revealing 1 case in mitochondria where tight spatiotemporal control over m1A levels was adopted as a potential means of posttranscriptional regulation.
Hartz (2013) mapped the TRMT10C gene to chromosome 3q12.3 based on an alignment of the TRMT10C sequence (GenBank AK000439) with the genomic sequence (GRCh37).
In 2 unrelated infants with fatal combined oxidative phosphorylation deficiency-30 (COXPD30; 616974), Metodiev et al. (2016) identified homozygous or compound heterozygous missense mutations in the TRMT10C gene (R181L, 615423.0001 and T272A, 615423.0002). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Detailed analysis of patient cells showed an impairment of mt-RNA processing efficiency with a mild accumulation of mitochondrial precursor RNA, but without severe effects on mature mt-mRNA or mt-tRNA steady-state levels. There was no effect on m(1)R9 methyltransferase activity. Transfection of patient cells with wildtype TRMT10C rescued the respiratory chain complex deficiencies and the defects in mitochondrial translation.
In a male infant, born of unrelated Caucasian parents, with fatal combined oxidative phosphorylation deficiency-30 (COXPD30; 616974), Metodiev et al. (2016) identified compound heterozygous mutations in the TRMT10C gene: a c.542G-T transversion (SCV000264779.0), resulting in an arg181-to-leu (R181L) substitution, and a c.814A-G transition, resulting in a thr272-to-ala substitution (T272A; 615423.0002). Both mutations occurred at highly conserved residues. An unrelated female infant, born of unrelated parents of Kurdish origin, with a similar fatal disorder was homozygous for the R181L mutation. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in families. The R181L variant was present at low levels in the ExAC database (10 of 120,324 alleles) and in the Exome Sequencing Project database (ESP6500; 1 of 11,824 alleles), whereas the T272A variant was absent in both of these databases. Western blot analysis of patient fibroblasts showed decreased levels of the MRPP1 protein compared to controls, suggesting instability of the mutant protein. Patient cells also showed decreased assembly of mitochondrial complex I and complex IV, with variable and mildly decreased levels of complex III, resulting from impaired mitochondrial protein synthesis. Transfection of patient cells with wildtype TRMT10C rescued the respiratory chain complex deficiencies and the defects in mitochondrial translation.
For discussion of the c.814A-G transition (SCV000264780.0) in the TRMT10C gene, resulting in a thr272-to-ala (T272A) substitution, that was found in compound heterozygous state in a male infant with combined oxidative phosphorylation deficiency-30 (COXPD30; 616974) by Metodiev et al. (2016), see 615423.0001.
Brzezniak, L. K., Bijata, M., Szczesny, R. J., Stepien, P. P. Involvement of human ELAC2 gene product in 3-prime end processing of mitochondrial tRNAs. RNA Biol. 8: 616-626, 2011. [PubMed: 21593607] [Full Text: https://doi.org/10.4161/rna.8.4.15393]
Hartz, P. A. Personal Communication. Baltimore, Md. 9/20/2013.
Holzmann, J., Frank, P., Loffler, E., Bennett, K. L., Gerner, C., Rossmanith, W. RNase P without RNA: identification and functional reconstitution of the human mitochondrial tRNA processing enzyme. Cell 135: 462-474, 2008. and SI. [PubMed: 18984158] [Full Text: https://doi.org/10.1016/j.cell.2008.09.013]
Metodiev, M. D., Thompson, K., Alston, C. L., Morris, A. A. M., He, L., Assouline, Z., Rio, M., Bahi-Buisson, N., Pyle, A., Griffin, H., Siira, S., Filipovska, A., Munnich, A., Chinnery, P. F., McFarland, R., Rotig, A., Taylor, R. W. Recessive mutations in TRMT10C cause defects in mitochondrial RNA processing and multiple respiratory chain deficiencies. Am. J. Hum. Genet. 98: 993-1000, 2016. Note: Erratum: Am. J. Hum. Genet. 99: 246 only, 2016. [PubMed: 27132592] [Full Text: https://doi.org/10.1016/j.ajhg.2016.03.010]
Safra, M., Sas-Chen, A., Nir, R., Winkler, R., Nachshon, A., Bar-Yaacov, D., Erlacher, M., Rossmanith, W., Stern-Ginossar, N., Schwartz, S. The m1A landscape on cytosolic and mitochondrial mRNA at single-base resolution. Nature 551: 251-255, 2017. [PubMed: 29072297] [Full Text: https://doi.org/10.1038/nature24456]