Alternative titles; symbols
HGNC Approved Gene Symbol: TRMT5
SNOMEDCT: 1173034002;
Cytogenetic location: 14q23.1 Genomic coordinates (GRCh38): 14:60,971,441-60,981,690 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q23.1 | Peripheral neuropathy with variable spasticity, exercise intolerance, and developmental delay | 616539 | Autosomal recessive | 3 |
tRNAs contain as many as 13 or 14 nucleotides that are modified posttranscriptionally by enzymes that are highly specific for particular nucleotides in the tRNA structure. TRMT5 methylates the N1 position of guanosine-37 (G37) in selected tRNAs using S-adenosyl methionine (Brule et al., 2004).
By sequencing clones obtained from a size-fractionated adult brain cDNA library, Nagase et al. (2000) cloned TRMT5, which they called KIAA1393. The deduced protein contains 500 amino acids. RT-PCR ELISA detected moderate to high expression of TRMT5 in all adult and fetal tissues examined, with highest expression in ovary, followed by testis, spinal cord, and liver. Moderate to high expression of TRMT5 was present in all specific brain regions examined, with highest expression in corpus callosum.
By searching databases for homologs of yeast Trm5, Brule et al. (2004) identified human TRMT5, which they called TRM5. The predicted protein contains 509 amino acids. Recombinant TRM5 had an apparent molecular mass of 60.5 kD by SDS-PAGE. Bioinformatic analysis identified TRM5 homologs in eukaryotes and archaea; however, no significant homologies were identified in prokaryotes, including the TrmD gene.
In HeLa cells, Powell et al. (2015) found that the TRMT5 protein localized within the mitochondria.
Brule et al. (2004) found that, unlike its bacterial counterpart, TrmD, recombinant human TRM5 methylated G37 regardless of which nucleotide was present at position 36. Human TRM5 also methylated inosine at position 37, unlike TrmD. TRM5 did not have an absolute requirement for magnesium ions and appeared to function as a monomer.
Brule et al. (2004) determined that the TRMT5 gene contains 5 exons and spans 11 kb.
Nagase et al. (2000) mapped the TRMT5 gene to chromosome 14 by radiation hybrid analysis. By genomic sequence analysis, Brule et al. (2004) mapped the TRMT5 gene to chromosome 14q23.1.
In 2 unrelated patients with peripheral neuropathy with variable spasticity, exercise intolerance, and developmental delay (PNSED; 616539), one of whom was previously reported by Haller et al. (1989), Powell et al. (2015) identified compound heterozygous mutations in the TRMT5 gene (611023.0001-611023.0003). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated within the families according to DNA available from family members. A reverse-transcription primer extension (RT-PEx) assay performed on patient-derived fibroblasts and skeletal muscle tissue indicated that mt-tRNA(Leu-CUN) had decreased G37 modification compared to controls, with a more significant effect in the patient with the more severe phenotype. In addition, neither missense mutation was able to rescue defective mitochondrial respiratory activity in a yeast knockout model, consistent with a loss of function. The findings indicated that TRMT5 is responsible for G37 modification in human mitochondrial tRNA molecules.
In 2 sisters with PNSED, Tarnopolsky et al. (2017) identified compound heterozygous mutations in the TRMT5 gene (611023.0001 and 611023.0002). The mutations were found by whole-exome sequencing; functional studies were not performed.
In 3 unrelated patients with PNSED, Argente-Escrig et al. (2022) identified compound heterozygous mutations in the TRMT5 gene (611023.0001 and 611023.0004). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families. Functional studies of the variants and studies of patient cells were not performed.
In 2 unrelated patients (patient 73901, previously reported by Haller et al. (1989), and patient 65205), with peripheral neuropathy with variable spasticity, exercise intolerance, and developmental delay (PNSED; 616539), Powell et al. (2015) identified compound heterozygous mutations in the TRMT5 gene. Both patients carried a 4-bp deletion (c.312_315del, NM_020810.3), resulting in a frameshift and premature termination (Ile105SerfsTer4) on 1 allele, and a different pathogenic mutation on the second allele: a c.872G-A transition, resulting in an arg291-to-his (R291H; 611023.0002) and a c.1156A-G transition, resulting in a met386-to-val (M386V; 611023.0003) substitution, respectively. Both missense mutations occurred at highly conserved residues. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated within the families according to DNA available from family members. None of the variants were present in an in-house exome database of over 5,700 samples. In the ExAC database, c.312_315del and c.872G-A were found at low frequencies (0.0009 and 0.00004, respectively). The Ile105SerfsTer4 mutation is predicted to truncate the protein upstream of the methyltransferase motif and thus be nonfunctional. A reverse-transcription primer extension (RT-PEx) assay performed on patient-derived fibroblasts and skeletal muscle tissue indicated that mt-tRNA(Leu-CUN) had decreased G37 modification compared to controls, with a more significant effect in the patient with the more severe phenotype. Downregulation of TRMT5 in HeLa cells resulted in a similar effect. In addition, neither missense mutation was able to rescue defective mitochondrial respiratory activity in a yeast knockout model, consistent with a loss of function.
In 2 sisters with PNSED, Tarnopolsky et al. (2017) identified compound heterozygosity for 2 mutations in the TRMT5 gene: c.312_315del and R291H (611023.0002). The mutations, which were found by whole-exome sequencing, occurred in trans. Functional studies of the variants and studies of patient cells were not performed.
In 3 unrelated patients of Southern European descent with PNSED, Argente-Escrig et al. (2022) identified compound heterozygosity for c.312_315del and a c.665T-C transition, resulting in an ile222-to-thr (I222T) substitution at a highly conserved residue in the D2 domain (611023.0004). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in all families. I222T was present once in the heterozygous state in the gnomAD database (1 of 241,828 alleles), whereas c.312_315del was found in the heterozygous state in 246 of 282,782 alleles. Functional studies of the variants and studies of patient cells were not performed.
For discussion of the c.872G-A transition (c.872G-A, NM_020810.3) in the TRMT5 gene, resulting in an arg291-to-his (R291H) substitution, that was found in compound heterozygous state in a woman with peripheral neuropathy with variable spasticity, exercise intolerance, and developmental delay (PNSED; 616539) by Powell et al. (2015), see 611023.0001. This patient was previously reported by Haller et al. (1989).
For discussion of the R291H substitution in the TRMT5 gene that was found in compound heterozygous state in 2 sisters with PNSED by Tarnopolsky et al. (2017), see 611023.0001.
For discussion of the c.1156A-G transition (c.1156A-G, NM_020810.3) in the TRMT5 gene, resulting in a met386-to-val (M386V) substitution, that was found in compound heterozygous state in a boy with peripheral neuropathy with variable spasticity, exercise intolerance, and developmental delay (PNSED; 616539) by Powell et al. (2015), see 611023.0001.
For discussion of the c.665T-C transition (c.665T-C, NM_020810.3) in the TRMT5 gene, resulting in an arg291-to-his (R291H) substitution, that was found in compound heterozygous state in 3 unrelated patients with peripheral neuropathy with variable spasticity, exercise intolerance, and developmental delay (PNSED; 616539) by Argente-Escrig et al. (2022), see 611023.0001.
Argente-Escrig, H., Vilchez, J. J., Frasquet, M., Muelas, N., Azorin, I., Vilchez, R., Millet-Sancho, E., Pitarch, I., Tomas-Vila, M., Vazquez-Costa, J. F., Mas-Estelles, F., Marco-Marin, C., Espinos, C., Serrano-Lorenzo, P., Martin, M. A., Lupo, V., Sevilla, T. A novel TRMT5 mutation causes a complex inherited neuropathy syndrome: The role of nerve pathology in defining a demyelinating neuropathy. Neuropath. Appl. Neurobiol. 48: e12817, 2022. [PubMed: 35342985] [Full Text: https://doi.org/10.1111/nan.12817]
Brule, H., Elliott, M., Redlak, M., Zehner, Z. E., Holmes, W. M. Isolation and characterization of the human tRNA-(N(1)G37) methyltransferase (TRM5) and comparison to the Escherichia coli TrmD protein. Biochemistry 43: 9243-9255, 2004. [PubMed: 15248782] [Full Text: https://doi.org/10.1021/bi049671q]
Haller, R. G., Lewis, S. F., Estabrook, R. W., DiMauro, S., Servidei, S., Foster, D. W. Exercise intolerance, lactic acidosis, and abnormal cardiopulmonary regulation in exercise associated with adult skeletal muscle cytochrome c oxidase deficiency. J. Clin. Invest. 84: 155-161, 1989. [PubMed: 2544623] [Full Text: https://doi.org/10.1172/JCI114135]
Nagase, T., Kikuno, R., Ishikawa, K., Hirosawa, M., Ohara, O. Prediction of the coding sequences of unidentified human genes. XVI. The complete sequences of 150 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 7: 65-73, 2000. [PubMed: 10718198] [Full Text: https://doi.org/10.1093/dnares/7.1.65]
Powell, C. A., Kopajtich, R., D'Souza, A. R., Rorbach, J., Kremer, L. S., Husain, R. A., Dallabona, C., Donnini, C., Alston, C. L., Griffin, H., Pyle, A., Chinnery, P. F., and 12 others. TRMT5 mutations cause a defect in post-transcriptional modification of mitochondrial tRNA associated with multiple respiratory-chain deficiencies. Am. J. Hum. Genet. 97: 319-328, 2015. [PubMed: 26189817] [Full Text: https://doi.org/10.1016/j.ajhg.2015.06.011]
Tarnopolsky, M. A., Brady, L., Tetreault, M. TRMT5 mutations are associated with features of complex hereditary spastic paraparesis. Neurology 89: 2210-2211, 2017. [PubMed: 29021354] [Full Text: https://doi.org/10.1212/WNL.0000000000004657]