Alternative titles; symbols
HGNC Approved Gene Symbol: TRMU
Cytogenetic location: 22q13.31 Genomic coordinates (GRCh38) : 22:46,335,714-46,357,340 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q13.31 | {Deafness, mitochondrial, modifier of} | 580000 | Mitochondrial | 3 |
| Liver failure, transient infantile | 613070 | Autosomal recessive | 3 |
TRMU is an evolutionarily conserved protein involved in mitochondrial tRNA modification, and is thus important for mitochondrial translation (Yan et al., 2005).
By searching a database for sequences similar to yeast Mto2, followed by RT-PCR of a human osteosarcoma cell line cDNA library, Yan et al. (2005) cloned TRMU, which they designated MTO2. Fluorescence-tagged MTO2 localized to mitochondria.
By 5-prime and 3-prime RACE, Yan et al. (2006) identified several TRMU splice variants. The full-length 421-amino acid protein has a calculated molecular mass of 47.7 kD. The other transcripts lack exon 3 and encode a deduced 99-amino acid protein. Northern blot analysis detected high expression of a 1.9-kb TRMU transcript in heart, skeletal muscle, and kidney. Intermediate expression was detected in brain, placenta, spleen, and small intestine, and low expression was detected in liver, colon, lung, thymus, and leukocytes. Expression was nearly uniform in 8 brain regions examined.
Yan and Guan (2004) cloned mouse Trmu. The deduced 417-amino acid protein contains a typical mitochondrial target sequence and shares 91% identity with human TRMU.
Yan et al. (2006) determined that the TRMU gene contains 11 exons and spans about 22 kb.
By genomic sequence analysis, Yan et al. (2006) mapped the TRMU gene to chromosome 22q13. Yan and Guan (2004) mapped the mouse Trmu gene to chromosome 15.
Yan et al. (2005) demonstrated that human MTO2 could partially restore the respiratory-deficient phenotype of Mto2-null yeast carrying a mutation in 15S ribosomal RNA (rRNA), 1409C-G, associated with aminoglycoside resistance. The yeast 1409C-G mutation in 15S rRNA corresponds to the deafness-associated 1494C-T mutation (561000.0004) in human 12S rRNA (MTRNR1; 561000).
In families with the deafness-associated 12S rRNA 1555A-G mutation (561000.0001), Yan et al. (2006) found suggestive linkage and linkage disequilibrium between microsatellite markers adjacent to TRMU and the presence of deafness. They hypothesized that TRMU may modulate the phenotypic manifestation of deafness-associated mitochondrial 12S rRNA mutations.
Guan et al. (2006) noted that TRMU is responsible for the 2-thiolation of hypermodified nucleoside 5-methyl-aminomethy-2-thio-uridine. This modified nucleotide, found in the wobble position of several bacterial and human mitochondrial tRNAs (mt tRNAs) specific for glutamate, lysine, and glutamine, has a pivotal role in the structure and function of tRNAs, including structural stabilization, aminoacylation, and codon recognition at the decoding site of small rRNA.
Deafness Modification
The 1555A-G mutation of mitochondrial 12S rRNA (561000.0001) is associated with aminoglycoside-induced and nonsyndromic deafness in many families worldwide (Prezant et al., 1993). Studies of Guan et al. (1996, 2001) revealed that the 1555A-G mutation, although a primary factor underlying the development of deafness, is not alone sufficient to produce a deafness phenotype. Nuclear modifier genes have been proposed as modulators of the phenotypic manifestations of the mitochondrial mutation. Guan et al. (2006) identified the nuclear modifier gene TRMU, which encodes a highly conserved mitochondrial protein related to transfer RNA (tRNA) modification. Studies in a large Arab Israeli kindred, in an Italian family, and in 6 Spanish families carrying the 1555A-G or the 1494C-T (561000.0004) mutation revealed a missense mutation (610230.0001) altering an invariant amino acid residue (A10S) in the evolutionarily conserved N-terminal region of the TRMU protein. All members of the Arab Israeli, Italian, and Spanish families carrying both the TRMU A10S and the 12S rRNA 1555A-G mutations exhibited prelingual profound deafness. Functional analysis showed that the A10S mutation did not affect importation of TRMU precursors into mitochondria. However, the homozygous A10S mutation led to a marked failure in mitochondrial tRNA metabolisms, specifically reducing the steady-state levels of mitochondrial tRNA. As a consequence, these defects contributed to the impairment of mitochondrial protein synthesis. These findings indicated that the mutated TRMU, acting as a modifier factor, modulates the phenotypic manifestation of the deafness-associated 12S rRNA mutations.
Transient Infantile Liver Failure
By linkage analysis, followed by candidate gene sequencing, Zeharia et al. (2009) identified homozygous and compound heterozygous mutations in the TRMU gene (see, e.g., 610230.0002-610230.0005) in patients with transient infantile liver failure (LFIT; 613070). Seven patients of Yemenite Jewish origin had the same Y77H mutation (610230.0002), indicating a founder effect. Overall, 9 mutations were identified in 13 patients. Those who survived the initial acute episode showed clinical and biochemical resolution of liver failure and had no further episodes. A study of tRNAs in cells derived from 3 of the patients showed a severe reduction of thio-modified mitochondrial tRNAs, whereas the pattern of hybridization obtained for the cytosolic tRNA-lys, modified by another enzyme, was similar to controls. The findings suggested that the mitochondrial translation defect resulted from reduced modification of several mitochondrial tRNAs. Noting that the availability of cysteine in the neonatal period is limited, Zeharia et al. (2009) proposed that there is a window of time during 1 to 4 months of age during which patients with TRMU mutations are at an increased risk of developing liver failure.
In a large Arab Israeli kindred, in an Italian family, and in 6 Spanish families with sensorineural deafness carrying the 1555A-G (561000.0001) or the 1494C-T (561000.0004) mutation in mitochondrial 12S ribosomal RNA (rRNA), Guan et al. (2006) found that a 28G-T transversion in exon 1 of the TRMU gene, resulting in an ala10-to-ser substitution (A10S), modified the phenotypic expression of the 12S rRNA mutation. All members of the Arab-Israeli and Italian-Spanish families carrying both the TRMU A10S and the 12S rRNA 1555A-G mutations exhibited prelingual profound deafness. The A10S mutation resulted in a defect in 2-thio modification in mitochondrial tRNAs, which led to decreases of the steady-state level of mitochondrial tRNAs, subsequently causing impairment of mitochondrial translation. Resultant biochemical defects aggravated the mitochondrial dysfunction below the threshold for normal cell function, thereby expressing the deafness phenotype.
Using molecular dynamic simulations, Meng et al. (2017) showed that the A10S mutation introduced a ser10 dynamic electrostatic interaction with lys106 in helix-4 of the TRMU catalytic domain. Western blot analysis revealed reduced levels of TRMU in cells with the A10S mutation, and thermal shift analysis showed that the Tm value of the mutant TRMU protein was lower than wildtype. The A10S mutation also caused marked decreases in 2-thiouridine modification of U34 in tRNAs for lys (MTTK; 590060), glu (MTTE; 590025), and gln (MTTQ; 590030), while mildly increasing the aminoacylated efficiency of the tRNAs. The altered 2-thiouridine modification worsened the impairment of mitochondrial translocation associated with the MTRNR1 1555A-G mutation. Defective translation resulted in reduced activity in mitochondrial respiration chains, leading to reduction of mitochondrial ATP production and elevated production of reactive oxidative species. Thus, the A10S mutation in TRMU worsened the mitochondrial dysfunction associated with the 1555A-G mutation, exceeding the threshold for expressing the deafness phenotype.
In 5 Yemenite Jewish patients with transient infantile liver failure (613070), Zeharia et al. (2009) identified a homozygous 232T-C transition in the TRMU gene, resulting in a tyr77-to-his (Y77H) substitution. Another Yemenite Jewish patient was compound heterozygous for Y77H and a splice site mutation (610230.0003).
In a Yemenite Jewish patient with transient infantile liver failure (613070), Zeharia et al. (2009) identified compound heterozygosity for 2 mutations in the TRMU gene: a G-to-A transition, resulting in the skipping of exon 3, and the Y77H mutation (610230.0002).
In an Arab patient with transient infantile liver failure (613070), Zeharia et al. (2009) identified a homozygous 815G-A transition in the TRMU gene, resulting in a gly272-to-asp (G272D) substitution.
In 2 Algerian patients with transient infantile liver failure (613070), Zeharia et al. (2009) identified a homozygous 2T-A transversion in the TRMU gene, resulting in a met1-to-lys (M1K) substitution in the initiation codon. The infants presented at ages 1 and 2 days, respectively, and died at ages 3 and 4 months, respectively. The mutation was not identified in 106 individuals of North African origin.
In a 4-year-old Irish girl with transient infantile liver failure (613070), Uusimaa et al. (2011) identified compound heterozygosity for 2 mutations in the TRMU gene: an 835G-A transition resulting in a val279-to-met (V279M) substitution in a highly conserved residue, and a splice site mutation (610230.0007). Each unaffected parent was heterozygous for 1 of the mutations. The patient presented in infancy with acute liver failure and lactic acidosis with profound cytochrome c oxidase deficiency in muscle and liver samples. Brain MRI showed abnormal high signal in the right thalamus, which disappeared by age 1 year. She also had feeding difficulties and hypotonia in early infancy. Although she recovered, she had mildly delayed walking, axial weakness, and bulbar involvement.
In a girl with transient infantile liver failure (613070), Uusimaa et al. (2011) identified compound heterozygosity for 2 mutations in the TRMU gene: a C-to-G transversion in intron 11, causing a splice site mutation, and V279M (610230.0006). The splice site mutation resulted in 50% aberrantly spliced transcript, which generated a frameshift and premature termination.
Guan, M. X., Fischel-Ghodsian, N., Attardi, G. Nuclear background determines biochemical phenotype in the deafness-associated mitochondrial 12S rRNA mutation. Hum. Molec. Genet. 10: 573-580, 2001. [PubMed: 11230176] [Full Text: https://doi.org/10.1093/hmg/10.6.573]
Guan, M.-X., Fischel-Ghodsian, N., Attardi, G. Biochemical evidence for nuclear gene involvement in phenotype of non-syndromic deafness associated with mitochondrial 12S rRNA mutation. Hum. Molec. Genet. 5: 963-971, 1996. [PubMed: 8817331] [Full Text: https://doi.org/10.1093/hmg/5.7.963]
Guan, M.-X., Yan, Q., Li, X., Bykhovskaya, Y., Gallo-Teran, J., Hajek, P., Umeda, N., Zhao, H., Garrido, G., Mengesha, E., Suzuki, T., del Castillo, I., and 10 others. Mutation in TRMU related to transfer RNA modification modulates the phenotypic expression of the deafness-associated mitochondrial 12S ribosomal RNA mutations. Am. J. Hum. Genet. 79: 291-302, 2006. [PubMed: 16826519] [Full Text: https://doi.org/10.1086/506389]
Meng, F., Cang, X., Peng, Y., Li, R., Zhang, Z., Li, F., Fan, Q., Guan, A. S., Fischel-Ghosian, N., Zhao, X., Guan, M.-X. Biochemical evidence for a nuclear modifier allele (A10S) in TRMU (methylaminomethyl-2-thiouridylate-methyltransferase) related to mitochondrial tRNA modification in the phenotypic manifestation of deafness-associated 12S rRNA mutation. J. Biol. Chem. 292: 2881-2892, 2017. [PubMed: 28049726] [Full Text: https://doi.org/10.1074/jbc.M116.749374]
Prezant, T. R., Agapian, J. V., Bohlman, M. C., Bu, X., Oztas, S., Qiu, W.-Q., Arnos, K. S., Cortopassi, G. A., Jaber, L., Rotter, J. I., Shohat, M., Fischel-Ghodsian, N. Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and non-syndromic deafness. Nature Genet. 4: 289-294, 1993. [PubMed: 7689389] [Full Text: https://doi.org/10.1038/ng0793-289]
Uusimaa, J., Jungbluth, H., Fratter, C., Crisponi, G., Feng, L., Zeviani, M., Hughes, I., Treacy, E. P., Birks, J., Brown, G. K., Sewry, C. A., McDermott, M., Muntoni, F., Poulton, J. Reversible infantile respiratory chain deficiency is a unique, genetically heterogenous mitochondrial disease. J. Med. Genet. 48: 660-668, 2011. [PubMed: 21931168] [Full Text: https://doi.org/10.1136/jmg.2011.089995]
Yan, Q., Bykhovskaya, Y., Li, R., Mengesha, E., Shohat, M., Estivill, X., Fischel-Ghodsian, N., Guan, M.-X. Human TRMU encoding the mitochondrial 5-methylaminomethyl-2-thiouridylate-methyltransferase is a putative nuclear modifier gene for the phenotypic expression of the deafness-associated 12S rRNA mutations. Biochem. Biophys. Res. Commun. 342: 1130-1136, 2006. [PubMed: 16513084] [Full Text: https://doi.org/10.1016/j.bbrc.2006.02.078]
Yan, Q., Guan, M.-X. Identification and characterization of mouse TRMU gene encoding the mitochondrial 5-methylaminomethyl-2-thiouridylate-methyltransferase. Biochim. Biophys. Acta 1676: 119-126, 2004. [PubMed: 14746906] [Full Text: https://doi.org/10.1016/j.bbaexp.2003.11.010]
Yan, Q., Li, X., Faye, G., Guan, M.-X. Mutations in MTO2 related to tRNA modification impair mitochondrial gene expression and protein synthesis in the presence of a paromomycin resistance mutation in mitochondrial 15 S rRNA. J. Biol. Chem. 280: 29151-29157, 2005. [PubMed: 15944150] [Full Text: https://doi.org/10.1074/jbc.M504247200]
Zeharia, A., Shaag, A., Pappo, O., Mager-Heckel, A.-M., Saada, A., Beinat, M., Karicheva, O., Mandel, H., Ofek, N., Segel, R., Marom, D., Rotig, A., Tarassov, I., Elpeleg, O. Acute infantile liver failure due to mutations in the TRMU gene. Am. J. Hum. Genet. 85: 401-407, 2009. Note: Erratum: Am. J. Hum. Genet. 86: 295 only, 2010. [PubMed: 19732863] [Full Text: https://doi.org/10.1016/j.ajhg.2009.08.004]