| LRTOMT | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | LRTOMT , CFAP111, DFNB63, LRRC51, leucine rich transmembrane and O-methyltransferase domain containing, TOMT, LRRC51-TOMT | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 612414 MGI: 3769724 HomoloGene: 19664 GeneCards: LRTOMT | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Transmembrane O-methyltransferase (TOMT) is a protein encoded by the LRTOMT gene in humans. Located on chromosome 11, mutations in LRTOMT are associated with the DFNB63 form of autosomal recessive nonsyndromic hearing loss.
LRTOMT is a fusion between the LRRC51 and TOMT genes in humans. The fusion gene contains 10 exons that encode two separate proteins translated from unique and overlapping open reading frames (ORFs). Translation of LRTOMT1, a protein that contains leucine-rich repeats, starts in exon 3 and stops at exon 6. Translation of LRTOMT2, also known as TOMT or COMT2, starts in exon 5 and ends at exon 10. Human TOMT has a predicted methyltransferase domain that is conserved with catechol-o-methyltransferase (COMT) and a single predicted transmembrane alpha helix. Mice and zebrafish have separate genes for Lrrc51 and Tomt. [5]
TOMT is required for cochlear hair cell function and is associated with components of the mechanoelectrical transduction (MET) channel, including TMC1. While the mechanism by which TOMT contributes to MET currents and auditory function is currently unknown, the methyltransferase domain is likely not involved. Mutations in TOMT disrupt the stereocilia localization of MET channel subunits and are thus thought to affect MET currents. These results have also been illustrated in multiple mutations in both mice and zebrafish. [6] [7]
Over 20 variants in TOMT have been shown to cause hearing loss in humans. Populations reported to be most affected by TOMT-related hearing loss include Iranian and Tunisian families. [8]
| Variant | Identified Population |
|---|---|
| Leu16Pro | Iranian |
| Ala29Ser (frameshift) | Turkish |
| Thr33His (frameshift) | American |
| Met34Ilu | Iranian |
| Pro36Leu (frameshift) | Iranian |
| Ser45Ser (frameshift) | Iranian |
| Glu40Asp | Iranian |
| Arg41Trp | Iranian |
| Arg52Trp | Pakistani |
| Arg54Gln | Japanese |
| Leu60Pro | Mauritanian |
| Trp65Arg | Tunisian |
| Arg70X | Iranian |
| Tyr71X | Iranian |
| Glu80Asp | Iranian |
| Arg81Gln | Tunisian |
| Phe83Leu | Czech |
| Trp105Arg | Tunisian |
| Glu110Lys | Tunisian |
| Tyr111X | Iranian |
| Arg158His | Chinese |
| Ala170Ala (frameshift) | Iranian |
| Ilu188Thr (frameshift) | Japanese |
| Arg219X | Chinese |
While most variations cause prelingual profound sensorineural deafness, one patient with compound heterozygous mutations (Arg52Trp and Arg54Gln) was reported to develop ski-slope hearing loss starting at age 11. [9]
TOMT has also been associated with postmenopausal osteoporosis in rats. Specifically, LRTOMT downregulation after ovariectomy was significantly correlated with decreased bone density and changes in bone microstructure. [10]
Nonsyndromic deafness is hearing loss that is not associated with other signs and symptoms. In contrast, syndromic deafness involves hearing loss that occurs with abnormalities in other parts of the body. Nonsyndromic deafness constitutes 75% of all hearing loss cases, and an estimated 100 genes are thought to be linked to this condition. About 80% are linked to autosomal recessive inheritance, 15% to autosomal dominant inheritance, 1-3% through the X chromosome, and 0.5-1% are associated with mitochondrial inheritance.
Gap junction beta-2 protein (GJB2), also known as connexin 26 (Cx26) — is a protein that in humans is encoded by the GJB2 gene.
Usherin is a protein that in humans is encoded by the USH2A gene.
Harmonin is a protein that in humans is encoded by the USH1C gene. It is expressed in sensory cells of the inner ear and retina, where it plays a role in hearing, balance, and vision. Mutations at the USH1C locus cause Usher syndrome type 1c and nonsyndromic sensorineural deafness.
Cadherin-23 is a protein that in humans is encoded by the CDH23 gene.
Gap junction beta-6 protein (GJB6), also known as connexin 30 (Cx30) — is a protein that in humans is encoded by the GJB6 gene. Connexin 30 (Cx30) is one of several gap junction proteins expressed in the inner ear. Mutations in gap junction genes have been found to lead to both syndromic and nonsyndromic deafness. Mutations in this gene are associated with Clouston syndrome.
Wolframin is a protein that in humans is encoded by the WFS1 gene.
Gap junction beta-3 protein (GJB3), also known as connexin 31 (Cx31) — is a protein that in humans is encoded by the GJB3 gene.
Transmembrane protease, serine 3 is an enzyme that in humans is encoded by the TMPRSS3 gene.
Alpha-tectorin is a protein that in humans is encoded by the TECTA gene.
Eyes absent homolog 4 is a protein that in humans is encoded by the EYA4 gene.
Otoferlin is a protein that in humans is encoded by the OTOF gene. It is involved in vesicle membrane fusion, and mutations in the OTOF gene are associated with a genetic form of deafness.
Transmembrane channel-like protein 1 is a protein that in humans is encoded by the TMC1 gene. TMC1 contains six transmembrane domains with both the C and N termini on the endoplasmic side of the membrane, as well as a large loop between domains 4 and 5. This topology is similar to that of transient receptor potential channels (TRPs), a family of proteins involved in the perception of senses such as temperature, taste, pressure, and vision. TMC1 has been located in the post-natal mouse cochlea, and knockouts for TMC1 and TMC2 result in both auditory and vestibular deficits indicating TMC1 is a molecular part of auditory transduction.
Stereocilin is a protein that in humans is encoded by the STRC gene.
Myosin-XV is a protein that in humans is encoded by the MYO15A gene.
Espin, also known as autosomal recessive deafness type 36 protein or ectoplasmic specialization protein, is a protein that in humans is encoded by the ESPN gene. Espin is a microfilament binding protein.
Sine oculis-binding protein homolog (SOBP) also known as Jackson circler protein 1 (JXC1) is a protein that in humans is encoded by the SOBP gene. The first SOBP gene was identified in Drosophila melanogaster in a yeast two-hybrid screen that used the SIX domain of the Sine oculis protein as bait. In most genomes, which harbor SOBP, the gene is present as a single copy.
Otogelin is a protein that in humans is encoded by the OTOG gene.
SCAPER is a gene located on the long arm of chromosome 15 (15q24.3). It was first identified in 2007.
Pejvakin is a protein that in humans is encoded by the PJVK gene.
Charif, Majida. "The c.242G>A mutation in LRTOMT gene is responsible for a high prevalence of deafness in the Moroccan population". Mol Biol Rep.
Gibriel, Abdullah. "Analysis of p.Gly12Valfs*2, p.Trp24* and p.Trp77Arg mutations in GJB2 and p.Arg81Gln variant in LRTOMT among non syndromic hearing loss Egyptian patients: implications for genetic diagnosis". Mol Biol Rep.
Ichinose, Aya. "Novel mutations in LRTOMT associated with moderate progressive hearing loss in autosomal recessive inheritance". Ann Otol Rhinol Laryngol.
Mosrati, Mohamed. "Deep analysis of the LRTOMTc.242G>A variant in non-syndromic hearing loss North African patients and the Berber population: Implications for genetic diagnosis and genealogical studies". Mol Genet Genomic Med.
Salame, Malak. "Identification a novel pathogenic LRTOMT mutation in Mauritanian families with nonsyndromic deafness". Eur Arch Otorhinolaryngol.
Schulze, JM. "LRTOMT: a new tone in understanding the symphony of non-syndromic deafness". Clin Genet.
Vanwesemael, Maarten. "A 1 bp deletion in the dual reading frame deafness gene LRTOMT causes a frameshift from the first into the second reading frame". Am J Med Genet A.
