LRTOMT

LRTOMT
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; OMA:LRTOMT - orthologs
Gene location (Human) Chr. Chromosome 11 (human) [1] Band 11q13.4 Start 72,080,331 bp [1] End 72,110,782 bp [1]
Gene location (Mouse) Chr. Chromosome 7 (mouse) [2] Band 7 E2|7 Start 101,547,577 bp [2] End 101,555,566 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in testicle right testis left testis olfactory zone of nasal mucosa ganglionic eminence stromal cell of endometrium fallopian tube islet of Langerhans gonad ventricular zone Top expressed in morula embryo granulocyte blastocyst primary oocyte epiblast white adipose tissue placenta ovary proximal tubule More reference expression data BioGPS n/a
Gene ontology Molecular function methyltransferase activity transferase activity O-methyltransferase activity L-dopa O-methyltransferase activity catechol O-methyltransferase activity orcinol O-methyltransferase activity Cellular component cytoplasm integral component of membrane membrane plasma membrane endoplasmic reticulum cellular component Biological process methylation hearing catecholamine metabolic process neurotransmitter catabolic process catecholamine catabolic process auditory receptor cell development developmental process dopamine metabolic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 220074 791260 Ensembl ENSG00000284922 ENSMUSG00000078630 UniProt Q8WZ04 Q96E66 A1Y9I9 RefSeq (mRNA) NM_001145308 NM_001145309 NM_001145310 NM_001081679 NM_001282088 RefSeq (protein) NP_001138779 NP_001138780 NP_001138781 NP_001138782 NP_001192067 NP_001258400 NP_001305732 NP_660352 NP_001138779.1 NP_001192067.1 NP_001258400.1 NP_660352.1 NP_001305732.1 NP_001075148 NP_001269017 Location (UCSC) Chr 11: 72.08 – 72.11 Mb Chr 7: 101.55 – 101.56 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Leucine rich transmembrane and O-methyltransferase domain containing is a protein that is encoded by the LRTOMT gene in humans. This locus represents naturally occurring read-through transcript between the neighboring LRRC51 (leucine-rich repeat containing 51) and TOMT (transmembrane O-methyltransferase) genes on chromosome 11. Mutations in LRTOMT are associated with the DFNB63 form of autosomal recessive nonsyndromic hearing loss.

Gene

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]

Function

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]}

Clinical significance

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]

Identified Variants

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]

References

1. GRCh38: Ensembl release 89: ENSG00000284922 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000078630 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Ahmed ZM, Masmoudi S, Kalay E, Belyantseva IA, Mosrati MA, Collin RW, et al. (November 2008). "Mutations of LRTOMT, a fusion gene with alternative reading frames, cause nonsyndromic deafness in humans". Nature Genetics. 40 (11): 1335–1340. doi:10.1038/ng.245. PMC   3404732 . PMID   18953341.
6. Cunningham C. "The murine catecholamine methyltransferase mTOMT is essential for mechanotransduction by cochlear hair cells". eLife.
7. Erickson T. "Integration of Tmc1/2 into the mechanotransduction complex in zebrafish hair cells is regulated by Transmembrane O-methyltransferase (Tomt)". eLife.
8. Sarmadi A, Nasrniya S, Soleimani Farsani M, Narrei S, Nouri Z, Sepehrnejad M, et al. (June 2020). "A novel pathogenic variant in the LRTOMT gene causes autosomal recessive non-syndromic hearing loss in an Iranian family". BMC Medical Genetics. 21 (1): 127. doi: 10.1186/s12881-020-01061-7 . PMC   7285524 . PMID   32517708.
9. Kim Y, Han JH, Yoo HS, Choi BY (October 2022). "Molecular aetiology of ski-slope hearing loss and audiological course of cochlear implantees". European Archives of Oto-Rhino-Laryngology. 279 (10): 4871–4882. doi:10.1007/s00405-022-07317-7. PMID   35212774.
10. Yang YJ, Li Y, Gao L (2023). "Postmenopausal osteoporosis: Effect of moderate-intensity treadmill exercise on bone proteomics in ovariectomized rats". Frontiers in Surgery. 9 1000464. doi: 10.3389/fsurg.2022.1000464 . PMC   9852312 . PMID   36684175.

Further reading

• Charif M, Bounaceur S, Abidi O, Nahili H, Rouba H, Kandil M, et al. (December 2012). "The c.242G>A mutation in LRTOMT gene is responsible for a high prevalence of deafness in the Moroccan population". Molecular Biology Reports. 39 (12): 11011–11016. doi:10.1007/s11033-012-2003-3. PMID   23053991.
• Gibriel AA, Abou-Elew MH, Masmoudi S (April 2019). "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". Molecular Biology Reports. 46 (2): 2139–2145. doi:10.1007/s11033-019-04667-0. PMID   30730013.
• Ichinose A, Moteki H, Hattori M, Nishio SY, Usami S (May 2015). "Novel mutations in LRTOMT associated with moderate progressive hearing loss in autosomal recessive inheritance". The Annals of Otology, Rhinology, and Laryngology. 124 Suppl 1: 142S –147S. doi:10.1177/0003489415575043. PMID   25788562.
• Mosrati MA, Fadhlaoui-Zid K, Benammar-Elgaaied A, Gibriel AA, Ben Said M, Masmoudi S (October 2021). "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". Molecular Genetics & Genomic Medicine. 9 (10) e1810. doi:10.1002/mgg3.1810. PMC   8580077 . PMID   34514748.
• Salame M, Bonnet C, Moctar EC, Brahim SM, Dedy A, Vetah LA, et al. (September 2023). "Identification a novel pathogenic LRTOMT mutation in Mauritanian families with nonsyndromic deafness". European Archives of Oto-Rhino-Laryngology. 280 (9): 4057–4063. doi:10.1007/s00405-023-07907-z. PMID   36928321.
• Schulze JM (March 2009). "LRTOMT: a new tone in understanding the symphony of non-syndromic deafness". Clinical Genetics. 75 (3): 227–229. doi:10.1111/j.1399-0004.2009.01150_3.x. PMID   19250379.
• Vanwesemael M, Schrauwen I, Ceuppens R, Alasti F, Jorssen E, Farrokhi E, et al. (August 2011). "A 1 bp deletion in the dual reading frame deafness gene LRTOMT causes a frameshift from the first into the second reading frame". American Journal of Medical Genetics. Part A. 155A (8): 2021–2023. doi:10.1002/ajmg.a.34096. PMID   21739586.