Abstract
Many proteins necessary for sound transduction have been identified through positional cloning of genes that cause deafness1,2,3. We report here that mutations of LRTOMT are associated with profound nonsyndromic hearing loss at the DFNB63 locus on human chromosome 11q13.3–q13.4. LRTOMT has two alternative reading frames and encodes two different proteins, LRTOMT1 and LRTOMT2, detected by protein blot analyses. LRTOMT2 is a putative methyltransferase. During evolution, new transcripts can arise through partial or complete coalescence of genes4. We provide evidence that in the primate lineage LRTOMT evolved from the fusion of two neighboring ancestral genes, which exist as separate genes (Lrrc51 and Tomt) in rodents.
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References
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Acknowledgements
We thank the families for their participation in this study, which was supported by NIDCD/NIH (intramural research fund ZO1DC00035-06 and ZO1DC00035-06 to T.B.F., ZO1DC000060 and ZO1DC000064 to A.J.G.), funds from the European Commission FP6 Integrated Project EUROHEAR (contract number LSHG-CT-20054-512063:2), the Heinsius Houbolt Foundation and the Karadeniz Technical University Research Fund (contract numbers 2002.114.001.3 and 2006.114.001.1). In Tunisia work was also funded by Le Ministère de l'Enseignement Supérieur, de la Recherche Scientifique et de la Technologie, Tunisia. In Pakistan the Higher Education Commission and the Ministry of Science and Technology in Islamabad, Pakistan supported this project. We thank B. Ploplis, M. Ansari, A. Lagziel, E. Boger, S. Kitajiri, E. van Wijk, T. Peters and H. Spierenburg for their technical help and G. Vriend, F. Cremers, H. Brunner and C. Cremers for discussion. We also thank J. Bird, D. Drayna, M. Meisler and S. Sullivan for advice and comments in preparing the manuscript. We thank the Southwest National Primate Research Center, San Antonio, Texas for providing brain tissue samples from chimpanzee and baboon, and the Duke Lemur Center, Durham, North Carolina for brain tissue samples from a lemur.
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Z.M.A., T.B.F., S.M., E.K. and H.K. conceived and directed the project; Z.M.A. performed linkage, RT-PCR, western and mutational analyses, cloned isoforms, provided bioinformatic evaluations, prepared figures and co-wrote the manuscript; S.M. enrolled Tunisian families, performed linkage analyses, mutational screening, molecular modeling and helped write the manuscript; E.K. enrolled family TR57 and Turkish controls, performed linkage analysis in family TR57, screened for mutations and did expression profile analysis in human fetal tissues; I.A.B. conducted immunocytochemistry, interpreted results and helped write the manuscript; M.A.M. enrolled Tunisian families and performed genetic linkage and mutational screening; R.W.J.C. performed in situ hybridizations and mutation analysis of candidate genes in the Turkish family; Saima Riazuddin ascertained Pakistani families, helped with RT-PCR analyses and editing the manuscript; M.H.-A. enrolled Tunisian families and performed genetic linkage analyses; H.V. conducted the molecular modeling and helped with the writing; M.N.K. performed mutational analyses; A.T. enrolled Tunisian families and performed genetic linkage analyses; B.v.d.Z. prepared the cRNA in situ hybridization probes and performed hybridizations; S.Y.K. mapped DFNB63 and ascertained Pakistani families; L.A. performed molecular modeling; S.A.R. obtained clinical data for FGF3 and DFNB63 families; R.J.M. evaluated experimental designs and data, and helped write the manuscript; A.J.G. planned clinical evaluation and evaluated the data, and edited the manuscript; I.C. enrolled and examined Tunisian families; R.Ç. performed audiological testing of family TR57; J.O. helped with mutational analyses of TR57; A.K. supervised the work at the Karadeniz Technical University in Trabzon; A.G. directed clinical evaluations in Tunisia; Sheikh Riazuddin directed all work in Pakistan; T.B.F. directed work at the NIDCD, helped with data interpretation and co-wrote the manuscript; H.A. directed work in Tunisia; H.K. directed work at Radboud University Nijmegen, helped with data interpretation and co-wrote the manuscript.
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Ahmed, Z., Masmoudi, S., Kalay, E. et al. Mutations of LRTOMT, a fusion gene with alternative reading frames, cause nonsyndromic deafness in humans. Nat Genet 40, 1335–1340 (2008). https://doi.org/10.1038/ng.245
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DOI: https://doi.org/10.1038/ng.245
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