Abstract
Approximately 50% of childhood deafness is caused by mutations in specific genes. Autosomal recessive loci account for approximately 80% of nonsyndromic genetic deafness1. Here we report the identification of a new transmembrane serine protease (TMPRSS3; also known as ECHOS1) expressed in many tissues, including fetal cochlea, which is mutated in the families used to describe both the DFNB10 and DFNB8 loci. An 8-bp deletion and insertion of 18 monomeric (∼68-bp) β-satellite repeat units, normally present in tandem arrays of up to several hundred kilobases on the short arms of acrocentric chromosomes, causes congenital deafness (DFNB10). A mutation in a splice-acceptor site, resulting in a 4-bp insertion in the mRNA and a frameshift, was detected in childhood onset deafness (DFNB8). This is the first description of β-satellite insertion into an active gene resulting in a pathogenic state, and the first description of a protease involved in hearing loss.
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Acknowledgements
We thank S. Dahoun, C. Vieux and M.A. Morris for help with the FISH analyses; all members of the S.E.A. laboratory, past and present, for transcription mapping; and A. Shintani, T. Sasaki, K. Nagamine, M. Takahashi, M. Sasaki and all members of the genomic sequencing team in the Laboratory of Genomic Medicine, Keio University School of Medicine for their contribution to this work. The laboratory of S.E.A. is supported by grants from the Swiss FNRS, the OFES/EU, and funds from the University and Cantonal Hospital of Geneva. The laboratory of B.B.-T. is supported in part by grants from the Applebaum Foundation. The Laboratory of Genomic Medicine, Keio University School of Medicine was supported in part by a Fund for Human Genome Sequencing Project from the Japan Science and Technology Corporation; Grants in Aid for Scientific Research on Priority Areas from the Ministry of Education, Science, Sports and Culture of Japan; and Grants in Aid for Scientific Research and a Fund for “Research for the Future” Program from the Japan Society for the Promotion of Science. The laboratory of A.G. is supported in part by grants from the FAUN-Stiftung.
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Figure A
Representative protein homologies with other transmembrane proteases are shown: human TMPRSS2 (O15393), mouse Tmprss2 (AAF64186), human TMPRSS4 (AAF74526), human TMPRSS1 (hepsin, P05981) and the human airway trypsin-like protease (ATRYPL, O60235). Domains, as detected in TMPRSS3, are boxed and labeled underneath with the active-site residues His257, Asp304 and Ser401 indicated (arrows). TMPRSS3 is predicted to cleave after the K or R residues, as it contains D395 at the base of the substrate-specificity-binding pocket (S1 subsite). Preceded by an R, the N terminus of the protease domain peptide sequence is IVGG. Proteolytic cleavage between R and I would result in protease activation similar to other serine protease zymogens11, converting TMPRSS3 to a non-catalytic and a catalytic subunit linked by a disulfide bond (probably C207 to C324). The TMPRSS3 serine protease domain contains six conserved cysteine residues which, by homology to other proteases and three-dimensional modeling, are likely to form the following intrasubunit disulfide bonds: C242-C258; C370-C386; C397-C425. The points of mutation in the DFNB8 and DFNB10 families are marked by 'Splice' and 'Ins', respectively. (GIF 59 kb)
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Scott, H., Kudoh, J., Wattenhofer, M. et al. Insertion of β-satellite repeats identifies a transmembrane protease causing both congenital and childhood onset autosomal recessive deafness. Nat Genet 27, 59–63 (2001). https://doi.org/10.1038/83768
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DOI: https://doi.org/10.1038/83768
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