A mutation in TMTC2 reveals a new mechanism causing sensorineural hearing loss. M. Olivier1, A. Indap2, Y. Zhou3, J. W. Kent Jr.1, E. King4, C. B. Erbe4, R. Cole5, J. Littrell5, K. Merath5, S. Mleziva4, J. Jensen4, L. S. Burg4, F. Rüschendorf6, J. E. Kerschner4, G. Marth2, N. Hübner6, H. H. H. Göring1, D. F. Friedland4, W.-M. Kwok3, C. L. Runge4,7 1) Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX., USA; 2) Department of Biology, Boston College, Chestnut Hill, MA, USA; 3) Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA; 4) Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee, WI, USA; 5) Biotechnology and Bioengineering Center, Medical College of Wisconsin, Milwaukee, WI, USA; 6) Max-Delbrück Centre for Molecular Medicine, Berlin-Buch, Germany; 7) Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA.
Sensorineural hearing loss (SNHL) is commonly caused by pathologies affecting cochlear structures or the auditory nerve. Over 32 independent genetic loci have been demonstrated to cause nonsyndromic autosomal dominant SNHL, and 190 mutations in 31genes have been described so far. Similarly, 53 loci have been identified for recessive forms of SNHL. Despite this large number, genes causing SNHL identified to date only explain a fraction of the overall genetic risk for this debilitating disorder. Here, we report on a six-generation family of Northern European descent with 18 individuals displaying bilateral, symmetric, progressive SNHL. Genome-wide exome sequencing identified a rare, fully penetrant variant in an uncharacterized gene, TMTC2, that segregates with SNHL in this family (Val381Ile, rs35725509, p=6x10-13). In contrast, no previously reported hearing loss mutations were identified in this family. Analysis of a cohort of unrelated individuals with SNHL (N=182) revealed that 3% also carried this same mutation, compared to 0.8% of individuals in the general population, as assessed by the NHLBI Exome Sequencing Project (p=5x10-6), making rs3572559 the third most common mutation causing autosomal dominant SNHL reported to date. The electrophysiological characterization of TMTC2 reveals that the Val381Ile mutation significantly accelerates the inactivation kinetics of ion channels when an expression plasmid with the coding sequence of TMTC2 carrying the Val381Ile variant is transiently transfected into HEK293 cells and compared to cells transfected with the TMTC2 wildtype expression plasmid. This suggests that TMTC2 is a regulatory protein modulating inner ear function and hearing, and is not an ion channel or structural protein as other genes previously implicated in SNHL. Such a functional role has not been described before for genes contributing to hearing loss, and may suggest a novel regulatory mechanism affecting auditory nerve function in normal hearing.
You may contact the first author (during and after the meeting) at