A catechol-O-methyltransferase that is essential for auditory function in mice and humans

Xin Du, Martin Schwander, Eva Marie Y Moresco, Pia Viviani, Claudia Haller, Michael S. Hildebrand, Kwang Pak, Lisa Tarantino, Amanda Roberts, Heather Richardson, George Koob, Hossein Najmabadi, Allen F. Ryan, Richard J H Smith, Ulrich Müller, Bruce Beutler

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

We have identified a previously unannotated catechol-O-methyltranferase (COMT), here designated COMT2, through positional cloning of a chemically induced mutation responsible for a neurobehavioral phenotype. Mice homozygous for a missense mutation in Comt2 show vestibular impairment, profound sensorineuronal deafness, and progressive degeneration of the organ of Corti. Consistent with this phenotype, COMT2 is highly expressed in sensory hair cells of the inner ear. COMT2 enzymatic activity is significantly reduced by the missense mutation, suggesting that a defect in catecholamine catabolism underlies the auditory and vestibular phenotypes. Based on the studies in mice, we have screened DNA from human families and identified a nonsense mutation in the human ortholog of the murine Comt2 gene that causes nonsyndromic deafness. Defects in catecholamine modification by COMT have been previously implicated in the development of schizophrenia. Our studies identify a previously undescribed COMT gene and indicate an unexpected role for catecholamines in the function of auditory and vestibular sense organs.

Original languageEnglish (US)
Pages (from-to)14609-14614
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number38
DOIs
StatePublished - Sep 23 2008

Keywords

  • Deafness
  • ENU
  • Genetics
  • Hearing
  • Positional cloning

ASJC Scopus subject areas

  • General

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    Du, X., Schwander, M., Moresco, E. M. Y., Viviani, P., Haller, C., Hildebrand, M. S., Pak, K., Tarantino, L., Roberts, A., Richardson, H., Koob, G., Najmabadi, H., Ryan, A. F., Smith, R. J. H., Müller, U., & Beutler, B. (2008). A catechol-O-methyltransferase that is essential for auditory function in mice and humans. Proceedings of the National Academy of Sciences of the United States of America, 105(38), 14609-14614. https://doi.org/10.1073/pnas.0807219105