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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2008-09, Vol.105 (38), p.14609-14614
• Main Authors: Du, Xin, Schwander, Martin, Moresco, Eva Marie Y, Viviani, Pia, Haller, Claudia, Hildebrand, Michael S, Pak, Kwang, Tarantino, Lisa, Roberts, Amanda, Richardson, Heather, Koob, George, Najmabadi, Hossein, Ryan, Allen F, Smith, Richard J.H, Müller, Ulrich, Beutler, Bruce
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Biological Sciences; Catechol O-Methyltransferase - chemistry; Catechol O-Methyltransferase - genetics; Catechol O-Methyltransferase - metabolism; Catecholamines; Cloning; Cochlea; Cochlea - enzymology; Deafness; Deafness - enzymology; Deafness - genetics; Deoxyribonucleic acid; DNA; Ears & hearing; Gene Expression Regulation; Genetic mutation; Genotype & phenotype; Hair cells; Hair Cells, Auditory, Inner - enzymology; Hair Cells, Auditory, Outer - enzymology; Hearing - genetics; Humans; Inner ear; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Molecular Sequence Data; Mutation; Organ of corti; Organ of Corti - enzymology; Organ of Corti - pathology; Pedigree; Phenotypes; Point Mutation; Rodents; Schizophrenia
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0807219105

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.