title: A catechol-O-methyltransferase that is essential for auditory function in mice and humans.
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.
authors.affiliation: Department of Genetics, Institute for Childhood and Neglected Diseases, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Du
authors.forename: Martin
authors.initials: M
authors.lastname: Schwander
authors.forename: Eva Marie Y
authors.initials: EM
authors.lastname: Moresco
authors.forename: Pia
authors.initials: P
authors.lastname: Viviani
authors.forename: Claudia
authors.initials: C
authors.lastname: Haller
authors.forename: Michael S
authors.initials: MS
authors.lastname: Hildebrand
authors.forename: Kwang
authors.initials: K
authors.lastname: Pak
authors.forename: Lisa
authors.initials: L
authors.lastname: Tarantino
authors.forename: Amanda
authors.initials: A
authors.lastname: Roberts
authors.forename: Heather
authors.initials: H
authors.lastname: Richardson
authors.forename: George
authors.initials: G
authors.lastname: Koob
authors.forename: Hossein
authors.initials: H
authors.lastname: Najmabadi
authors.forename: Allen F
authors.initials: AF
authors.lastname: Ryan
authors.forename: Richard J H
authors.initials: RJ
authors.lastname: Smith
authors.forename: Ulrich
authors.initials: U
authors.lastname: Müller
authors.forename: Bruce
authors.initials: B
authors.lastname: Beutler
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002394:Catechol O-Methyltransferase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003051:Cochlea / Q000201:enzymology; D003638:Deafness / Q000201:enzymology* / Q000235:genetics*; D005786:Gene Expression Regulation; D006199:Hair Cells, Auditory, Inner / Q000201:enzymology; D018072:Hair Cells, Auditory, Outer / Q000201:enzymology; D006309:Hearing / Q000235:genetics*; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009925:Organ of Corti / Q000201:enzymology / Q000473:pathology; D010375:Pedigree; D017354:Point Mutation
chemical_list: D002394:Catechol O-Methyltransferase
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