A catechol-O-methyltransferase that is essential for auditory function in mice and humans.
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.
Du
Xin
X
Department of Genetics, Institute for Childhood and Neglected Diseases, The Scripps Research Institute, La Jolla, CA 92037, USA.
Schwander
Martin
M
Moresco
Eva Marie Y
EM
Viviani
Pia
P
Haller
Claudia
C
Hildebrand
Michael S
MS
Pak
Kwang
K
Tarantino
Lisa
L
Roberts
Amanda
A
Richardson
Heather
H
Koob
George
G
Najmabadi
Hossein
H
Ryan
Allen F
AF
Smith
Richard J H
RJ
Müller
Ulrich
U
Beutler
Bruce
B
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
D002394:Catechol O-Methyltransferase
Eur J Neurosci. 2002 Jan;15(2):246-56
11849292
Neuron. 2006 Oct 5;52(1):139-53
17015232
Nature. 1995 Mar 2;374(6517):60-1
7870171
Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7612-6
7644464
Arch Gen Psychiatry. 1999 Oct;56(10):940-5
10530637
Nature. 1995 Mar 2;374(6517):62-4
7870172
J Neurosci. 2007 Feb 28;27(9):2163-75
17329413
Nature. 1996 Feb 15;379(6566):606-12
8628395
Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):9991-6
9707588
Nature. 2003 Aug 14;424(6950):743-8
12872135
J Comp Neurol. 2006 Sep 20;498(3):403-14
16871528
Am J Hum Genet. 2002 Dec;71(6):1296-302
12402217
Prog Neurobiol. 1995 Dec;47(6):449-76
8787031
Physiol Rev. 1993 Apr;73(2):309-73
8097330
Biol Psychiatry. 2006 Jul 15;60(2):141-51
16476412
Eur J Biochem. 1994 Aug 1;223(3):1049-59
8055944
Hum Genet. 2005 Mar;116(4):319-28
15645182
J Pharmacol Exp Ther. 2002 Dec;303(3):1309-16
12438556