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Originally published as Genetics Published Articles Ahead of Print on April 28, 2006.
Genetics, Vol. 173, 2111-2119, August 2006, Copyright © 2006
doi:10.1534/genetics.106.057372
Multiple Quantitative Trait Loci Modify Cochlear Hair Cell Degeneration in the Beethoven (Tmc1Bth) Mouse Model of Progressive Hearing Loss DFNA36
Yoshihiro Noguchi*,
,
Kiyoto Kurima*,
Tomoko Makishima*,1,
Martin Hrabé de Angelis
,
Helmut Fuchs,
Gregory Frolenkov*,2,
Ken Kitamura and
Andrew J. Griffith*,
,3
* Section on Gene Structure and Function and Hearing Section, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, Maryland 20850-3320, Department of Otolaryngology, Tokyo Medical and Dental University Graduate School, Tokyo 113-8519, Japan and GSF Research Center for Environment and Health, Institute of Experimental Genetics, Neuherberg 85764, Germany
3 Corresponding author: National Institutes of Health, 5 Research Court, Rockville, MD 20850-3320.
E-mail: griffita{at}nidcd.nih.gov
Dominant mutations of transmembrane channel-like gene 1 (TMC1) cause progressive sensorineural hearing loss in humans and Beethoven (Tmc1Bth/+) mice. Here we show that Tmc1Bth/+ mice on a C3HeB/FeJ strain background have selective degeneration of inner hair cells while outer hair cells remain structurally and functionally intact. Inner hair cells primarily function as afferent sensory cells, whereas outer hair cells are electromotile amplifiers of auditory stimuli that can be functionally assessed by distortion product otoacoustic emission (DPOAE) analysis. When C3H-Tmc1Bth/Bth is crossed with either C57BL/6J or DBA/2J wild-type mice, F1 hybrid Tmc1Bth/+ progeny have increased hearing loss associated with increased degeneration of outer hair cells and diminution of DPOAE amplitudes but no difference in degeneration of inner hair cells. We mapped at least one quantitative trait locus (QTL), Tmc1m1, for DPOAE amplitude on chromosome 2 in [(C/B)F1 x C]N2-Tmc1Bth/+ backcross progeny, and three other QTL on chromosomes 11 (Tmc1m2), 12 (Tmc1m3), and 5 (Tmc1m4) in [(C/D)F1 x C]N2-Tmc1Bth/+ progeny. The polygenic basis of outer hair cell degeneration in Beethoven mice provides a model system for the dissection of common, complex hearing loss phenotypes, such as presbycusis, that involve outer hair cell degeneration in humans.
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