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doi:10.1534/genetics.106.057372
A more recent version of this article appeared on August 1, 2006.
REGULAR RESEARCH PAPERS |
Multiple quantitative trait loci modify cochlear hair cell degeneration in the Beethoven (Tmc1Bth) mouse model of progressive hearing loss DFNA36
Yoshihiro Noguchi 1, Kiyoto Kurima 2, Tomoko Makishima 2, Martin Hrabe de Angelis 3, Helmut Fuchs 3, Gregory Frolenkov 2, Ken Kitamura 1 and Andrew Griffith 2*
1 Tokyo Medical and Dental University
2 National Institutes of Health
3 GSF Research Center for Environment and Health
* To whom correspondence should be addressed. E-mail: griffita{at}nidcd.nih.gov.
Submitted on February 17, 2006
Revised on March 28, 2006
Accepted on 26 April 2006
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/+ 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)F1xC]N2-Tmc1Bth/+ backcross progeny, and three other QTLs on chromosomes 11 (Tmc1m2), 12 (Tmc1m3), and 5 (Tmc1m4) in [(C/D)F1xC]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.
Key Words: auditory neuropathy, complex trait, hearing, modifier, quantitative trait
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