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, Martin Hrabé De Angelis, Helmut Fuchs, Gregory Frolenkov, Ken Kitamura, Andrew J. Griffith

Research output: Contribution to journalArticle

33 Scopus citations


Dominant mutations of transmembrane channel-like gene 1 (TMC1) cause progressive sensorineural hearing loss in humans and Beethoven (Tmc1 Bth/+) 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-Tmc1 Bth/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.

Original languageEnglish (US)
Pages (from-to)2111-2119
Number of pages9
Issue number4
StatePublished - 2006


ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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