Multiple quantitative trait loci modify cochlear hair cell degeneration in the Beethoven (Tmc1Bth) mouse model of progressive hearing loss DFNA36.
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)F1xC]N2-Tmc1Bth/+ backcross progeny, and three other QTL 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.
Noguchi
Yoshihiro
Y
Section on Gene Structure and Function, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, MD 20850-3320, USA.
Kurima
Kiyoto
K
Makishima
Tomoko
T
de Angelis
Martin Hrabé
MH
Fuchs
Helmut
H
Frolenkov
Gregory
G
Kitamura
Ken
K
Griffith
Andrew J
AJ
D000818:Animals; D002874:Chromosome Mapping; D002875:Chromosomes / Q000235:genetics*; D004195:Disease Models, Animal; D018072:Hair Cells, Auditory, Outer / Q000473:pathology; D006319:Hearing Loss, Sensorineural / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D040641:Quantitative Trait Loci / Q000235:genetics*
D008565:Membrane Proteins; C451751:TMC1 protein, human; C514628:TMC1 protein, mouse