Deafness in TRbeta mutants is caused by malformation of the tectorial membrane.
Thyroid hormone receptor beta (TRbeta) dysfunction leads to deafness in humans and mice. Deafness in TRbeta(-/-) mutant mice has been attributed to TRbeta-mediated control of voltage- and Ca(2+)-activated K(+) (BK) channel expression in inner hair cells (IHCs). However, normal hearing in young constitutive BKalpha(-/-) mutants contradicts this hypothesis. Here, we show that mice with hair cell-specific deletion of TRbeta after postnatal day 11 (P11) have a delay in BKalpha expression but normal hearing, indicating that the origin of hearing loss in TRbeta(-/-) mutant mice manifested before P11. Analyzing the phenotype of IHCs in constitutive TRbeta(-/-) mice, we found normal Ca(2+) current amplitudes, exocytosis, and shape of compound action potential waveforms. In contrast, reduced distortion product otoacoustic emissions and cochlear microphonics associated with an abnormal structure of the tectorial membrane and enhanced tectorin levels suggest that disturbed mechanical performance is the primary cause of deafness resulting from TRbeta deficiency.
Winter
Harald
H
Department of Otorhinolaryngology, Tübingen Hearing Research Center, University of Tübingen, 72076 Tübingen, Germany.
Rüttiger
Lukas
L
Müller
Marcus
M
Kuhn
Stephanie
S
Brandt
Niels
N
Zimmermann
Ulrike
U
Hirt
Bernhard
B
Bress
Andreas
A
Sausbier
Matthias
M
Conscience
Aude
A
Flamant
Frederic
F
Tian
Yong
Y
Zuo
Jian
J
Pfister
Markus
M
Ruth
Peter
P
Löwenheim
Hubert
H
Samarut
Jacques
J
Engel
Jutta
J
Knipper
Marlies
M
D000161:Acoustic Stimulation / Q000379:methods; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001309:Auditory Threshold / Q000502:physiology; D003638:Deafness / Q000235:genetics* / Q000473:pathology*; D005089:Exocytosis / Q000235:genetics; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics*; D017084:Otoacoustic Emissions, Spontaneous / Q000235:genetics / Q000502:physiology; D024681:Potassium Channels, Calcium-Activated / Q000235:genetics / Q000378:metabolism*; D013680:Tectorial Membrane / Q000503:physiopathology*; D037042:Thyroid Hormone Receptors beta / Q000172:deficiency*
D008565:Membrane Proteins; D024681:Potassium Channels, Calcium-Activated; D037042:Thyroid Hormone Receptors beta; C111170:tectonin I; C111171:tectonin II