Influence of gain of function epithelial chloride channel ClC-Kb mutation on hearing thresholds.
Hearing depends on functional ClC-K-type chloride channels composed of barttin with ClC-Ka or ClC-Kb. Loss-of-function mutations of the barttin gene BSND or of both, the ClC-Ka gene CLNKA and the ClC-Kb gene CLNKB lead to congenital deafness and renal salt wasting. Recently, we identified the gain-of-function mutation ClC-Kb(T481S) which is associated with increased blood pressure. To explore the impact of ClC-Kb(T481S) on hearing, healthy volunteers (n=329) and individuals suffering from tinnitus (n=246) volunteered for hearing tests (n=348) and genetic analysis (n=575). 19.1% of the individuals were heterozygote (ClC-Kb(T481S)/ClC-Kb) and 1.7% homozygote carriers. Pure tone average hearing threshold (PTAt) for air conduction was significantly (p<0.033) lower in ClC-Kb(T481S) carriers (13.2+/-1.2dB) than in wild-type individuals (17.1+/-0.9dB). The prevalence of ClC-Kb(T481S) carriers was significantly increased (29.7%) in individuals with PTAt<15dB (p<0.05) and significantly decreased (13.2%) in individuals with PTAt>30 dB (p<0.017). The difference was largely due to the female population. Bone conduction was less affected pointing to an effect of the mutation on middle ear function. Tinnitus tended to be more frequent in ClC-Kb(T481S) carriers, a difference, however, not statistically significant. In conclusion, hearing thresholds are slightly lower in carriers of ClC-Kb(T481S), i.e., the gain-of-function polymorphism ClC-Kb(T481S) exerts a subtle but significant protective effect against hearing loss.
Frey
Andreas
A
Department of Physiology, University of Tübingen, Gmelinstrasse 5, D-72076 Tübingen, Germany.
Lampert
Angelika
A
Waldegger
Siegfried
S
Jeck
Nikola
N
Waldegger
Petra
P
Artunc
Ferruh
F
Seebohm
Guiscard
G
Lang
Undine E
UE
Kupka
Susan
S
Pfister
Markus
M
Hoppe
Julia
J
Gerloff
Christian
C
Schaeffeler
Elke
E
Schwab
Matthias
M
Lang
Florian
F
D000328:Adult; D000818:Animals; D001301:Audiometry, Pure-Tone; D001309:Auditory Threshold / Q000502:physiology*; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D018118:Chloride Channels / Q000235:genetics* / Q000502:physiology; D004252:DNA Mutational Analysis; D003638:Deafness / Q000151:congenital / Q000235:genetics*; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D017136:Ion Transport / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D012737:Sex Factors; D013316:Stria Vascularis / Q000378:metabolism; D014012:Tinnitus / Q000235:genetics; D014982:Xenopus laevis
C440005:BSND protein, human; C412733:CLCNKB protein, human; D018118:Chloride Channels; D008565:Membrane Proteins