Ion channels play important roles in signal transduction and in the regulation of the ionic composition of intra- and extracellular fluids. Mutations in ion channels have long been thought to be responsible for some forms of hearing loss. Defects in KCNQ4, a voltage-gated potassium channel, are a cause of nonsyndromic sensorineural deafness type 2, an autosomal dominant form of progressive hearing loss. We present data of mutation analysis of KCNQ4 from 185 unrelated Taiwanese probands with nonsyndromic hearing loss. The analysis revealed three novel KCNQ4 mutations and many polymorphisms. The prevalence of KCNQ4 gene mutations in this study was 1.62% (3/185). The mutations include a missense mutation (F182L) and two silent mutations (R216R and T501T). The F182L missense mutation was located in the S3 domain of KCNQ4. The F182 residue of KCNQ4 is highly conserved in KCNQ4 among various species and is less conserved in all members of the KCNQ family. In addition, although R216R is a silent mutation and does not alter the content of amino acid residue, the neural network prediction system revealed that it can potentially create a novel splice donor site during transcription. This mutation might affect the protein structure of KCNQ4 and consequently the normal function of the K+ channel. Our data provide the first comprehensive analysis of the KCNQ4 gene in Taiwanese patients with nonsyndromic deafness.

Keywords:
KCNQ4, Nonsyndromic hearing loss, K+ channel, Mutation
1.
Akita J, Abe S, Shinkawa H, Kimberling WJ, Usami S: Clinical and genetic features of nonsyndromic autosomal dominant sensorineural hearing loss: KCNQ4 is a gene responsible in Japanese. J Hum Genet 2001;46:355–361.
2.
Beisel KW, Nelson NC, Delimont DC, Fritzsch B: Longitudinal gradients of KCNQ4 expression in spiral ganglion and cochlear hair cells correlate with progressive hearing loss in DFNA2. Brain Res Mol Brain Res 2000;82:137–149.
3.
Catterall WA: Structure and function of voltage-sensitive ion channels. Science 1988;242:50–61.
4.
Chamary JV, Parmley JL, Hurst LD: Hearing silence: non-neutral evolution at synonymous sites in mammals. Nat Rev Genet 2006;7:98–108.
5.
Coucke PJ, Van Hauwe P, Kelley PM, Kunst H, Schatteman I, Van Velzen D, Meyers J, Ensink RJ, Verstreken M, Declau F, Marres H, Kastury K, Bhasin S, McGuirt WT, Smith RJ, Cremers CW, Van de Heyning P, Willems PJ, Smith SD, Van Camp G: Mutations in the KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families. Hum Mol Genet 1999;8:1321–1328.
6.
Finsterer J, Fellinger J: Nuclear and mitochondrial genes mutated in nonsyndromic impaired hearing. Int J Pediatr Otorhinolaryngol 2005;69:621–647.
7.
Kharkovets T, Hardelin JP, Safieddine S, Schweizer M, El-Amraoui A, Petit C, Jentsch TJ: KCNQ4, a K+ channel mutated in a form of dominant deafness, is expressed in the inner ear and the central auditory pathway. Proc Natl Acad Sci USA 2000;97:4333–4338.
8.
Kubisch C, Schroeder BC, Friedrich T, Lutjohann B, El-Amraoui A, Marlin S, Petit C, Jentsch TJ: KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness. Cell 1999;96:437–446.
9.
Reese MG, Eeckman FH, Kulp D, Haussler D: Improved splice site detection in Genie. J Comput Biol 1997;4:311–323.
10.
Schroeder BC, Kubisch C, Stein V, Jentsch TJ: Moderate loss of function of cyclic-AMP-modulated KCNQ2/KCNQ3 K+ channels causes epilepsy. Nature 1998;396:687–690.
11.
Talebizadeh Z, Kelley PM, Askew JW, Beisel KW, Smith SD: Novel mutation in the KCNQ4 gene in a large kindred with dominant progressive hearing loss. Hum Mutat 1999;14:493–501.
12.
Van Camp G, Coucke PJ, Akita J, Fransen E, Abe S, De Leenheer EMR, Huygen PLM, Cremers CWRJ, Usami SI: A mutational hot spot in the KCNQ4 gene responsible for autosomal dominant hearing impairment. Hum Mutat2002;20:15–19.
13.
Van Hauwe P, Coucke PJ, Ensink RJ, Huygen P, Cremers CWRJ, Van Camp G: Mutations in the KCNQ4 K(+) channel gene, responsible for autosomal dominant hearing loss, cluster in the channel pore region. Am J Med Genet 2000;93:184–187.
© 2007 S. Karger AG, Basel
2006
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.