Mutations in potassium voltage-gated channel subfamily Q member 4 (KCNQ4) are etiologically linked to nonsyndromic hearing loss (NSHL), deafness nonsyndromic autosomal dominant 2 (DFNA2). To identify causative mutations of hearing loss in 98 Korean families, we performed whole exome sequencing. In four independent families with NSHL, we identified a cosegregating heterozygous missense mutation, c.140T>C (p.Leu47Pro), in KCNQ4. Individuals with the c.140T>C KCNQ4 mutation shared a haplotype flanking the mutated nucleotide, suggesting that this mutation may have arisen from a common ancestor in Korea. The mutant KCNQ4 protein could reach the plasma membrane and interact with wild-type (WT) KCNQ4, excluding a trafficking defect; however, it exhibited significantly decreased voltage-gated potassium channel activity and fast deactivation kinetics compared with WT KCNQ4. In addition, when co-expressed with WT KCNQ4, mutant KCNQ4 protein exerted a dominant-negative effect. Interestingly, the channel activity of the p.Leu47Pro KCNQ4 protein was rescued by the KCNQ activators MaxiPost and zinc pyrithione. The c.140T>C (p.Leu47Pro) mutation in KCNQ4 causes progressive NSHL; however, the defective channel activity of the mutant protein can be rescued using channel activators. Hence, in individuals with the c.140T>C mutation, NSHL is potentially treatable, or its progression may be delayed by KCNQ activators.
Bibliographical noteFunding Information:
information:This research was supported by the Research Program through the National Research Foundation of Korea (NRF) funded by the Korea government (MSIT, 2018R1A5A2025079 to H.Y.G, 2018R1A2B6002952 to J.Y.C., 2017M3A9E8029721 to J.J., and 2013R1A3A2042197 to M.G.L.).The authors thank the families for participating in this study. The authors also thank Yonsei Advanced Imaging Center in cooperation with Carl Zeiss Microscopy. This study was provided with bioresources from the National Biobank of Korea, Centers for Disease Control and Prevention, Republic of Korea (4845-301, 4851-302 and -307). H.Y.G., J.Y.C., and M.G.L. contributed to the conception and design of this study; J.Y.C. and J.J. referred the patients to the study; J.H.R., J.S.L., H.J.C., S.Y.J., S.Y., D.H.C., and J.H.L. analyzed WES data; Y.I.K., S.Y.L. and H.Y.G. performed surface biotinylation, immunoprecipitation, and immunofluorescence assays; D.H.S. and M.G.L. performed electrophysiological experiments and analyzed data; H.Y.G., J.Y.C., M.G.L., and J.J. drafted the manuscript. All authors have read and approved the final manuscript.
This research was supported by the Research Program through the National Research Foundation of Korea (NRF) funded by the Korea government (MSIT, 2018R1A5A2025079 to H.Y.G, 2018R1A2B6002952 to J.Y.C., 2017M3A9E8029721 to J.J., and 2013R1A3A2042197toM.G.L.).
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