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정진세 고영익 지헌영(약리학교실) Hum Mutat
등록일 : 2019-01-02 오후 2:52:00       조회 : 1820
첨   부 :
제1저자 정진세(약리학교실/현 이비인후과학교실, Phy-Sci 의과학과 졸업) 고영익(약리학교실, BK21)
공동교신저자 지헌영(약리학교실, BK21)

Hum Mutat. 2018 Dec 17. doi: 10.1002/humu.23698. [Epub ahead of print]
A recurrent mutation in KCNQ4 in Korean families with nonsyndromic hearing loss and rescue of the channel activity by KCNQ activators.
Shin DH1, Jung J2, Koh YI1, Rim JH1, Lee JS1, Choi HJ2, Joo SY1, Yu S1, Cha DH3, Lee SY3, Lee JH4, Lee MG1, Choi JY2, Gee HY1.

Author information
1Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, 03722, Korea.2Department of Otorhinolaryngology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, 03722, Korea.3Department of Medicine, Yonsei University College of Medicine, Seoul, 03722, Korea.4Department of Dermatology, Seoul St. Mary''s Hospital, College of Medicine, The Catholic University of Korea, Seoul, 03722, Korea.

Abstract
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.
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