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A recurrent mutation in KCNQ4 in Korean families with nonsyndromic hearing loss and rescue of the channel activity by KCNQ activators

 Dong Hoon Shin  ;  Jinsei Jung  ;  Young Ik Koh  ;  John Hoon Rim  ;  Joon Suk Lee  ;  Hye Ji Choi  ;  Sun Young Joo  ;  Seyoung Yu  ;  Do Hyeon Cha  ;  Seung Yeon Lee  ;  Ji Hyun Lee  ;  Min Goo Lee  ;  Jae Young Choi  ;  Heon Yung Gee 
 HUMAN MUTATION, Vol.40(3) : 335-346, 2019 
Journal Title
Issue Date
deafness nonsyndromic autosomal dominant 2 ; nonsyndromic hearing loss ; potassium voltage-gated channel subfamily Q member 4 ; voltage-gated potassium channel ; whole-exome sequencing
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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Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Otorhinolaryngology (이비인후과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Shin, Dong Hoon(신동훈)
Lee, Min Goo(이민구) ORCID logo https://orcid.org/0000-0001-7436-012X
Jung, Jinsei(정진세) ORCID logo https://orcid.org/0000-0003-1906-6969
Gee, Heon Yung(지헌영) ORCID logo https://orcid.org/0000-0002-8741-6177
Choi, Jae Young(최재영) ORCID logo https://orcid.org/0000-0001-9493-3458
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