A recurrent mutation in KCNQ4 in Korean families with nonsyndromic hearing loss and rescue of the channel activity by KCNQ activators. Issue 3 (25th December 2018)

• Record Type: Journal Article
• Authors: Shin, Dong Hoon; Jung, Jinsei; Koh, Young Ik; Rim, John Hoon; Lee, Joon Suk; Choi, Hye Ji; Joo, Sun Young; Yu, Seyoung; Cha, Do Hyeon; Lee, Seung Yeon; Lee, Ji Hyun; Lee, Min Goo; Choi, Jae Young; Gee, Heon Yung
• Is Part Of: Human mutation. Volume 40:Issue 3(2019)
• Page Start: 335
• Page End: 346
• Publication Date: 2018-12-25
• Subjects: deafness nonsyndromic autosomal dominant 2 -- nonsyndromic hearing loss -- potassium voltage‐gated channel subfamily Q member 4 -- voltage‐gated potassium channel -- whole‐exome sequencing; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.23698
• Languages: English
• ISSNs: 1059-7794

Abstract

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. Abstract : KQNQ4 is a voltage‐gated potassium channel and essential for outer hair cell function in the inner ear. Its mutations lead to nonsyndromic hearing loss. In this study, we identified a recurrent mutation c.140T>C (p.Leu47Pro) in KCNQ4 from four Korean families with hearing loss. The resulting mutant protein p.Leu47Pro exhibited reduced potassium channel activity; however, this defective channel activity was rescued by KCNQ activators, suggesting the possibility of medical intervention for hearing loss resulting from c.140T>C (p.Leu47Pro) KCNQ4 mutation.