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

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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.

Original languageEnglish
Pages (from-to)335-346
Number of pages12
JournalHuman mutation
Volume40
Issue number3
DOIs
Publication statusPublished - 2019 Mar

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All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Shin, D. H., Jung, J., Koh, Y. I., Rim, J. H., Lee, J. S., Choi, H. J., Joo, S. Y., Yu, S., Cha, D. H., Lee, S. Y., Lee, J. H., Lee, M. G., Choi, J. Y., & Gee, H. Y. (2019). A recurrent mutation in KCNQ4 in Korean families with nonsyndromic hearing loss and rescue of the channel activity by KCNQ activators. Human mutation, 40(3), 335-346. https://doi.org/10.1002/humu.23698