Rare KCNQ4 variants found in public databases underlie impaired channel activity that may contribute to hearing impairment

Jinsei Jung, Haiyue Lin, Young Ik Koh, Kunhi Ryu, Joon Suk Lee, John Hoon Rim, Hye Ji Choi, Hak Joon Lee, Hye Youn Kim, Seyoung Yu, Hyunsoo Jin, Ji Hyun Lee, Min Goo Lee, Wan Namkung, Jae Young Choi, Heon Yung Gee

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)


KCNQ4 is frequently mutated in autosomal dominant non-syndromic hearing loss (NSHL), a typically late-onset, initially high-frequency loss that progresses over time (DFNA2). Most KCNQ4 mutations linked to hearing loss are clustered around the pore region of the protein and lead to loss of KCNQ4-mediated potassium currents. To understand the contribution of KCNQ4 variants to NSHL, we surveyed public databases and found 17 loss-of-function and six missense KCNQ4 variants affecting amino acids around the pore region. The missense variants have not been reported as pathogenic and are present at a low frequency (minor allele frequency < 0.0005) in the population. We examined the functional impact of these variants, which, interestingly, induced a reduction in potassium channel activity without altering expression or trafficking of the channel protein, being functionally similar to DFNA2-associated KCNQ4 mutations. Therefore, these variants may be risk factors for late-onset hearing loss, and individuals harboring any one of these variants may develop hearing loss during adulthood. Reduced channel activity could be rescued by KCNQ activators, suggesting the possibility of medical intervention. These findings indicate that KCNQ4 variants may contribute more to late-onset NSHL than expected, and therefore, genetic screening for this gene is important for the prevention and treatment of NSHL.

Original languageEnglish
Article number99
JournalExperimental and Molecular Medicine
Issue number8
Publication statusPublished - 2019 Aug 1

Bibliographical note

Funding Information:
We thank Yonsei Advanced Imaging Center in cooperation with Carl Zeiss Microscopy. This study was supported by the Basic Science Research Program of the National Research Foundation of Korea (NRF) (MSIT; 2018R1A5A2025079 to H.Y.G. and 2016R1A2B4007268 to C.J.Y.), by the Ministry of Health & Welfare, Republic of Korea (2017M3A9E8029714 to J.J.), and by the National Biobank of Korea, Centers for Disease Control and Prevention, Republic of Korea (4845-301, 4851-302 and -307).

Publisher Copyright:
© 2019, The Author(s).

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry


Dive into the research topics of 'Rare KCNQ4 variants found in public databases underlie impaired channel activity that may contribute to hearing impairment'. Together they form a unique fingerprint.

Cite this