Novel KCNQ4 variants in different functional domains confer genotype- and mechanism-based therapeutics in patients with nonsyndromic hearing loss

Sang Yeon Lee, Hyun Been Choi, Mina Park, Il Soon Choi, Jieun An, Ami Kim, Eunku Kim, Nahyun Kim, Jin Hee Han, Min young Kim, Seung min Lee, Doo Yi Oh, Bong Jik Kim, Nayoung Yi, Nayoung, K.D. Kim, Chung Lee, Woong Yang Park, Young Ik Koh, Heon Yung Gee, Hyun Sung ChoTong Mook Kang, Byung Yoon Choi

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)


Loss-of-function variant in the gene encoding the KCNQ4 potassium channel causes autosomal dominant nonsyndromic hearing loss (DFNA2), and no effective pharmacotherapeutics have been developed to reverse channel activity impairment. Phosphatidylinositol 4,5-bisphosphate (PIP2), an obligatory phospholipid for maintaining KCNQ channel activity, confers differential pharmacological sensitivity of channels to KCNQ openers. Through whole-exome sequencing of DFNA2 families, we identified three novel KCNQ4 variants related to diverse auditory phenotypes in the proximal C-terminus (p.Arg331Gln), the C-terminus of the S6 segment (p.Gly319Asp), and the pore region (p.Ala271_Asp272del). Potassium currents in HEK293T cells expressing each KCNQ4 variant were recorded by patch-clamp, and functional recovery by PIP2 expression or KCNQ openers was examined. In the homomeric expression setting, the three novel KCNQ4 mutant proteins lost conductance and were unresponsive to KCNQ openers or PIP2 expression. Loss of p.Arg331Gln conductance was slightly restored by a tandem concatemer channel (WT-p.R331Q), and increased PIP2 expression further increased the concatemer current to the level of the WT channel. Strikingly, an impaired homomeric p.Gly319Asp channel exhibited hyperactivity when a concatemer (WT-p.G319D), with a negative shift in the voltage dependence of activation. Correspondingly, a KCNQ inhibitor and chelation of PIP2 effectively downregulated the hyperactive WT-p.G319D concatemer channel. Conversely, the pore-region variant (p.Ala271_Asp272del) was nonrescuable under any condition. Collectively, these novel KCNQ4 variants may constitute therapeutic targets that can be manipulated by the PIP2 level and KCNQ-regulating drugs under the physiological context of heterozygous expression. Our research contributes to the establishment of a genotype/mechanism-based therapeutic portfolio for DFNA2.

Original languageEnglish
Pages (from-to)1192-1204
Number of pages13
JournalExperimental and Molecular Medicine
Issue number7
Publication statusPublished - 2021 Jul

Bibliographical note

Funding Information:
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. 2019R1A2C1009915 to T. M. Kang). This work was supported by the NRF funded by the Ministry of Education (No. 2018R1A2B2001054 to B.Y. Choi), a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare Republic of Korea (No. HI17C0952 to B.Y. Choi.), and a research grant through Seoul National University Bundang Hospital (16-2019-006 to B.Y. Choi.,13-2019-002 to B.Y. Choi and 13-2018-015 to B.Y. Choi). This work was supported by the grant (No. 0420210670-2021 to S.Y. Lee) from the SNUH Research Fund.

Publisher Copyright:
© 2021, The Author(s).

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry


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