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

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dc.contributor.author지헌영-
dc.date.accessioned2022-02-23T01:28:16Z-
dc.date.available2022-02-23T01:28:16Z-
dc.date.issued2021-07-
dc.identifier.issn1226-3613-
dc.identifier.urihttps://ir.ymlib.yonsei.ac.kr/handle/22282913/187716-
dc.description.abstractLoss-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.-
dc.description.statementOfResponsibilityopen-
dc.languageEnglish-
dc.publisherNature Publishing Group-
dc.relation.isPartOfEXPERIMENTAL AND MOLECULAR MEDICINE-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.titleNovel KCNQ4 variants in different functional domains confer genotype- and mechanism-based therapeutics in patients with nonsyndromic hearing loss-
dc.typeArticle-
dc.contributor.collegeCollege of Medicine (의과대학)-
dc.contributor.departmentDept. of Pharmacology (약리학교실)-
dc.contributor.googleauthorSang-Yeon Lee-
dc.contributor.googleauthorHyun Been Choi-
dc.contributor.googleauthorMina Park-
dc.contributor.googleauthorIl Soon Choi-
dc.contributor.googleauthorJieun An-
dc.contributor.googleauthorAmi Kim-
dc.contributor.googleauthorEunku Kim-
dc.contributor.googleauthorNahyun Kim-
dc.contributor.googleauthorJin Hee Han-
dc.contributor.googleauthorMin Young Kim-
dc.contributor.googleauthorSeung Min Lee-
dc.contributor.googleauthorDoo-Yi Oh-
dc.contributor.googleauthorBong Jik Kim-
dc.contributor.googleauthorNayoung Yi-
dc.contributor.googleauthorNayoung K D Kim-
dc.contributor.googleauthorChung Lee-
dc.contributor.googleauthorWoong-Yang Park-
dc.contributor.googleauthorYoung Ik Koh-
dc.contributor.googleauthorHeon Yung Gee-
dc.contributor.googleauthorHyun Sung Cho-
dc.contributor.googleauthorTong Mook Kang-
dc.contributor.googleauthorByung Yoon Choi-
dc.identifier.doi10.1038/s12276-021-00653-4-
dc.contributor.localIdA03971-
dc.relation.journalcodeJ00860-
dc.identifier.eissn2092-6413-
dc.identifier.pmid34316018-
dc.contributor.alternativeNameGee, Heon Yung-
dc.contributor.affiliatedAuthor지헌영-
dc.citation.volume53-
dc.citation.number7-
dc.citation.startPage1192-
dc.citation.endPage1204-
dc.identifier.bibliographicCitationEXPERIMENTAL AND MOLECULAR MEDICINE, Vol.53(7) : 1192-1204, 2021-07-
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers

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