한빛사논문
- 조회498
Kyung Seok Oh1,7, Jae Won Roh1,7, Sun Young Joo1,7, Kunhi Ryu2, Jung Ah Kim1, Se Jin Kim1, Seung Hyun Jang1, Young Ik Koh1, Da Hye Kim3, Hye-Youn Kim1, Murim Choi4, Jinsei Jung3, Wan Namkung2, Joo Hyun Nam5,6, Jae Young Choi3 and Heon Yung Gee1
1Department of Pharmacology, Graduate School of Medical Science, Yonsei University College of Medicine, Brain Korea 21 Project, Seoul 03722, Republic of Korea.
2Yonsei University College of Pharmacy, Incheon 21983, Republic of Korea.
3Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
4Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
5Department of Physiology, Dongguk University College of Medicine, Gyeongju 38066, Republic of Korea.
6Channelopathy Research Center (CRC), Dongguk University College of Medicine, Gyeonggi-do 10326, Republic of Korea.
7These authors contributed equally: Kyung Seok Oh, Jae Won Roh, Sun Young Joo.
Corresponding authors : Correspondence to Joo Hyun Nam, Jae Young Choi or Heon Yung Gee.
Abstract
Pathogenic variants of KCNQ4 cause symmetrical, late-onset, progressive, high-frequency-affected hearing loss, which eventually involves all frequencies with age. To understand the contribution of KCNQ4 variants to hearing loss, we analyzed whole-exome and genome sequencing data from patients with hearing loss and individuals whose hearing phenotypes were unknown. In KCNQ4, we identified seven missense variants and one deletion variant in 9 hearing loss patients and 14 missense variants in the Korean population with an unknown hearing loss phenotype. The p.R420W and p.R447W variants were found in both cohorts. To investigate the effects of these variants on KCNQ4 function, we performed whole-cell patch clamping and examined their expression levels. Except for p.G435Afs*61, all KCNQ4 variants exhibited normal expression patterns similar to those of wild-type KCNQ4. The p.R331Q, p.R331W, p.G435Afs*61, and p.S691G variants, which were identified in patients with hearing loss, showed a potassium (K+) current density lower than or similar to that of p.L47P, a previously reported pathogenic variant. The p.S185W and p.R216H variants shifted the activation voltage to hyperpolarized voltages. The channel activity of the p.S185W, p.R216H, p.V672M, and p.S691G KCNQ4 proteins was rescued by the KCNQ activators retigabine or zinc pyrithione, whereas p.G435Afs*61 KCNQ4 proteins were partially rescued by sodium butyrate, a chemical chaperone. Additionally, the structure of the variants predicted using AlphaFold2 showed impaired pore configurations, as did the patch-clamp data. Our findings suggest that KCNQ4 variants may be overlooked in hearing loss that starts in adulthood. Some of these variants are medically treatable; hence, genetic screening for KCNQ4 is important.
논문정보
- Research article
- 2023년 04월 (BRIC 등록일 2023-04-04)
- 국내 연구진
- 의약학 > 유전 및 유전체의학
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