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Exp. Mol. Med., 01 November 2024 | https://doi.org/10.1038/s12276-024-01338-4 MYH1 deficiency disrupts outer hair cell electromotility, resulting in hearing loss

Jinsei Jung ^1,2,10, Sun Young Joo^2,3,10, Hyehyun Min ^4,10, Jae Won Roh ^3,5,10, Kyung Ah Kim ⁶, Ji-Hyun Ma⁴, John Hoon Rim ³, Jung Ah Kim^2,3, Se Jin Kim ^2,3, Seung Hyun Jang ^2,3, Young Ik Koh ^3,5, Hye-Youn Kim^3,5, Ho Lee⁷, Byoung Choul Kim ⁶, Heon Yung Gee^2,3,5,*, Jinwoong Bok ^1,2,4,*, Jae Young Choi ^1,2,* and Je Kyung Seong ^8,9,*

¹Department of Otorhinolaryngology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea.
²Institute for Lee Won Sang Yonsei Ear Science, Seoul, Republic of Korea.
³Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea.
⁴Department of Anatomy, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea.
⁵Woo Choo Lee Institute for Precision Drug Development, Seoul, Republic of Korea.
⁶Department of Nanobioengineering, Incheon National University, Incheon, Korea.
⁷Graduate School of Cancer Science and Policy, National Cancer Center, Goyang-si, Republic of Korea.
⁸Korea Mouse Phenotyping Center, Seoul National University, Seoul, Republic of Korea.
⁹Laboratory of Developmental Biology and Genomics, BK21 Program Plus for Advanced Veterinary Science, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
¹⁰These authors contributed equally: Jinsei Jung, Sun Young Joo, Hyehyun Min, Jae Won Roh.

^*Corresponding authors: correspondence to Heon Yung Gee, Jinwoong Bok, Jae Young Choi or Je Kyung Seong

Abstract

Myh1 is a mouse deafness gene with an unknown function in the auditory system. Hearing loss in Myh1-knockout mice is characterized by an elevated threshold for the auditory brainstem response and the absence of a threshold for distortion product otoacoustic emission. Here, we investigated the role of MYH1 in outer hair cells (OHCs), crucial structures in the organ of Corti responsible for regulating cochlear amplification. Direct whole-cell voltage-clamp recordings of OHCs revealed that prestin activity was lower in Myh1-knockout mice than in wild-type mice, indicating abnormal OHC electromotility. We analyzed whole-exome sequencing data from 437 patients with hearing loss of unknown genetic causes and identified biallelic missense variants of MYH1 in five unrelated families. Hearing loss in individuals harboring biallelic MYH1 variants was non-progressive, with an onset ranging from congenital to childhood. Three of five individuals with MYH1 variants displayed osteopenia. Structural prediction by AlphaFold2 followed by molecular dynamic simulations revealed that the identified variants presented structural abnormalities compared with wild-type MYH1. In a heterogeneous overexpression system, MYH1 variants, particularly those in the head domain, abolished MYH1 functions, such as by increasing prestin activity and modulating the membrane traction force. Overall, our findings suggest an essential function of MYH1 in OHCs, as observed in Myh1-deficient mice, and provide genetic evidence linking biallelic MYH1 variants to autosomal recessive hearing loss in humans.

논문정보

형식Research article
게재일2024년 11월 (BRIC 등록일 2024-11-01)
연구진국내 연구진
분야 의약학 > 유전 및 유전체의학

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