MYH1 deficiency disrupts outer hair cell electromotility, resulting in hearing loss
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 t...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2024-11-01
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| Series: | Experimental and Molecular Medicine |
| Online Access: | https://doi.org/10.1038/s12276-024-01338-4 |
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| author | Jinsei Jung Sun Young Joo Hyehyun Min Jae Won Roh Kyung Ah Kim Ji-Hyun Ma John Hoon Rim Jung Ah Kim Se Jin Kim Seung Hyun Jang Young Ik Koh Hye-Youn Kim Ho Lee Byoung Choul Kim Heon Yung Gee Jinwoong Bok Jae Young Choi Je Kyung Seong |
| author_facet | Jinsei Jung Sun Young Joo Hyehyun Min Jae Won Roh Kyung Ah Kim Ji-Hyun Ma John Hoon Rim Jung Ah Kim Se Jin Kim Seung Hyun Jang Young Ik Koh Hye-Youn Kim Ho Lee Byoung Choul Kim Heon Yung Gee Jinwoong Bok Jae Young Choi Je Kyung Seong |
| author_sort | Jinsei Jung |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-c8867c2bc8f2426cbb34d60e09e8b79f |
| institution | Kabale University |
| issn | 2092-6413 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Experimental and Molecular Medicine |
| spelling | doaj-art-c8867c2bc8f2426cbb34d60e09e8b79f2024-12-08T12:19:51ZengNature Publishing GroupExperimental and Molecular Medicine2092-64132024-11-0156112423243510.1038/s12276-024-01338-4MYH1 deficiency disrupts outer hair cell electromotility, resulting in hearing lossJinsei Jung0Sun Young Joo1Hyehyun Min2Jae Won Roh3Kyung Ah Kim4Ji-Hyun Ma5John Hoon Rim6Jung Ah Kim7Se Jin Kim8Seung Hyun Jang9Young Ik Koh10Hye-Youn Kim11Ho Lee12Byoung Choul Kim13Heon Yung Gee14Jinwoong Bok15Jae Young Choi16Je Kyung Seong17Department of Otorhinolaryngology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of MedicineInstitute for Lee Won Sang Yonsei Ear ScienceDepartment of Anatomy, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of MedicineDepartment of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of MedicineDepartment of Nanobioengineering, Incheon National UniversityDepartment of Anatomy, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of MedicineDepartment of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of MedicineInstitute for Lee Won Sang Yonsei Ear ScienceInstitute for Lee Won Sang Yonsei Ear ScienceInstitute for Lee Won Sang Yonsei Ear ScienceDepartment of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of MedicineDepartment of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of MedicineGraduate School of Cancer Science and Policy, National Cancer CenterDepartment of Nanobioengineering, Incheon National UniversityInstitute for Lee Won Sang Yonsei Ear ScienceDepartment of Otorhinolaryngology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of MedicineDepartment of Otorhinolaryngology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of MedicineKorea Mouse Phenotyping Center, Seoul National UniversityAbstract 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.https://doi.org/10.1038/s12276-024-01338-4 |
| spellingShingle | Jinsei Jung Sun Young Joo Hyehyun Min Jae Won Roh Kyung Ah Kim Ji-Hyun Ma John Hoon Rim Jung Ah Kim Se Jin Kim Seung Hyun Jang Young Ik Koh Hye-Youn Kim Ho Lee Byoung Choul Kim Heon Yung Gee Jinwoong Bok Jae Young Choi Je Kyung Seong MYH1 deficiency disrupts outer hair cell electromotility, resulting in hearing loss Experimental and Molecular Medicine |
| title | MYH1 deficiency disrupts outer hair cell electromotility, resulting in hearing loss |
| title_full | MYH1 deficiency disrupts outer hair cell electromotility, resulting in hearing loss |
| title_fullStr | MYH1 deficiency disrupts outer hair cell electromotility, resulting in hearing loss |
| title_full_unstemmed | MYH1 deficiency disrupts outer hair cell electromotility, resulting in hearing loss |
| title_short | MYH1 deficiency disrupts outer hair cell electromotility, resulting in hearing loss |
| title_sort | myh1 deficiency disrupts outer hair cell electromotility resulting in hearing loss |
| url | https://doi.org/10.1038/s12276-024-01338-4 |
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