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MYH1 deficiency disrupts outer hair cell electromotility, resulting in hearing loss

김병철|성제경|Rim John Hoon|Kim Jung Ah|Jang Seung Hyun|Kim Se Jin|Choi Jae Young|Gee Heon Yung|Lee Ho|Roh Jae Won|Joo Sun Young|Koh Young Ik|Kim Hye-Youn|Jung Jinsei|Min Hyehyun|Kim Kyung Ah|Ma Ji-Hyun|Bok Jinwoong
생화학분자생물학회 (Korean Society Of Biochemistry And Molecular Biology)|2024.12|Experimental and Molecular Medicine|제56권 |pp. 2423-2435|DOI 10.1038/s12276-024-01338-4

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초록

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.

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.

참고문헌 (76)

  1. Venkatesh, M., "Genetics of non syndromic hearing loss", Med. J. Armed Forces India, 71, pp.363~368 (2015)
  2. Vos, B., "Risk factors for hearing loss in children : a systematic literature review and meta-analysis protocol", Syst. Rev, 8, pp.1~7 (2019)
  3. Schrijver, I., "Hereditary non-syndromic sensorineural hearing loss : transforming silence to sound", J. Mol. Diagn, 6, pp.275~284 (2004)
  4. Angeli, S., "Genetics of hearing and deafness", Anat. Rec, 295, pp.1812~1829 (2012)[DOI]
  5. Shearer, A. E., "GeneReviews®" (1999), University of Washington
  6. Investigators, G. P. P., "100,000 genomes pilot on rare-disease diagnosis in health care- preliminary report", N. Engl. J. Med, 385, pp.1868~1880 (2021)[DOI]
  7. Shearer, A. E., "Comprehensive genetic testing for hereditary hearing loss using massively parallel sequencing", Proc. Natl. Acad. Sci. USA, 107, pp.21104~21109 (2010)[DOI]
  8. Sloan-Heggen, C. M., "Comprehensive genetic testing in the clinical evalua tion of 1119 patients with hearing loss", Hum. Genet, 135, pp.441~450 (2016)[DOI]
  9. Bowl, M. R., "A large scale hearing loss screen reveals an extensive unex plored genetic landscape for auditory dysfunction", Nat. Commun, 8, pp.886~ (2017)[DOI]
  10. Ingham, N. J., "Mouse screen reveals multiple new genes underlying mouse and human hearing loss", PLoS Biol, 17, pp.e3000194~ (2019)[DOI]
  11. Masters, T. A, "Handbook of Experimental Pharmacology Vol. 235", pp.77~122 (2017)
  12. Zheng, J., "Prestin is the motor protein of cochlear outer hair cells", Nature, 405, pp.149~155 (2000)[DOI]
  13. Liberman, M. C., "Prestin is required for electromotility of the outer hair cell and for the cochlear amplifier", Nature, 419, pp.300~304 (2002)[DOI]
  14. He, D. Z., "Prestin and the dynamic stiffness of cochlear outer hair cells", J. Neurosci, 23, pp.9089~9096 (2003)[DOI]
  15. Takahashi, S., "Prestin’s fast motor kinetics is essential for mammalian cochlear amplification", Proc. Natl. Acad. Sci. USA, 120, pp.e2217891120~ (2023)[DOI]
  16. Ge, J., "Molecular mechanism of prestin electromotive signal amplification", Cell, 184, pp.4669~4679 (2021)[DOI]
  17. Bavi, N., "The conformational cycle of prestin underlies outer-hair cell elec tromotility", Nature, 600, pp.553~558 (2021)[DOI]
  18. Liu, X. Z., "Prestin, a cochlear motor protein, is defective in non-syndromic hearing loss", Hum. Mol. Genet, 12, pp.1155~1162 (2003)[DOI]
  19. Koo, H. Y., "Follistatin regulates the specification of the apical cochlea responsible for low-frequency hearing in mammals", Proc. Natl. Acad. Sci. USA, 120, pp.e2213099120~ (2023)[DOI]
  20. Lindau, M., "Patch-clamp techniques for time-resolved capacitance measurements in single cells", Pflug. Arch, 411, pp.137~146 (1988)[DOI]
  21. Altoe, A., "The effects of the activation of the inner-hair-cell basolateral K+ channels on auditory nerve responses", Hear. Res, 364, pp.68~80 (2018)[DOI]
  22. Dierich, M., "Optimized tuning of auditory inner hair cells to encode complex sound through synergistic activity of six independent K+ current entities", Cell Rep, 32, pp.107869~ (2020)[DOI]
  23. Mammano, F., "Differential expression of outer hair cell potassium currents in the isolated cochlea of the guinea-pig", J. Physiol, 496, pp.639~646 (1996)[DOI]
  24. Virtanen, P., "SciPy 1.0: fundamental algorithms for scientific computing in Python", Nat. Methods, 17, pp.261~272 (2020)[DOI]
  25. Harris, "Array programming with NumPy", Nature, 585, pp.357~362 (2020)[DOI]
  26. Jung, J., "Genetic predisposition to sporadic congenital hearing loss in a pediatric population", Sci. Rep, 7, pp.45973~ (2017)[DOI]
  27. Chang, M. Y., "Identification and clinical implications of novel MYO15A mutations in a non-consanguineous Korean family by targeted exome sequen cing", Mol. Cells, 38, pp.781~788 (2015)[DOI]
  28. Mirdita, M., "ColabFold: making protein folding accessible to all", Nat. Methods, 19, pp.679~682 (2022)[DOI]
  29. Jumper, J., "Highly accurate protein structure prediction with AlphaFold", Nature, 596, pp.583~589 (2021)[DOI]
  30. Pettersen, E. F., "UCSF ChimeraX: structure visualization for researchers, educators, and developers", Protein Sci, 30, pp.70~82 (2021)[DOI]
  31. Jo, S., "CHARMM-GUI: a web-based graphical user interface for CHARMM", J. Comput. Chem, 29, pp.1859~1865 (2008)[DOI]
  32. Brooks, B. R., "CHARMM: the biomolecular simulation program", J. Comput. Chem, 30, pp.1545~1614 (2009)[DOI]
  33. Lee, J., "CHARMM-GUI input generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM", OpenMM simulations using the CHARMM36 additive force field, 2016, pp.12, 405~413
  34. Abraham, M. J., "GROMACS : high performance molecular simulations through multi-level parallelism from laptops to supercomputers", SoftwareX, 1, pp.19~25 (2015)
  35. Ryckaert, J. -P., "Numerical integration of the carte sian equations of motion of a system with constraints : molecular dynamics of n-alkanes", J. Comput. Phys, 23, pp.327~341 (1977)
  36. Nosé, S., "A unified formulation of the constant temperature molecular dynamics methods", J. Chem. Phys, 81, pp.511~519 (1984)
  37. Hoover, W. G., "Canonical dynamics : equilibrium phase-space distributions", Phys. Rev. A, 31, pp.1695~ (1985)
  38. Humphrey, W., "VMD: visual molecular dynamics", J. Mol. Graph, 14, pp.33~38 (1996)[DOI]
  39. Grant, B. J., "Bio3d:an R package for the comparative analysis of protein structures", Bioinformatics, 22, pp.2695~2696 (2006)[DOI]
  40. Grant, B. J., "The Bio3D packages for structural bioin formatics", Protein Sci, 30, pp.20~30 (2021)[DOI]
  41. Gee, H. Y., "Syntaxin 16 binds to cystic fibrosis transmembrane conductance regulator and regulates its membrane trafficking in epithelial cells", J. Biol. Chem, 285, pp.35519~35527 (2010)[DOI]
  42. Oh, K. S., "Overlooked KCNQ4 variants augment the risk of hearing loss", Exp. Mol. Med, 55, pp.844~859 (2023)[DOI]
  43. Butler, J. P., "Traction fields, moments, and strain energy that cells exert on their surroundings", Am. J. Physiol. Cell Physiol, 282, pp.C595~C605 (2002)[DOI]
  44. Wang, N., "Cell prestress. I. Stiffness and prestress are closely associated in adherent contractile cells", Am. J. Physiol. Cell Physiol, 282, pp.C606~C616 (2002)[DOI]
  45. An, S. S., "Do biophysical properties of the airway smooth muscle in culture predict airway hyperresponsiveness?", Am. J. Respir. Cell Mol. Biol, 35, pp.55~64 (2006)[DOI]
  46. Zhang, X. D., "Prestin amplifies cardiac motor functions", Cell Rep, 35, pp.109097~ (2021)[DOI]
  47. Kubisch, C., "KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness", Cell, 96, pp.437~446 (1999)[DOI]
  48. Kharkovets, T., "Mice with altered KCNQ4 K+ channels implicate sensory outer hair cells in human progressive deafness", EMBO J, 25, pp.642~652 (2006)[DOI]
  49. Housley, G. D., "Direct measurement of the action of acetylcholine on isolated outer hair cells of the guinea pig cochlea", Proc. Biol. Sci, 244, pp.161~167 (1991)[DOI]
  50. Shin, D. H., "A recurrent mutation in KCNQ4 in Korean families with non syndromic hearing loss and rescue of the channel activity by KCNQ activators", Hum. Mutat, 40, pp.335~346 (2019)[DOI]
  51. Yu, S., "A novel early truncation mutation in OTOG causes prelingual mild hearing loss without vestibular dysfunction", Eur. J. Med. Genet, 62, pp.81~84 (2019)[DOI]
  52. Hwang, D., "Data speak how to treat disease big data-based precision medicine", Mol. Cells, 45, pp.620~621 (2022)[DOI]
  53. Joo, S. Y., "Clinical heterogeneity associated with variants relies on affected domains", Biomedicines, 10, pp.798~ (2022)[DOI]
  54. Koh, Y. I., "mutations impair autophagy and lead to hearing loss, potentially remedied by rapamycin", Autophagy, 18, pp.2593~2614 (2022)[DOI]
  55. Oh, K. S., "COCH-related autosomal dominant nonsyndromic hearing loss: a phenotype-genotype study", Hum. Genet, 141, pp.889~901 (2022)[DOI]
  56. Rim, J. H., "Differential genetic diagnoses of adult post-lingual hearing loss according to the audiogram pattern and novel candidate gene evaluation", Hum. Genet, 141, pp.915~927 (2022)[DOI]
  57. Lee, J., "A database of 5305 healthy Korean individuals reveals genetic and clinical implications for an East Asian population", Exp. Mol. Med, 54, pp.1862~1871 (2022)[DOI]
  58. Oza, A. M., "Expert specification of the ACMG", AMP variant interpretation guidelines for genetic hearing loss, 2018, pp.39, 1593~1613
  59. Gordon, C. M., "2013 Pediatric Position Development Conference: executive summary and reflections", J. Clin. Densitom, 17, pp.219~224 (2014)[DOI]
  60. Oldfors, A., "Myopathies associated with myosin heavy chain mutations", Acta Myol, 23, pp.90~96 (2004)
  61. Sfondouris, J., "Membrane com position modulates prestin-associated charge movement", J. Biol. Chem, 283, pp.22473~22481 (2008)[DOI]
  62. Dehghani-Ghahnaviyeh, S., "Lipid-mediated prestin organization in outer hair cell membranes and its implications in sound amplification", Nat. Commun, 13, pp.6877~ (2022)[DOI]
  63. Belyantseva, I. A., "Myosin XVa localizes to the tips of inner ear sensory cell stereocilia and is essential for staircase formation of the hair bundle", Proc. Natl. Acad. Sci. USA, 100, pp.13958~13963 (2003)[DOI]
  64. Ebrahim, S., "Stereocilia-staircase spacing is influenced by myosin III motors and their cargos espin-1 and espin-like", Nat. Commun, 7, pp.10833~ (2016)[DOI]
  65. Dallos, P., "Cochlear amplification, outer hair cells and prestin", Curr. Opin. Neurobiol, 18, pp.370~376 (2008)[DOI]
  66. Meltzer, J., "Temperature dependence of non-linear capacitance in human embryonic kidney cells transfected with prestin, the outer hair cell motor protein", Neurosci. Lett, 313, pp.141~144 (2001)[DOI]
  67. Lek, M., "Analysis of protein-coding genetic variation in 60,706 humans", Nature, 536, pp.285~291 (2016)[DOI]
  68. Wang, Y., "Genetic variants identified from epilepsy of unknown etiology in Chinese children by targeted exome sequencing", Sci. Rep, 7, pp.40319~ (2017)[DOI]
  69. Donaudy, F., "Nonmuscle myosin heavy-chain gene MYH14 is expressed in cochlea and mutated in patients affected by autosomal dominant hearing impairment (DFNA4)", Am. J. Hum. Genet, 74, pp.770~776 (2004)[DOI]
  70. Lalwani, A. K., "Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myosin MYH9", Am. J. Hum. Genet, 67, pp.1121~1128 (2000)[DOI]
  71. Melchionda, S., "MYO6, the human homologue of the gene responsible for deafness in Snell’s waltzer mice, is mutated in autosomal dominant non syndromic hearing loss", Am. J. Hum. Genet, 69, pp.635~640 (2001)[DOI]
  72. Ahmed, Z. M., "Mutations of MYO6 are associated with recessive deafness, DFNB37", Am. J.Hum.Genet, 72, pp.1315~1322 (2003)[DOI]
  73. Liu, X. Z., "Mutations in the myosin VIIA gene cause non-syndromic recessive deafness", Nat. Genet, 16, pp.188~190 (1997)[DOI]
  74. Liu, X. Z., "Autosomal dominant non-syndromic deafness caused by a mutation in the myosin VIIA gene", Nat. Genet, 17, pp.268~269 (1997)[DOI]
  75. Wang, A., "Association of unconventional myosin MYO15 mutations with human nonsyndromic deafness DFNB3", Science, 280, pp.1447~1451 (1998)[DOI]
  76. Rehman, A. U., "Mutational Spectrum of MYO15A and the molecular mechanisms of DFNB3 human deafness", Hum. Mutat, 37, pp.991~1003 (2016)[DOI]

관련 논문AI추천

Prestin and Motility of the Cochlear Outer Hair CellChul-Hee Choi대한청각학회 · Journal of Audiology & Otology2011 · 제15권 제3호A Novel Heterozygous Missense Variant (c.667G>T;p.Gly223Cys) in USH1C That Interferes With Cadherin-Related 23 and Harmonin Interaction Causes Autosomal Dominant Nonsyndromic Hearing Loss이진혁, Amel Bahloul, Change-Seok Ki, Christine Petit, Il Joon Moon, Ju Sun Song, Sang Jin Kim대한진단검사의학회 · Annals of Laboratory Medicine2020 · 제40권 제3호Strategy for the Customized Mass Screening of Genetic Sensorineural Hearing Loss in Koreans장문영, 최병윤대한청각학회 · Journal of Audiology & Otology2014 · 제18권 제2호Systematic genetic assessment of hearing loss using whole-genome sequencing identifies pathogenic variantsChoi Jae Young, Gee Heon Yung, Jang Seung Hyun, Joo Sun Yung, Jung Jinsei, Kim Jung Ah, Kim Se Jin생화학분자생물학회 · Experimental and Molecular Medicine2025 · 제57권 enAdvances in Understanding the Molecular Dynamics of Autosomal Dominant Auditory Neuropathy: Unveiling a Novel DIAPH3 Gene Variant Associated With Sensorineural Hearing Loss and Bilateral Vestibular Aqueduct EnlargementCorona Giuseppe, Margiotta Francesco, Miolo Gianmaria, Murgia Alessandra, Puppa Lara Della대한청각학회 · Journal of Audiology & Otology2025 · 제29권 제2호A Novel Frameshift Mutation of SLC26A4 in a Korean Family With Nonsyndromic Hearing Loss and Enlarged Vestibular Aqueduct김언경, 백정인, 이규엽, 보름사공대한이비인후과학회 · Clinical and Experimental Otorhinolaryngology2017 · 제10권 제1호

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