Abstract
Stereocilia protrude up to 100 µm from the apical surface of vertebrate inner ear hair cells and are packed with cross-linked filamentous actin (F-actin). They function as mechanical switches to convert sound vibration into electrochemical neuronal signals transmitted to the brain. Several genes encode molecular components of stereocilia including actin monomers, actin regulatory and bundling proteins, motor proteins and the proteins of the mechanotransduction complex. A stereocilium F-actin core is a dynamic system, which is continuously being remodeled while maintaining an outwardly stable architecture under the regulation of F-actin barbed-end cappers, severing proteins and crosslinkers. The F-actin cores of stereocilia also provide a pathway for motor proteins to transport cargos including components of tip-link densities, scaffolding proteins and actin regulatory proteins. Deficiencies and mutations of stereocilia components that disturb this “dynamic equilibrium” in stereocilia can induce morphological changes and disrupt mechanotransduction causing sensorineural hearing loss, best studied in mouse and zebrafish models. Currently, at least 23 genes, associated with human syndromic and nonsyndromic hearing loss, encode proteins involved in the development and maintenance of stereocilia F-actin cores. However, it is challenging to predict how variants associated with sensorineural hearing loss segregating in families affect protein function. Here, we review the functions of several molecular components of stereocilia F-actin cores and provide new data from our experimental approach to directly evaluate the pathogenicity and functional impact of reported and novel variants of DIAPH1 in autosomal-dominant DFNA1 hearing loss using single-molecule fluorescence microscopy.
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Abbreviations
- ATP:
-
Adenosine triphosphate
- ADP:
-
Adenosine diphosphate
- DFNA :
-
Locus for dominantly inherited nonsyndromic deafness
- DFNB :
-
Locus for recessively inherited nonsyndromic deafness
- GFP:
-
Green fluorescent protein
- USH:
-
Usher syndrome
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Acknowledgements
We thank Drs. Mhamed Grati and Dennis Winkler for valuable comments and Ms. Erina He for her beautiful diagrams. Informed written consent was obtained from all subjects. This study was approved by the Ethics Committee of Shinshu University School of Medicine (No. 576: 2 May 2017), the Institutional Review Board of Seoul National University Bundang Hospital (IRB-B-1007-105-402) and the ethics committees of all other participating institutions listed in a previous report (Nishio and Usami 2015).
Funding
TM, IAB and TBF were supported (in part) by NIDCD intramural research funds DC000039. HS was supported by NIBIB intramural research funds. This review was also supported by JSPS Overseas Research Fellowships to TM and a research fund from Chungnam National University to BJK. SU was supported by the Health and Labor Sciences Research Grant for Research on Rare and Intractable Diseases and Comprehensive Research on Disability Health and Welfare from the Ministry of Health, Labor and Welfare of Japan (20FC1048) and Grants-in-Aid from the Japan Agency for Medical Research and Development (AMED) (20ek0109363h0003). BYC was funded by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHDI), the ministry of Health & Welfare, Republic of Korea (2018R1A2B2001054) and SNUBH Intramural research fund (16–2019-006).
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Supplementary file1 (AVI 2480 KB) Time-lapse images showing single-molecule fluorescence microscopy of XTC cells expressing GFP-DIAPH1 (wild-type, p.R1213X and p.M1199D). Frequent directional movements were observed in cells expressing GFP-DIAPH1 (p.R1213X) and GFP-DIAPH1 (p.M1199D) although the density of moving molecules was higher in cells expressing GFP-DIAPH1 (p.M1199D). Circles indicates molecules moving directionally for more than two frames. Time-lapse, every 300 ms. Bar, 5 µm
Supplementary file2 (AVI 1609 KB) Time-lapse images showing single-molecule fluorescence microscopy of XTC cells expressing GFP-DIAPH1 (p.A265S and p.N1140S). Frequent directional movements were observed only in cells expressing GFP-DIAPH1 (p.A265S) while frequency and distances of directional movements of GFP-DIAPH1 (p.N1140S) were similar to wild-type GFP-DIAPH1. Circles indicates molecules moving directionally for more than two frames. Time-lapse, every 300 ms. Bar, 5 µm
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Miyoshi, T., Belyantseva, I.A., Kitajiri, Si. et al. Human deafness-associated variants alter the dynamics of key molecules in hair cell stereocilia F-actin cores. Hum Genet 141, 363–382 (2022). https://doi.org/10.1007/s00439-021-02304-0
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DOI: https://doi.org/10.1007/s00439-021-02304-0