Background Otosclerosis is a common cause of adult-onset progressive hearing loss, affecting 0.3%–0.4% of the population. It results from dysregulation of bone homeostasis in the otic capsule, most commonly leading to fixation of the stapes bone, impairing sound conduction through the middle ear. Otosclerosis has a well-known genetic predisposition including familial cases with apparent autosomal dominant mode of inheritance. While linkage analysis and genome-wide association studies suggested an association with several genomic loci and with genes encoding structural proteins involved in bone formation or metabolism, the molecular genetic pathophysiology of human otosclerosis is yet mostly unknown.
Methods Whole-exome sequencing, linkage analysis, generation of CRISPR mutant mice, hearing tests and micro-CT.
Results Through genetic studies of kindred with seven individuals affected by apparent autosomal dominant otosclerosis, we identified a disease-causing variant in SMARCA4, encoding a key component of the PBAF chromatin remodelling complex. We generated CRISPR-Cas9 transgenic mice carrying the human mutation in the mouse SMARCA4 orthologue. Mutant Smarca4+/E1548K mice exhibited marked hearing impairment demonstrated through acoustic startle response and auditory brainstem response tests. Isolated ossicles of the auditory bullae of mutant mice exhibited a highly irregular structure of the incus bone, and their in situ micro-CT studies demonstrated the anomalous structure of the incus bone, causing disruption in the ossicular chain.
Conclusion We demonstrate that otosclerosis can be caused by a variant in SMARCA4, with a similar phenotype of hearing impairment and abnormal bone formation in the auditory bullae in transgenic mice carrying the human mutation in the mouse SMARCA4 orthologue.
- human genetics
- molecular biology
- mutation, missense
Data availability statement
Data are available on reasonable request. The data that support the findings of this study are available from the corresponding author on reasonable request.
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Contributors OSB is the guarantor, accepts full responsibility for the finished work and/or the conduct of the study.
MD and OSB initiated the study, contributed to its conception and design and drafted the text. MD, MMJ, YN, DH, YY, OW, RP-O, VD, NL, VB, SO, MK, KBA and OSB contributed to the acquisition and analysis of data. UK, IS and OSB provided the clinical data.
Funding The research was funded by the Morris Kahn Family Foundation (OSB) and by the National Knowledge Center for Rare/Orphan Diseases of the Israel Ministry of Science, Technology and Space, Ben-Gurion University of the Negev, Beer-Sheva, Israel (OSB) and the National Institutes of Health /NIDCD grant R01DC011835 (KBA).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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