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Genotype-phenotype correlations
Original research
SMARCA4 mutation causes human otosclerosis and a similar phenotype in mice
  1. Max Drabkin1,
  2. Matan M Jean1,
  3. Yael Noy2,
  4. Daniel Halperin1,
  5. Yuval Yogev1,
  6. Ohad Wormser1,
  7. Regina Proskorovski-Ohayon1,
  8. Vadim Dolgin1,
  9. Noam Levaot3,
  10. Vlad Brumfeld4,
  11. Shira Ovadia5,
  12. Mor Kishner6,
  13. Udi Kazenell7,
  14. Karen B Avraham2,
  15. Ilan Shelef8,
  16. Ohad S Birk1,9
  1. 1The Morris Kahn Laboratory of Human Genetics, Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
  2. 2Department of Human Molecular Genetics and Biochemistry, Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
  3. 3Department of Physiology and Cell Biology, Ben-Gurion University of the Negev, Beer-Sheva, Israel
  4. 4Department of Chemical Research Support, Weizmann Institute of Science, Rehovot, Israel
  5. 5Ben-Gurion University of the Negev, Beer-Sheva, Israel
  6. 6Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
  7. 7Department of Otolaryngology, Head and Neck Surgery, Kaplan Medical Center, Rehovot, Israel
  8. 8Department of Radiology, Ben-Gurion University of the Negev, Beer-Sheva, Israel
  9. 9Genetics Institute, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
  1. Correspondence to Dr Ohad S Birk, Ben-Gurion University of the Negev, Beer-Sheva 84101, Israel; obirk{at}bgu.ac.il

Abstract

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.

  • genetics
  • human genetics
  • molecular biology
  • mutation, missense
  • phenotype

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.

https://doi.org/10.1136/jmg-2023-109264

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    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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    Footnotes

    • Twitter @yogevyu, @OhadBirk

    • 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.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.