SMARCA4 mutation causes human otosclerosis and a similar phenotype in mice

Max Drabkin, Matan M. Jean, Yael Noy, Daniel Halperin, Yuval Yogev, Ohad Wormser, Regina Proskorovski-Ohayon, Vadim Dolgin, Noam Levaot, Vlad Brumfeld, Shira Ovadia, Mor Kishner, Udi Kazenell, Karen B. Avraham, Ilan Shelef, Ohad S. Birk

Research output: Contribution to journalArticlepeer-review


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.

Original languageAmerican English
Article numberjmg-2023-109264
Pages (from-to)117-124
Number of pages8
JournalJournal of Medical Genetics
Issue number2
Early online dateJun 2023
StatePublished - 30 Jun 2023


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

All Science Journal Classification (ASJC) codes

  • Genetics(clinical)
  • Genetics


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