{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T02:07:26Z","timestamp":1780452446065,"version":"3.54.1"},"reference-count":46,"publisher":"BMJ","issue":"2","funder":[{"name":"National Institutes of Health \/NIDCD","award":["R01DC011835"],"award-info":[{"award-number":["R01DC011835"]}]},{"name":"National Knowledge Center for Rare\/Orphan Diseases of the Israel Ministry of Science"},{"name":"Morris Kahn Family Foundation"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2023,6,9]]},"published-print":{"date-parts":[[2024,2]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Otosclerosis is a common cause of adult-onset progressive hearing loss, affecting 0.3%\u20130.4% 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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Whole-exome sequencing, linkage analysis, generation of CRISPR mutant mice, hearing tests and micro-CT.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Through genetic studies of kindred with seven individuals affected by apparent autosomal dominant otosclerosis, we identified a disease-causing variant in <jats:italic>SMARCA4<\/jats:italic>, encoding a key component of the PBAF chromatin remodelling complex. We generated CRISPR-Cas9 transgenic mice carrying the human mutation in the mouse <jats:italic>SMARCA4<\/jats:italic> orthologue. Mutant <jats:italic>Smarca4<jats:sup>+\/E1548K<\/jats:sup>\n                     <\/jats:italic> 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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>We demonstrate that otosclerosis can be caused by a variant in <jats:italic>SMARCA4<\/jats:italic>, 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 <jats:italic>SMARCA4<\/jats:italic> orthologue.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmg-2023-109264","type":"journal-article","created":{"date-parts":[[2023,6,30]],"date-time":"2023-06-30T13:26:45Z","timestamp":1688131605000},"page":"117-124","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":5,"title":["<i>SMARCA4<\/i> mutation causes human otosclerosis and a similar phenotype in mice"],"prefix":"10.1136","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0616-6776","authenticated-orcid":false,"given":"Max","family":"Drabkin","sequence":"first","affiliation":[{"name":"The 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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matan M","family":"Jean","sequence":"additional","affiliation":[{"name":"The Morris Kahn Laboratory of Human Genetics, Shraga Segal Department of 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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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vadim","family":"Dolgin","sequence":"additional","affiliation":[{"name":"The 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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noam","family":"Levaot","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cell Biology, Ben-Gurion University of the Negev, Beer-Sheva, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vlad","family":"Brumfeld","sequence":"additional","affiliation":[{"name":"Department of Chemical Research Support, Weizmann Institute of Science, Rehovot, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shira","family":"Ovadia","sequence":"additional","affiliation":[{"name":"Ben-Gurion University of the Negev, Beer-Sheva, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mor","family":"Kishner","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Udi","family":"Kazenell","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Head and Neck Surgery, Kaplan Medical Center, Rehovot, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen B","family":"Avraham","sequence":"additional","affiliation":[{"name":"Department of Human Molecular Genetics and Biochemistry, Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, 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