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Otosclerosis is a bone disorder of the otic capsule and common form of late-onset hearing impairment. Considered a complex disease, little is known about its pathogenesis. Over the past 20 years, ten autosomal dominant loci (OTSC1-10) have been mapped but no genes identified. Herein, we map a new OTSC locus to a 9.96 Mb region within the FOX gene cluster on 16q24.1 and identify a 15 bp coding deletion in Forkhead Box L1 co-segregating with otosclerosis in a Caucasian family. Pre-operative phenotype ranges from moderate to severe hearing loss to profound sensorineural loss requiring a cochlear implant. Mutant FOXL1 is both transcribed and translated and correctly locates to the cell nucleus. However, the deletion of 5 residues in the C-terminus of mutant FOXL1 causes a complete loss of transcriptional activity due to loss of secondary (alpha helix) structure. FOXL1 (rs764026385) was identified in a second unrelated case on a shared background. We conclude that FOXL1 (rs764026385) is pathogenic and causes autosomal dominant otosclerosis and propose a key inhibitory role for wildtype Foxl1 in bone remodelling in the otic capsule. New insights into the molecular pathology of otosclerosis from this study provide molecular targets for non-invasive therapeutic interventions. © 2021. The Author(s).


Nelly Abdelfatah, Ahmed A Mostafa, Curtis R French, Lance P Doucette, Cindy Penney, Matthew B Lucas, Anne Griffin, Valerie Booth, Christopher Rowley, Jessica E Besaw, Lisbeth Tranebjærg, Nanna Dahl Rendtorff, Kathy A Hodgkinson, Leichelle A Little, Sumit Agrawal, Lorne Parnes, Tony Batten, Susan Moore, Pingzhao Hu, Justin A Pater, Jim Houston, Dante Galutira, Tammy Benteau, Courtney MacDonald, Danielle French, Darren D O'Rielly, Susan G Stanton, Terry-Lynn Young. A pathogenic deletion in Forkhead Box L1 (FOXL1) identifies the first otosclerosis (OTSC) gene. Human genetics. 2022 Apr;141(3-4):965-979

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PMID: 34633540

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