A pathogenic deletion in Forkhead Box L1 (FOXL1) identifies the first otosclerosis (OTSC) gene

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. PaterJim Houston, Dante Galutira, Tammy Benteau, Courtney MacDonald, Danielle French, Darren D. O’Rielly, Susan G. Stanton, Terry Lynn Young*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

6 Citations (Scopus)
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Abstract

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.

Original languageEnglish
JournalHuman Genetics
Volume141
Pages (from-to)965–979
ISSN0340-6717
DOIs
Publication statusPublished - 2022

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