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

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  • 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
Vis graf over relationer

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.

OriginalsprogEngelsk
TidsskriftHuman Genetics
Vol/bind141
Udgave nummer3-4
Sider (fra-til)965-979
Antal sider15
ISSN0340-6717
DOI
StatusUdgivet - apr. 2022

Bibliografisk note

© 2021. The Author(s).

ID: 73253401