@article{b12bd33cef57443681b4bc18598224c9,
title = "A pathogenic deletion in Forkhead Box L1 (FOXL1) identifies the first otosclerosis (OTSC) gene",
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.",
author = "Nelly Abdelfatah and Mostafa, {Ahmed A.} and French, {Curtis R.} and Doucette, {Lance P.} and Cindy Penney and Lucas, {Matthew B.} and Anne Griffin and Valerie Booth and Christopher Rowley and Besaw, {Jessica E.} and Lisbeth Tranebj{\ae}rg and Rendtorff, {Nanna Dahl} and Hodgkinson, {Kathy A.} and Little, {Leichelle A.} and Sumit Agrawal and Lorne Parnes and Tony Batten and Susan Moore and Pingzhao Hu and Pater, {Justin A.} and Jim Houston and Dante Galutira and Tammy Benteau and Courtney MacDonald and Danielle French and O{\textquoteright}Rielly, {Darren D.} and Stanton, {Susan G.} and Young, {Terry Lynn}",
note = "Funding Information: We are grateful to the study participants and to Elspeth Drinkell and Carol Negrijn for drawing pedigrees and the peer reviewers for guidance that improved this manuscript. This study was funded by the Canadian Institutes of Health Research (#222294), Canadian Foundation for Innovation (#9384, #13120), and Genome Canada/Genome Atlantic (AMGGI). Support was also provided by the Janeway Children{\textquoteright}s Hospital Foundation, Memorial University, Town of Grand Falls-Windsor (Excite Corporation) and the Government of Newfoundland and Labrador. The first author N.A. is a Canadian Institutes of Health Research-Fellowship awardee. Publisher Copyright: {\textcopyright} 2021, The Author(s).",
year = "2022",
doi = "10.1007/s00439-021-02381-1",
language = "English",
volume = "141",
pages = "965–979",
journal = "Human Genetics",
issn = "0340-6717",
publisher = "Springer",
}