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

Nelly Abdelfatah,Susan Moore,Darren D O’Rielly,Christopher Rowley,Lisbeth Tranebjærg,Ahmed A Mostafa,Courtney Macdonald,Sumit Agrawal,Cindy Penney,Curtis R French,Kathy Hodgkinson ,Lorne S Parnes ,Dante Galutira,Tony Batten,Jessica E Besaw,Justin A Pater,Lance P Doucette,Tammy Benteau,Anne Griffin,Leichelle Little ,Valerie Booth,Matthew B Lucas ,Danielle V French ,Susan G Stanton,Nanna Dahl Rendtorff,Pingzhao Hu,Jim Houston,Terry‐Lynn Young

doi:10.1007/s00439-021-02381-1

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.

Highlights

Otosclerosis is a primary bone disorder of abnormal bone resorption and deposition in the otic capsule, and a common form of conductive hearing loss (HL)
Using haplotype and linkage exclusion, we ruled out previously published OTSC loci and several associated genes and mapped a new OTSC locus within the FOX gene cluster on chromosome 16q24.1
Significant research resources were dedicated to family recruitment and clinical assessment, which turned out to be essential to mapping the new OTSC locus and identifying the causal gene by reducing the number of rare heterozygous variants that required functional followup

Summary

Introduction

Otosclerosis is a primary bone disorder of abnormal bone resorption and deposition in the otic capsule (bony labyrinth), and a common form of conductive hearing loss (HL) Both environmental and genetic risk factors have. In the early stages of otosclerosis, it becomes highly vascularized with activated macrophages (osteoclast progenitors) causing foci of reabsorption of endochondral bone and deposition of new dense bone by osteoblasts (Babcock and Liu 2018). Invasion of these osteosclerotic foci into the stapediovestibular joint immobilizes the stapes resulting in conductive HL (Nager 1969). The key molecular triggers in the otic capsule activating remodelling and the onset of otosclerosis remain elusive (Babcock and Liu 2018)

Methods

Results

Conclusion