Article ; Online: A pathogenic deletion in Forkhead Box L1 (FOXL1) identifies the first otosclerosis (OTSC) gene.
2021 Volume 141, Issue 3-4, Page(s) 965–979
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 ... ...
| 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. |
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| MeSH term(s) | Forkhead Transcription Factors/genetics ; Humans ; Otosclerosis/genetics | |||||
| Chemical Substances | FOXL1 protein, human ; Forkhead Transcription Factors | |||||
| Language | English | |||||
| Publishing date | 2021-10-11 | |||||
| Publishing country | Germany | |||||
| Document type | Journal Article | |||||
| ZDB-ID | 223009-4 | |||||
| ISSN | 1432-1203 ; 0340-6717 | |||||
| ISSN (online) | 1432-1203 | |||||
| ISSN | 0340-6717 | |||||
| DOI | 10.1007/s00439-021-02381-1 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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