A pathogenic deletion in Forkhead Box L1 (FOXL1) identifies the first otosclerosis (OTSC) gene
| Autor: | Anne Griffin, Tammy Benteau, Sumit K. Agrawal, Cindy Penney, Christopher N. Rowley, Courtney MacDonald, Valerie Booth, Lorne S. Parnes, Ahmed A. Mostafa, Susan J Moore, Terry-Lynn Young, Lisbeth Tranebjærg, Tony Batten, Darren D. O’Rielly, Matthew B. Lucas, Curtis R. French, Leichelle A. Little, Nanna Dahl Rendtorff, Jim Houston, Pingzhao Hu, Justin A. Pater, Danielle French, Susan G. Stanton, Dante Galutira, Kathy Hodgkinson, Nelly Abdelfatah, Lance P. Doucette, Jessica E. Besaw |
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| Rok vydání: | 2021 |
| Předmět: |
Genetics
0303 health sciences Molecular pathology Hearing loss Wild type Locus (genetics) Forkhead Transcription Factors Biology medicine.disease Phenotype 03 medical and health sciences 0302 clinical medicine Otosclerosis Gene cluster medicine Humans medicine.symptom 030223 otorhinolaryngology Gene Genetics (clinical) 030304 developmental biology |
| Zdroj: | Abdelfatah, N, Mostafa, A A, French, C R, Doucette, L P, Penney, C, Lucas, M B, Griffin, A, Booth, V, Rowley, C, Besaw, J E, Tranebjærg, L, Rendtorff, N D, Hodgkinson, K A, Little, L A, Agrawal, S, Parnes, L, Batten, T, Moore, S, Hu, P, Pater, J A, Houston, J, Galutira, D, Benteau, T, MacDonald, C, French, D, O’Rielly, D D, Stanton, S G & Young, T L 2022, ' A pathogenic deletion in Forkhead Box L1 (FOXL1) identifies the first otosclerosis (OTSC) gene ', Human Genetics, vol. 141, pp. 965–979 . https://doi.org/10.1007/s00439-021-02381-1 |
| ISSN: | 1432-1203 |
| DOI: | 10.1007/s00439-021-02381-1 |
| Popis: | 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. Phenotype ranges from moderate to severe hearing loss resolved by stapedectomy, 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. |
| Databáze: | OpenAIRE |
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