Dataset Information

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.

SUBMITTER: Abdelfatah N

PROVIDER: S-EPMC9034980 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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

Abdelfatah Nelly N Mostafa Ahmed A AA French Curtis R CR Doucette Lance P LP Penney Cindy C Lucas Matthew B MB Griffin Anne A Booth Valerie V Rowley Christopher C Besaw Jessica E JE Tranebjærg Lisbeth L Rendtorff Nanna Dahl ND Hodgkinson Kathy A KA Little Leichelle A LA Agrawal Sumit S Parnes Lorne L Batten Tony T Moore Susan S Hu Pingzhao P Pater Justin A JA Houston Jim J Galutira Dante D Benteau Tammy T MacDonald Courtney C French Danielle D O'Rielly Darren D DD Stanton Susan G SG Young Terry-Lynn TL

Human genetics 20211011 3-4

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 phenot ...[more]

PMID: 34633540

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Project description:PurposeThe potential of targeting forkhead box C1 (FOXC1) as a therapeutic approach for triple-negative breast cancer (TNBC) is promising. However, a comprehensive understanding of FOXC1 regulation, particularly upstream factors, remains elusive. Expression of the L1 cell adhesion molecule (L1CAM), a transmembrane glycoprotein associated with brain metastasis, was observed to be positively associated with FOXC1 transcripts. Thus, this study aims to investigate their relationship in TNBC progression.MethodsPublicly available FOXC1 and L1CAM transcriptomic data were obtained, and their corresponding proteins were analyzed in four TNBC cell lines. In BT549 cells, FOXC1 and L1CAM were individually silenced, while L1CAM was overexpressed in BT549-shFOXC1, MDA-MB-231, and HCC1937 cells. CCK-8, transwell, and wound healing assays were performed in these cell lines, and immunohistochemical staining was conducted in tumor samples.ResultsA positive correlation between L1CAM and FOXC1 transcripts was observed in publicly available datasets. In BT549 cells, knockdown of FOXC1 led to reduced L1CAM expression at both the transcriptional and protein levels, and conversely, silencing of L1CAM decreased FOXC1 protein levels, but interestingly, FOXC1 transcripts remained largely unaffected. Overexpressing L1CAM resulted in increased FOXC1 protein expression without significant changes in FOXC1 mRNA levels. This trend was also observed in BT549-shFOXC1, MDA-MB-231-L1CAM, and HCC1937-L1CAM cells. Notably, alterations in FOXC1 or L1CAM levels corresponded to changes in cell proliferation, migration, and invasion capacities. Furthermore, a positive correlation between L1CAM and FOXC1 protein expression was detected in human TNBC tumors.ConclusionFOXC1 and L1CAM exhibit co-regulation at the protein level, with FOXC1 regulating at the transcriptional level and L1CAM regulating at the post-transcriptional level, and together they positively influence cell proliferation, migration, and invasion in TNBC.

Dataset Information

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

Publications

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

Similar Datasets

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