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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 |

REPOSITORIES: biostudies-literature

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Pathogenic missense mutation pattern of forkhead box genes in neurodevelopmental disorders.

Project description:BackgroundForkhead box (FOX) proteins are a family of transcription factors. Mutations of three FOX genes, including FOXP1, FOXP2, and FOXG1, have been reported in neurodevelopmental disorders (NDDs). However, due to the lack of site-specific statistical significance, the pathogenicity of missense mutations of these genes is difficult to determine.MethodsDNA and RNA were extracted from peripheral blood lymphocytes. The mutation was detected by single-molecule molecular inversion probe-based targeted sequencing, and the variant was validated by Sanger sequencing. Real-time quantitative PCR and western blot were performed to assay the expression of the mRNA and protein. To assess the pattern of disorder-related missense mutations of NDD-related FOX genes, we manually curated de novo and inherited missense or inframeshift variants within FOXP1, FOXP2, and FOXG1 that co-segregated with phenotypes in NDDs. All variants were annotated by ANNOVAR.ResultsWe detected a novel de novo missense mutation (NM_001244815: c.G1444A, p.E482K) of FOXP1 in a patient with intellectual disability and severe speech delay. Real-time PCR and western blot revealed a dramatic reduction of mRNA and protein expression in patient-derived lymphocytes, indicating a loss-of-function mechanism. We observed that the majority of the de novo or transmitted missense variants were located in the FOX domains, and 95% were classified as pathogenic mutations. However, 10 variants were located outside of the FOX domain and were classified as likely pathogenic or variants of uncertain significance.ConclusionOur study shows the pathogenicity of missense and inframeshift variants of NDD-related FOX genes, which is important for clinical diagnosis and genetic counseling. Functional analysis is needed to determine the pathogenicity of the variants with uncertain clinical significance.

| S-EPMC6625093 | biostudies-literature

Mutation of <i>foxl1</i> Results in Reduced Cartilage Markers in a Zebrafish Model of Otosclerosis.

Project description:Bone diseases such as otosclerosis (conductive hearing loss) and osteoporosis (low bone mineral density) can result from the abnormal expression of genes that regulate cartilage and bone development. The forkhead box transcription factor FOXL1 has been identified as the causative gene in a family with autosomal dominant otosclerosis and has been reported as a candidate gene in GWAS meta-analyses for osteoporosis. This potentially indicates a novel role for foxl1 in chondrogenesis, osteogenesis, and bone remodelling. We created a foxl1 mutant zebrafish strain as a model for otosclerosis and osteoporosis and examined jaw bones that are homologous to the mammalian middle ear bones, and mineralization of the axial skeleton. We demonstrate that foxl1 regulates the expression of collagen genes such as collagen type 1 alpha 1a and collagen type 11 alpha 2, and results in a delay in jawbone mineralization, while the axial skeleton remains unchanged. foxl1 may also act with other forkhead genes such as foxc1a, as loss of foxl1 in a foxc1a mutant background increases the severity of jaw calcification phenotypes when compared to each mutant alone. Our zebrafish model demonstrates atypical cartilage formation and mineralization in the zebrafish craniofacial skeleton in foxl1 mutants and demonstrates that aberrant collagen expression may underlie the development of otosclerosis.

| S-EPMC9319681 | biostudies-literature

Upregulated forkhead-box A3 elevates the expression of forkhead-box A1 and forkhead-box A2 to promote metastasis in esophageal cancer.

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| S-EPMC6444456 | biostudies-literature

A genome-wide analysis identifies genetic variants in the RELN gene associated with otosclerosis.

Project description:Otosclerosis is a common form of progressive hearing loss, characterized by abnormal bone remodeling in the otic capsule. The etiology of the disease is largely unknown, and both environmental and genetic factors have been implicated. To identify genetic factors involved in otosclerosis, we used a case-control discovery group to complete a genome-wide association (GWA) study with 555,000 single-nucleotide polymorphisms (SNPs), utilizing pooled DNA samples. By individual genotyping of the top 250 SNPs in a stepwise strategy, we were able to identify two highly associated SNPs that replicated in two additional independent populations. We then genotyped 79 tagSNPs to fine map the two genomic regions defined by the associated SNPs. The region with the strongest association signal, p(combined) = 6.23 x 10(-10), is on chromosome 7q22.1 and spans intron 1 to intron 4 of reelin (RELN), a gene known for its role in neuronal migration. Evidence for allelic heterogeneity was found in this region. Consistent with the GWA data, expression of RELN was confirmed in the inner ear and in stapes footplate specimens. In conclusion, we provide evidence that implicates RELN in the pathogenesis of otosclerosis.

| S-EPMC2667982 | biostudies-literature

Diagnostic and prognostic values of forkhead box D4 gene in colonic adenocarcinoma.

Project description:Previous studies found that Forkhead box D4 (FOXD4) overexpressed in human colorectal cancer had the worst prognosis. However, the diagnostic value and further mechanism have not been fully researched. Statistical examinations for FOXD4 expression colon adenocarcinoma (COAD) patients were obtained from The Cancer Genome Atlas (TCGA). Survival analysis was used to assess its prognostic value. Nomogram model was used for visual prediction of patient survival rate. The online functional enrichment analysis tool was used to evaluate the biological functions and pathways of FOXD4 and its co-expressed genes. Receiver operating characteristic curve analysis suggested that FOXD4 might be a diagnostic biomarker for COAD (P<0.001, area under the curve [AUC]=0.728, 95% confidence interval [CI]=0.669-0.787). Low expression of FOXD4 was associated with a good clinical outcome (P=0.001, HR=0.517, 95% CI=0.341-0.782). A total of 797 genes were correlated with FOXD4 and associated with cell proliferation, cell differentiation, nuclear matrix, Rap1 signaling pathway, RNA transport, and VEGF signaling pathway. In conclusion, expression of FOXD4 may be a diagnostic and prognostic biomarker in COAD.

| S-EPMC7642708 | biostudies-literature

Forkhead box L1 is frequently downregulated in gallbladder cancer and inhibits cell growth through apoptosis induction by mitochondrial dysfunction.

Project description:BackgroundForkhead box L1 (FOXL1), considered as a novel candidate tumor suppressor, suppresses proliferation and invasion in certain cancers. However, the regulation and function of FOXL1 in gallbladder cancer (GBC) remains unclear.MethodsFOXL1 expression at mRNA and protein levels in GBC tissues and cell lines were examined by RT-PCR, immunohistochemistry and western blot assay. FOXL1 expression in GBC cell lines was up-regulated by transfection with pcDNA-FOXL1. The effects of FOXL1 overexpression on cell proliferation, apoptosis, migration and invasion were evaluated in vitro or in vivo. In addition, the status of mediators involved in migration, invasion and apoptosis was examined using western blot after transfection with pcDNA-FOXL1.ResultsFOXL1 was frequently downregulated in GBC tissues and cell lines. Its higher expression is associated with better prognosis, while its lower expression is correlated with advanced TNM stage and poor differentiation. FOXL1 overexpression in NOZ cells significantly suppresses cell proliferation, migration and invasion in vitro and tumorigenicity in nude mice. FOXL1 overexpression disrupted mitochondrial transmembrane potential and triggered mitochondria-mediated apoptosis in NOZ cells. In addition, FOXL1 overexpression suppressed ZEB1 expression and induced E-cadherin expression in NOZ cells.ConclusionOur findings suggested that dysregulated FOXL1 is involved in tumorigenesis and progression of GBC and may serve as a predictor of clinical outcome or even a therapeutic target for patients with GBC.

| S-EPMC4092092 | biostudies-literature

The crystal structure of human forkhead box N1 in complex with DNA reveals the structural basis for forkhead box family specificity.

Project description:Forkhead box N1 (FOXN1) is a member of the forkhead box family of transcription factors and plays an important role in thymic epithelial cell differentiation and development. FOXN1 mutations in humans and mice give rise to the "nude" phenotype, which is marked by athymia. FOXN1 belongs to a subset of the FOX family that recognizes an alternative forkhead-like (FHL) consensus sequence (GACGC) that is different from the more widely recognized forkhead (FKH) sequence RYAAAYA (where R is purine, and Y is pyrimidine). Here, we present the FOXN1 structure in complex with DNA containing an FHL motif at 1.6 Å resolution, in which the DNA sequence is recognized by a mixture of direct and water-mediated contacts provided by residues in an α-helix inserted in the DNA major groove (the recognition helix). Comparisons with the structure of other FOX family members revealed that the FKH and FHL DNA sequences are bound in two distinct modes, with partially different registers for the protein DNA contacts. We identified a single alternative rotamer within the recognition helix itself as an important determinant of DNA specificity and found protein sequence features in the recognition helix that could be used to predict the specificity of other FOX family members. Finally, we demonstrate that the C-terminal region of FOXN1 is required for high-affinity DNA binding and that FOXN1 has a significantly reduced affinity for DNA that contains 5'-methylcytosine, which may have implications for the role of FOXN1 in thymic involution.

| S-EPMC7062188 | biostudies-literature

The Role of Forkhead Box Class O3A and SIRT1 Gene Variants in Early-Onset Psoriasis.

Project description:Psoriasis is a chronic inflammatory skin disorder, which is characterized by a heightened immunological response. Although the immunogenetics of this chronic inflammatory disorder is poorly understood, its expression is known to be dependent on proinflammatory cytokines. It is known that two distinct subtypes of chronic plaque psoriasis: Early-onset psoriasis (EOP) before the age of 40 years and late-onset psoriasis after the age of 40 years. Forkhead box class O3A (FOXO3A) is a transcription factor, which plays an important role in cell-cycle regulation, apoptosis, oxidative stress, and DNA repair. The silent information regulator (SIRT) is thought to have a role in skin disorders, including psoriasis, that are characterized by hyperproliferation and inflammation.The aim of this study was to investigate FOXO3A and SIRT1 gene polymorphisms in EOP.The study group consisted of 142 EOP patients and 123 unrelated healthy controls. FOXO3A polymorphisms were determined using the polymerase chain reaction (PCR)-restriction fragment length polymorphism method. SIRT1 gene polymorphisms were determined by PCR-confronting two-pair primers methods.The FOXO3A rs4946936 and SIRT1 rs7069102 gene polymorphisms were positively correlated with EOP and disease severity. The GG genotype frequency of SIRT1 rs7069102 gene polymorphisms was increased in severe EOP. The CC frequency of FOXO3A rs4946936 was increased in EOP with nail disorders.The rs7069102 gene polymorphism of SIRT1 and rs4946936 polymorphism of FOXO3A are associated with early onset psoriasis; this may be responsible for increased keratinocyte proliferation in the pathogenesis of psoriasis and disease severity.

| S-EPMC5996633 | biostudies-literature

cGMP Signaling Increases Antioxidant Gene Expression by Activating Forkhead Box O3A in the Colon Epithelium.

Project description:Signaling through cGMP has therapeutic potential in the colon, where it has been implicated in the suppression of colitis and colon cancer. In this study, we tested the ability of cGMP and type 2 cGMP-dependent protein kinase (PKG2) to activate forkhead box O (FoxO) in colon cancer cells and in the colon epithelium of mice. We show that activation of PKG2 in colon cancer cells inhibited cell proliferation, inhibited AKT, and activated FoxO. Treatment of colon explants with 8Br-cGMP also activated FoxO target gene expression at both RNA and protein levels, and reduced epithelial reduction-oxidation (redox) stress. FoxO3a was the most prominent isoform in the distal colon epithelium, with prominent luminal staining. FoxO3a levels were reduced in Prkg2-/- animals, and FoxO target genes were unaffected by 8Br-cGMP challenge in vitro. Treatment of mice with the phosphodiesterase-5 inhibitor vardenafil (Levitra) mobilized FoxO3a to the nucleus of luminal epithelial cells, which corresponded to increased FoxO target gene expression, reduced redox stress, and increased epithelial barrier integrity. Treatment of human colonic biopsy specimens with 8Br-cGMP also activated catalase and manganese superoxide dismutase expression, indicating that this pathway is conserved in humans. Taken together, these results identify a novel signaling pathway in the colon epithelium, where FoxO tumor suppressors could provide protection from redox stress. Moreover, this pathway is regulated by endogenous cGMP/PKG2 signaling, and can be targeted using phosphodiesterase-5 inhibitors.

| S-EPMC5389370 | biostudies-literature

A novel forkhead box C1 gene mutation in a Korean family with Axenfeld-Rieger syndrome.

Project description:PURPOSE: To report a case series of patients with novel forkhead box CI (FOXC1) mutations in a Korean family with Axenfeld-Rieger syndrome (ARS). METHODS: Four members of the same family underwent complete ophthalmologic and systemic examinations and genetic analysis. Genomic DNA was isolated from peripheral blood leukocytes, and all coding exons with flanking intronic regions of the FOXC1 and pituitary homeobox 2 genes were amplified using PCR, and sequenced. RESULTS: The patients were 40, 12, 11, and 10 years old (father, son, and two sisters, respectively). All four had uncontrolled intraocular pressure, glaucomatous visual field defect, retinal nerve fiber layer defect, iridocorneal adhesion on gonioscopy, hypoplasia and marked atrophy of the iris, flattening of the midface, and broad flat noses. A diagnosis of ARS was made based on characteristic ocular and systemic traits. A novel FOXC mutation, c.317delA, was identified in all affected members of the family with ARS. CONCLUSIONS: We found a novel c.317delA mutation in FOXC1 in a Korean family with ARS. We suggest that this FOXC1 mutation causes typical ARS, and that our results may be useful for better understanding of the spectrum of FOXC1 mutations and the role of FOXC1 in the development and progression of ARS.

| S-EPMC3654851 | biostudies-other

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