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The Genetic and Clinical Features of FOXL2-Related Blepharophimosis, Ptosis and Epicanthus Inversus Syndrome.

ABSTRACT: Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is a craniofacial disorder caused by heterozygous variants of the forkhead box L2 (FOXL2) gene. It shows autosomal dominant inheritance but can also occur sporadically. Depending on the mutation, two phenotypic subtypes have been described, both involving the same craniofacial features: type I, which is associated with premature ovarian failure (POF), and type II, which has no systemic features. The genotype-phenotype correlation is not fully understood, but it has been hypothesised that type I BPES involves more severe loss of function variants spanning the whole gene. Type II BPES has been linked to frameshift mutations that result in elongation of the protein rather than complete loss of function. A mutational hotspot has been identified within the poly-alanine domain, although the exact function of this region is still unknown. However, the BPES subtype cannot be determined genetically, necessitating informed genetic counselling and careful discussion of family planning advice in view of the associated POF particularly as the patient may still be a child. Following puberty, female patients should be referred for ovarian reserve and response assessment. Oculofacial features can be managed with surgical intervention and regular monitoring to prevent amblyopia.

SUBMITTER: Mejecase C

PROVIDER: S-EPMC7998575 | biostudies-literature |

REPOSITORIES: biostudies-literature

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FOXL2 mutations in Chinese patients with blepharophimosis-ptosis-epicanthus inversus syndrome.

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Novel FOXL2 mutations cause blepharophimosis-ptosis-epicanthus inversus syndrome with premature ovarian insufficiency.

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Functional Studies of Novel FOXL2 Variants in Chinese Families With Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome.

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Novel <i>FOXL2</i> variants in two Chinese families with blepharophimosis, ptosis, and epicanthus inversus syndrome.

Project description:Introduction: Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is a rare inherited disorder. This study was aimed to identify and functionally validate FOXL2 variants in two Chinese families with BPES. Methods: The proband and his family members were subjected to whole-exome sequencing to identify disease-associated variants. Several bioinformatic tools were used to computationally predict altered proteins. In vitro functional assays were conducted by transfecting wild-type and mutant FOXL2 cDNAs into HEK-293 cells, followed by subcellular localization assays, luciferase reporter gene assays, and quantitative real-time polymerase chain reaction. Results: The clinical features of BPES, including small palpebral fissures, ptosis, telecanthus, and epicanthus inversus, were present in all affected patients. Two novel mutations were detected, c.292T>A and c.383G>T. Whole-exome sequencing analysis and prediction software suggested that these mutations were pathogenic. Functional studies showed that these two point mutations decreased FOXL2 protein expression, resulting in subcellular mislocalization and aberrant transcriptional activity of the steroidogenic acute regulatory protein gene promoter. Conclusion: Our results add to the current understanding of known FOXL2 variants in, and our in vitro experiments provide reference data and insights into the etiology of BPES. Further studies are needed to identify the possible mechanisms underlying the action of this mutation on the development of BPES.

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Functional study on new FOXL2 mutations found in Chinese patients with blepharophimosis, ptosis, epicanthus inversus syndrome.

Project description:BackgroundBlepharophimosis, ptosis, epicanthus inversus syndrome (BPES) is a rare inheritable disease that mainly affects eyelid development associated with (type I) or without (type II) ovarian dysfunction, resulting in premature ovarian failure (POF). Mutations in the gene forkhead box L2 (FOXL2) have been shown to be responsible for BPES. The aim of this study was to determine and functionally validate the FOXL2 mutation in a Chinese BPES family.MethodsTwelve individuals including five BPES patients from a Chinese family were enrolled. Genomic DNA was extracted from peripheral blood of enrolled subjects. The coding region of the FOXL2 gene was amplified and mutations were determined by sequencing analyses. Functional analysis was carried out to study changes in expression and transcriptional activity of the mutant FOXL2 protein.ResultsA novel mutation in the FOXL2 gene (c.931C > T) was detected in all five BPES patients, which converts a histidine residue into a tyrosine (p.H311Y) in the FOXL2 protein. Functional analysis revealed that this point mutation reduces FOXL2 protein expression, concomitant with decreased transcriptional activity on the steroidogenic acute regulatory (StAR) gene promotor.ConclusionsOur results expand the mutational spectrum of the FOXL2 gene and provide additional insights to the research on the molecular pathogenesis of FOXL2 in BPES.

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Differential apoptotic and proliferative activities of wild-type FOXL2 and blepharophimosis-ptosis-epicanthus inversus syndrome (BPES)-associated mutant FOXL2 proteins.

Project description:FOXL2 is an essential transcription factor that is required for proper development of the ovary and eyelid. Mutations in FOXL2 cause an autosomal dominant genetic disorder, blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). BPES type I patients have eyelid malformation and premature ovarian failure leading to infertility, whereas women with type II BPES are fertile or subfertile. In the present study, we evaluated and compared apoptotic and antiproliferative activities of wild-type (WT) and mutant FOXL2 proteins found in BPES type I and II in human granulosa cell tumor-derived KGN cells. Ectopic expression of WT FOXL2 induced apoptosis and inhibited cell cycle progression in human granulosa cells. In contrast, mutated FOXL2s found in BPES type I significantly reduced these activities, whereas mutated FOXL2s in BPES type II showed intermediate activities. Furthermore, mutant FOX L2 proteins were defective in activating transcription of target genes including Caspase 8, TNF-R1, FAS, p21, and BMP4, which regulate apoptosis, proliferation, and differentiation of granulosa cells. Thus, decreased apoptotic and antiproliferative activities caused by mutant forms of FOXL2 found in BPES patients may at least partially contribute to the pathophysiology of ovarian dysfunction.

| S-EPMC3958583 | biostudies-literature

Genetic analysis of the FOXL2 gene using quantitative real-time PCR in Chinese patients with blepharophimosis-ptosis-epicanthus inversus syndrome.

Project description:PurposeThe purpose of this study was to identify the mutation(s) or deletion(s) of the forkhead box protein L2 (FOXL2) gene in Chinese patients with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES).MethodsGenomic DNA extracted from peripheral blood was collected from two Chinese families and from one sporadic case. PCR direct sequencing and quantitative real-time PCR-based copy number screening for the whole exon of FOXL2 were performed.ResultsDirect sequencing revealed an indel mutation c.50C→TA in the sporadic case which resulted in a frameshift generating 78 novel amino acids and terminating prematurely at codon 95. Deletions in the FOXL2 gene were confirmed by quantitative real-time PCR (q-real-time PCR) in two families in which intragenic mutations were excluded by direct sequencing. These changes containing deletions and a de novo mutation were not detected either in the non-carrier relatives or in 100 normal controls.ConclusionsThis study identified two deletions and a de novo mutation in the FOXL2 gene in Chinese BPES patients. This is the first study to report FOXL2 gene deletions detected by q-real-time PCR in this ethnic group. This technique enriches the diagnostic methods of molecular genetics in BPES patients. The de novo mutation expands the mutation spectrum of FOXL2.

| S-EPMC3038209 | biostudies-literature

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