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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.

Project description:PurposeBlepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is an autosomal dominant disorder where eyelid malformation associated with (type I) or without (type II) premature ovarian failure (POF). It is ascribed to mutations in the forkhead transcriptional factor2 (FOXL2) gene. The purpose of this study is to identify mutations in FOXL2 of Chinese patients with BPES.MethodsGenomic DNA was prepared from leucocytes of peripheral venous blood. The coding regions and nearby intron sequences of FOXL2 were analyzed by cycle and cloning sequencing.ResultsFour mutations in FOXL2 were identified in six families, including c.241T>C, c.650C>G, c.804dupC, and c.672_701dup. Of the four, the c.241T>C and c.650C>G were novel and would result in missense changes of the encoded proteins, i.e., p.Tyr81His and p.Ser217Cys, respectively. The c.672_701dup (p.Ala224_Ala234dup) was detected in three families, indicating a mutation hotspot. The c.804dupC (p.Gly269ArgfsX265) mutation was found in one family.ConclusionsOur results expand the spectrum of FOXL2 mutations and confirm the mutation hotspot in FOXL2.

| S-EPMC2533039 | biostudies-literature

Novel FOXL2 mutations in two Chinese families with blepharophimosis-ptosis-epicanthus inversus syndrome.

Project description:BACKGROUND: Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare autosomal dominant disease. Mutations in the forkhead box L2 (FOXL2) gene cause two types of BPES distinguished by the presence (type I) and absence (type II) of premature ovarian failure (POF). The purpose of this study was to identify possible mutations in FOXL2 in two Chinese families with BPES. METHODS: Two large autosomal dominant Chinese BPES families were enrolled in this study. Genomic DNA was obtained from the leukocytes in peripheral venous blood. Four overlapping sets of primers were used to amplify the entire coding region and nearby intron sequences of the FOXL2 gene for mutations detection using polymerase chain reaction (PCR) and sequencing analyses. The sequencing results were analyzed using DNAstar software. RESULTS: All patients of the two families demonstrated typical features of BPES type II, including small palpebral fissures, ptosis, telecanthus, and epicanthus inversus without female infertility (POF). A novel FOXL2 heterozygous indel mutation c.675_690delinsT, including a 16-bp deletion and a 1-bp(T) insertion (p.Ala226_Ala230del), which would result in deletion of 5 alanine residues of a poly-alanine (poly-Ala) tract in the protein, was identified in all affected members of family A. A novel heterozygous missense mutation (c.223C?>?T, p.Leu75Phe) was identified in family B. CONCLUSIONS: Two novel FOXL2 mutations were identified in Chinese families with BPES. Our results expand the spectrum of FOXL2 mutations and provide additional structure-function insights into the FOXL2 protein.

| S-EPMC4593235 | biostudies-literature

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

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A novel FOXL2 mutation in a Chinese family with blepharophimosis, ptosis, epicanthus inversus syndrome.

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A novel FOXL2 mutation in two infertile patients with blepharophimosis-ptosis-epicanthus inversus syndrome.

Project description:BackgroundBlepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare, autosomal dominant disease. There are two clinical types of BPES: type I patients have eyelid abnormalities accompanied by infertility in affected females, while type II patients only display eyelid malformations. Previous studies have reported that the forkhead box L2 (FOXL2) gene mutations cause BPES.PurposeTo identify plausible FOXL2 mutation in a Chinese family with BPES and infertility METHODS: Mutational screening of FOXL2 was performed in the affected members and 223 controls. Functional characterization of the novel mutation identified was carried out in vitro by luciferase reporter assay and subcellular localization experiment.ResultsA novel heterozygous mutation c.188 T > A (p.I63N) in FOXL2 was identified in two BPES patients in this family. The mutation abolished the transcriptional repression of FOXL2 on the promoters of CYP19A1 and CCND2 genes, as shown by luciferase reporter assays. However, no dominant-negative effect was observed for the mutation, and it did not impact FOXL2 protein nuclear localization and distribution.ConclusionsThe mutation c.188 T > A (p.I63N) in FOXL2 might be causative for BPES and infertility in this family and further amplified the spectrum of FOXL2 mutations.

| S-EPMC7000634 | biostudies-literature

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

Project description:The blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare autosomal dominant disease mainly caused by FOXL2 variants. This genetic disorder is usually characterized by eyelid malformation and ovarian dysfunction. However, no reliable genotype/phenotype correlations have been established considering the ovarian phenotype. Here, we detected 15 FOXL2 variants including nine novel ones from 7 families and 8 sporadic cases, which expanded the spectrum of FOXL2 variants and identified a potential clinical cause. Functional studies, with respect to the effect of FOXL2 on the StAR promoter, showed that non-sense variants that lead to protein truncation before the polyalanine tract and missense variants [c.307C > T; p.(Arg103Cys), c.311A > C; p.(His104Pro), c.320G > A; p.(Ser107Asn), and c.335T > A; p.(Phe112Tyr)] within the central portion of the FOXL2 forkhead domain significantly affect its suppressor activity. Such changes may explain the mechanism underlying a more severe phenotype, more likely to result in BPES type I. Furthermore, the missenses variants c.307C > T; p.(Arg103Cys), c.311A > C; p.(His104Pro), and c.320G > A; p.(Ser107Asn) were not able to transactivate OSR2, which is consistent with the eyelid malformation in these patients. The results from our cohort have expanded the spectrum of FOXL2 variants and have provided insights into genotype/phenotype correlations.

| S-EPMC8007913 | biostudies-literature

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.

| S-EPMC10894958 | biostudies-literature

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.

| S-EPMC6053710 | biostudies-literature

Ovarian Reserve and ART Outcomes in Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome Patients With <i>FOXL2</i> Mutations.

Project description:ObjectiveTo characterize the status of ovarian reserve and ART outcomes in BPES women and provide informative reference for clinical diagnosis and treatment.MethodsTwenty-one women with BPES were screened for mutations in the FOXL2 gene and underwent assisted reproductive technology (ART) treatment. Indicators for ovarian reserve and ART outcomes were compared between patients with and without FOXL2 mutations. Additionally, ART outcomes were compared among patients with different subtypes of FOXL2 mutations.ResultsA total of 13 distinct heterozygous variants in the FOXL2 gene were identified in 80.95% of BPES women, including 4 novel mutations with plausible pathogenicity (c.173_175dup, c.481C>T, c.576del and c.675_714del). Compared to non-mutation group, patients with FOXL2 mutations had elevated levels of FSH (P=0.007), decreased AMH levels (P=0.012) and less AFC (P=0.015). They also had worse ART outcomes with large amount of Gn dosage (P=0.008), fewer oocytes (P=0.001), Day3 good quality embryos (P=0.001) and good quality blastocysts (P=0.037), and a higher cancellation rate (P=0.272). High heterogeneity of ART outcomes existed in BPES patients with different FOXL2 mutation types.ConclusionsBPES patients with FOXL2 mutations had diminished ovarian reserve and adverse ART outcomes. The genotype-reproductive phenotype correlations were highly heterogeneous and cannot be generalized. Genetic counseling for fertility planning and preimplantation or prenatal genetic diagnosis to reduce offspring inheritance are recommended.

| S-EPMC9097277 | biostudies-literature

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

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