Analysis of FOXL2 detects three novel mutations and an atypical phenotype of blepharophimosis‐ptosis‐epicanthus inversus syndrome

Křepelová, Anna; Simandlová, Martina; Vlčková, Markéta; Kuthan, Pavel; Vincent, Andrea L.; Lišková, Petra

doi:10.1111/ceo.12783

Cited by 11 publications

(6 citation statements)

References 20 publications

(34 reference statements)

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“…The rate of FOXL2 mutations in our population of patients with eyelid anomalies and hypopituitarism (3 out of 10 patients) is much higher than previously reported mutation rates for genes associated with hypopituitarism in Western Europe. FOXL2 mutation in our cohort was found only for patients with typical BPES eyelid anomalies, but, again, a variable expressivity seems possible since a pathogenic FOXL2 mutation was recently reported in a woman with moderate ptosis [33]. Further studies are necessary to determine whether FOXL2 should be sequenced in patients presenting hypopituitarism with milder eyelid anomalies.…”

Section: Discussionmentioning

confidence: 78%

Hypopituitarism in Patients with Blepharophimosis and FOXL2 Mutations

Castets¹,

Roucher‐Boulez²,

Saveanu³

et al. 2020

Horm Res Paediatr

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Background: FOXL2 is the gene involved in blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES). There have been few single case reports of growth hormone deficiency (GHD) with this syndrome, and Foxl2 is known to be involved in pituitary development in mice. Our aim was to analyze the prevalence of FOXL2 gene alteration in a series of patients with congenital hypopituitarism and eyelid anomalies. Methods: FOXL2 was analyzed in 10 patients with hypopituitarism (ranging from isolated GHD to complete pituitary hormone deficiency) and eyelid anomalies (typical BPES in 4 patients and milder anomalies in 6 patients). In patients with an FOXL2 mutation, we ruled out other possible molecular explanations by analyzing a panel of 20 genes known to be associated with hypopituitarism, and a candidate gene approach was used for patients without an FOXL2 mutation. Results: Three patients had an FOXL2 mutation. All 3 had typical BPES. Their pituitary phenotype varied from GHD to complete pituitary hormone deficiency and their pituitary morphology ranged from normal to an interrupted pituitary stalk. No mutations were found in genes previously associated with hypopituitarism. Conclusion: Our study shows that some patients with BPES have hypopituitarism with no molecular explanation other than FOXL2 mutation. This points toward an involvement of FOXL2 in human pituitary development.

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Section: Discussionmentioning

confidence: 78%

Hypopituitarism in Patients with Blepharophimosis and FOXL2 Mutations

Castets¹,

Roucher‐Boulez²,

Saveanu³

et al. 2020

Horm Res Paediatr

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“…As an essential transcription factor, FOXL2 is not only involved in the normal development of the ovary and the eyelid [20], but is also related to steroid metabolism, reactive oxygen species detoxification, estrogen production, stress response and inflammatory processes [21]. In addition, FOXL2 mutations were reported to be associated with polycystic ovary syndrome (PCOS) [22] and blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) [23, 24]. Among those processes, researchers mainly focus on the downstream regulation of FOXL2 while ignoring the upstream regulation, and there are only a small number of studies regarding this regulation to date.…”

Section: Discussionmentioning

confidence: 99%

New STAT3-FOXL2 pathway and its function in cancer cells

Han

Yang

et al. 2019

BMC Mol and Cell Biol

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Background The forkhead transcription factor (FOXL2) plays a crucial role in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), sex determination, ovary growth and development, and cell cycle regulation. Emerging investigations have focused on the downstream targets of FOXL2, while little is known about its upstream regulation. Results In this study, we show that FOXL2 could be regulated by STAT3 in cancer cells and that STAT3 binds to FOXL2 at the 5′- GCCTGATGTTTGTCTTCCCAGTCTGTGGCAA-3′ site using EMSA and ChIP. We further found that knockdown of STAT3 or FOXL2 could significantly induce cancer cell apoptosis, indicating the importance of these two genes in cancer cell growth and apoptosis. Our data also indicated that the increased apoptotic cell rate may be caused by changes in apoptosis-related genes, such as TNF , TRAIL and GnRHR . Conclusion This study presents a new upstream regulator of FOXL2 and demonstrats that this new STAT3-FOXL2 pathway has an important function in HeLaHeLa cell apoptosis, providing new insights regarding the targeting of FOXL2 for cancer prevention and treatment. Electronic supplementary material The online version of this article (10.1186/s12860-019-0206-3) contains supplementary material, which is available to authorized users.

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“…At least 460 patients have been reported with FOXL2-related BPES [1,6,10,. The most common variants affect two intragenic regions ( Figure 1): (i) the poly-alanine region with c.663_692dup p.(Ala221_Ala231dup) reported in 12 patients (four BPES-II cases and eight with undefined type) [6,14,16,[30][31][32], c.664_693dup p.(Ala222_Ala231dup) reported in five patients (two BPES-II, two BPES-I, and one with undefined type), and c.672_701dup p.(Ala225_Ala234dup), which was reported in at least 80 patients (24 BPES-II, 2 BPES-I, and 54 with undefined type) [6,14,16,22,26,[30][31][32]54,61,63], and (ii) the poly-proline region, which encompasses amino acids at positions 284 to 292, has two duplications variants: c.843_859dup p.(Pro287Argfs*75) reported in 46 patients (3 BPES-I, 2 BPES-II, and 41 with undefined type) [6,14,16,31,32,63] and c.855_871dup p.(His291Argfs*71) in 15 patients (3 BPES-I and 12 undefined type) [6,14,16,24,38,63], and the deletion c.855_871del p.(Pro287Alafs*71) in 5 patients (3 BPES-I, 1 BPES-II, and 1 with undefined type) [6,14,34,40,63].…”

Section: Genetics Of Bpes 21 Foxl2 Genementioning

confidence: 99%

“…However, as ovarian function was largely unavailable due to the young age or sex of the patient, this was not possible. A tendency was observed with variants leading to an expanded poly-alanine region, such as c.663_692dup p.(Ala221_Ala231dup), c.664_693dup p.(Ala222_Ala231dup), and c.672_701dup p.(Ala225_Ala234dup), which are mostly associated with BPES-II [6,14,16,22,26,[30][31][32]43,45,51,54,61,63]. Interfamilial variability was observed for these variants, where some cases are reported to be associated with BPES-I.…”

Section: Genetics Of Bpes 21 Foxl2 Genementioning

confidence: 99%

“…Poly-alanine tract expansion is the most common mutation to have been described in BPES-II [67]. [6,14,16,22,24,[30][31][32]41,54,55,61,63]. These expansions may be caused by slippage of DNA polymerase when duplicating trinucleotide repeats, accounting for about 33% of all intragenic mutations in BPES overall [6,11,41,67].…”

Section: Poly-alanine Tract Expansion Variantsmentioning

confidence: 99%

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

Méjécase¹,

Nigam

Moosajee

et al. 2021

Genes

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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.

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Analysis of FOXL2 detects three novel mutations and an atypical phenotype of blepharophimosis‐ptosis‐epicanthus inversus syndrome

Abstract: Background: Mutations in FOXL2 are known to cause autosomal dominant blepharophimosisptosis-epicanthus inversus syndrome (BPES), variably associated with premature ovarian failure. In this study, we report results of mutational screening in a Czech and Slovak patient population with BPES.

Cited by 11 publications

References 20 publications

Hypopituitarism in Patients with Blepharophimosis and <b><i>FOXL2</i></b> Mutations

Hypopituitarism in Patients with Blepharophimosis and <b><i>FOXL2</i></b> Mutations

New STAT3-FOXL2 pathway and its function in cancer cells

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

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