<i>FOXL2</i>mutations and genomic rearrangements in BPES

Beysen, Diane; Paepe, Anne De; Baere, Elfride De

doi:10.1002/humu.20807

Cited by 100 publications

(112 citation statements)

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“…23 So far, more than 100 different mutations have been described involving FOXL2, and pathogenic variants can be found in approximately 88% of cases. 24 The presence of other loci causing the syndrome also has been proposed, although a clear association is still lacking. 17,25,26 We performed molecular screening of FOXL2 in 16 patients to analyze specifically the LG phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…32 The third missense mutation (c.313A>C), found in 2 related patients, is a novel pathogenic variant and causes the substitution of an asparagine for a histidine in the forkhead domain of FOXL2. 24 The remaining 4 mutations included 2 insertions, c.919_920insACCGCCGC and c.768-769insG, a nonsense mutation, c.370A>T, and a deletion, c.172_176delTCGTA. Only the first insertion has been described.…”

Section: Discussionmentioning

confidence: 99%

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Lacrimal Gland Involvement in Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome

et al. 2017

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Purpose: To describe the involvement of the lacrimal gland (LG) in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES).Design: Observational, cross-sectional study. Participants: Twenty-one patients with BPES (10 female, 11 male) aged on average 15 years (range, 2e39 years), from 3 Brazilian medical centers and 1 Portuguese medical center.Methods: Patients had their ocular surface evaluated with slit-lamp biomicroscopy, and tear production quantified with the Schirmer test I. The LG volumes were measured on computed tomography (CT) scans in the BPES sample and in a group of age-matched subjects imaged for nonorbital diseases. Sixteen patients were screened for mutations in the FOXL2 gene.Main Outcome Measures: Lacrimal meniscus height, Schirmer test I, presence of superficial punctate keratopathy (SPK), LG volume, and molecular analysis of the FOXL2 gene.Results: Absence of LG was detected bilaterally in 9 patients (42.8%) and unilaterally in 2 patients (9.5%). When considering only patients with measurable LG, the median volume was 0.22 cm 3 in the right eye (range, 0.06e0.36 cm 3 ) and 0.24 cm 3 in the left eye (range, 0.08e0.34 cm 3 ). These values were significantly lower than those for the age-matched controls (median ¼ 0.54 right eye and 0.53 left eye; P < 0.05). There was a significant association between deficiency of tear production and LG volume reduction and agenesis. Molecular analysis of the FOXL2 gene revealed the presence of 8 distinct mutations, 4 of them novel ones. A significant reduction of LG size or agenesis was associated with mutations affecting protein size (due to underlying changes in the stop codon location) or the DNA-binding forkhead domain (Fisher exact test, P ¼ 0.021). In 3 probands, the underlying genetic defect was not found.Conclusions: This is the first study reporting LG volumes in BPES, describing a significant number of patients with LG agenesis. The association between alacrima and BPES is not incidental, and a thorough evaluation of tear production is recommended especially if ptosis surgery is planned. Ophthalmology 2017;124:399-406 ª

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Lacrimal Gland Involvement in Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome

et al. 2017

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“…BPES patients represent an autosomal-dominant condition characterized by defects in eyelid development with (type I) or without (type II) premature ovarian failure (Fraser et al 1988;Crisponi et al 2001;De Baere et al 2005Raile et al 2005;Nallathambi et al 2007;Beysen et al 2009;Dipietromaria et al 2009;Méduri et al 2010). Within the ovary, FOXL2 has been shown to be essential for ovary development and function (Pisarska et al 2011).…”

Section: Discussionmentioning

confidence: 99%

The <i>FOXL2</i> Mutation (c.402C>G) in Adult-Type Ovarian Granulosa Cell Tumors of Three Japanese Patients: Clinical Report and Review of the Literature

Takahashi

Kimura

Yamanaka

et al. 2013

Tohoku J. Exp. Med.

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Adult-type granulosa cell tumor (AGCT) is a rare class of malignant ovarian tumor with unique features, characterized by slow growth, late recurrence, relatively good prognosis and unified cause in almost all patients. The forkhead box L2 (FOXL2) gene encodes an essential transcription factor in the ovary. FOXL2 is important in female sex determination, follicle recruitment, and granulosa cell development. About 70-97% of AGCTs were reported to carry a somatic mutation c.402C>G (C134W) in the FOXL2 gene. However, it is unknown whether AGCTs of Japanese patients harbor the FOXL2 c.402C>G mutation. Here, we report a mutational analysis of the FOXL2 gene in four Japanese patients with AGCTs, and we review the literature to determine the precise incidence of FOXL2 mutations in AGCTs. All four patients were analyzed by immunohistochemistry for FOXL2. Genomic DNA was extracted from paraffin-embedded tissues, and was analyzed to detect the c.402C>G mutation in FOXL2 by direct sequencing. All tumors were stained with FOXL2. Three of the four tumors harbor the c.402C>G mutation. Based on the literature review, FOXL2 immunostaining is a highly specific marker for sex cord-stromal tumors (SCSTs), but it is not specific for AGCTs, one subtype of SCSTs. We identified 340 patients with the FOXL2 mutation (c.402C>G) and determined that the incidence of the mutation is 91.9% in AGCT patients. Therefore, this FOXL2 mutation is specific to AGCTs in the ovary and is useful for diagnosis of this disease.

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“…The prevalence of the disorder is about 1:2500 live female births (Sybert & McCauley 2004). In women with 45,X karyotype, oocyte loss occurs in the early stages of meiotic prophase, resulting in gonadal dysgenesis and PA with Sedgwick & Boder (1991), Perheentupa (1996), Weinstein et al (2004), Fogli et al (2003Fogli et al ( , 2004, Beysen et al (2009) Zhao et al (2008a,b) elevated FSH levels since early childhood (Reynaud et al 2004, Fechner et al 2006. However, spontaneous menarche and pregnancy have been reported not only in patients with mosaic karyotype, but also in few nonmosaic 45,X women (Pasquino et al 1997, Cools et al 2004, Livadas et al 2005.…”

Section: Syndromic Poimentioning

confidence: 99%

“…More than 125 FOXL2 variants have been described in individuals with BPES types I and II, demonstrating that phenotypic features are caused by the pleiotropic effect of a single gene, rather than by a contiguous gene syndrome. Beysen et al (2009) recently reviewed a total of 106 unique intragenic FOXL2 mutations identified in 206 unrelated families with BPES of different ethnic origins. Detailed information on most FOXL2 mutations and on affected individuals or families with BPES was made available in the FOXL2 mutation database (http://users.ugent.be/ wdbeysen/foxl2).…”

Section: Blepharophimosis-ptosis-epicanthus Inversus Syndromementioning

confidence: 99%

Genes involved in human premature ovarian failure

Persani

Rossetti

Cacciatore

2010

Journal of Molecular Endocrinology

209

108

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Premature ovarian failure (POF) is an ovarian defect characterized by the premature depletion of ovarian follicles before the age of 40 years, representing one major cause of female infertility. POF relevance is continuously growing because women tend to conceive ever more frequently in their thirties and forties. POF can present very early with a pubertal defect. More frequently, it is the end stage of an occult process (primary ovarian insufficiency, POI) affecting w1-2% of under-40 women. POI is a heterogeneous disease caused by a variety of mechanisms. Though the underlying cause remains unexplained in the majority of cases, various data indicate that POI has a strong genetic component. These data include the existence of several causal genetic defects in humans, experimental and natural models, as well as the frequent familiarity. The variable expressivity of POI defect in women of the same family may indicate that, in addition to some monogenic forms, POI may frequently be considered as a multifactorial defect resulting from the contribution of several predisposing alleles. The X chromosome-linked defects play a major role among the presently known causal defects. Here, we review the principal X-linked and autosomal genes involved in syndromic and nonsyndromic forms of POI with the wish that this list will soon become upgraded because of the discovery of novel contributing mechanisms. A better understanding of POI pathogenesis will indeed allow the construction of tests able to predict the age of menopause in women at higher risk of POI.

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FOXL2mutations and genomic rearrangements in BPES

Cited by 100 publications

References 86 publications

Lacrimal Gland Involvement in Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome

Lacrimal Gland Involvement in Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome

The <i>FOXL2</i> Mutation (c.402C>G) in Adult-Type Ovarian Granulosa Cell Tumors of Three Japanese Patients: Clinical Report and Review of the Literature

Genes involved in human premature ovarian failure

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