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Query: UMLS:C0033377 (prolapse)
 11,717 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is an autosomal dominant syndrome of eyelid malformations with (type I) or without (type II) associated premature ovarian failure. Multiple mutations in the exon and the putative core promoter region of FOXL2 gene encoding a putative forkhead transcription factor have been linked to this disease. To examine whether FOXL2 gene mutations contribute to BPES in the Chinese patient population, we screened 33 patients from 18 Chinese families with BPES of unknown types, together with 57 healthy individuals, including 27 relatives of the affected families. Genomic DNA was extracted from the participants' peripheral blood leukocytes, and amplified by polymerase chain reaction for various regions of the FOXL2 gene, followed by sequencing analysis. Ten mutations in the FOXL2 gene were detected: four were previously reported (g.1041_1042insC, g.1366_1367insT, g.909_938dup30, and g.900_929dup30), and six were novel ones (g.406T>A, g.-14G>A, g.1108_1109insC, g.2577C>T, g.1987C>A, and g.1002C>G). Among them, mutations in the coding region for the polyalanine tract, as well as novel mutations in the core promoter, the 3'-UTR, and in the forkhead domain were identified. Our results expanded the spectrum of FOXL2 mutations in BPES and provided additional valuable genetic information for this rare disease.
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PMID:Mutations of the transcription factor FOXL2 gene in Chinese patients with blepharophimosis-ptosis-epicanthus inversus syndrome. 1937 Dec 27

FOXL2 is a gene encoding a forkhead transcription factor, whose germline mutations are responsible for the blepharophimosis ptosis epicanthus inversus syndrome. We have previously shown that expression levels of FOXL2 in a series of juvenile ovarian granulosa cell tumors (OGCTs) were markedly reduced. More recently, a whole-transcriptome 'next-generation' sequencing study has identified the somatic mutation p.Cys134Trp as recurring in adult OGCTs. This mutation may thus provide the tumor with either a striking proliferative potential or increased survival abilities. These studies of FOXL2 in OGCTs suggest that it may act as a tumor suppressor gene. This is in line with the fact that other forkhead transcription factors have already been involved in the etiology of cancer. Indeed, an in-depth review of existing data on FOXL2 reveals that its target genes and molecular partners can often be linked to cancer progression.
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PMID:The forkhead factor FOXL2: a novel tumor suppressor? 1974 61

The Blepharophimosis Ptosis Epicanthus-inversus Syndrome is a genetic disease characterized by complex eyelid malformations often associated with premature ovarian failure (POF). BPES is basically an autosomal dominant disease, due to mutations in the FOXL2 gene, which encodes a forkhead transcription factor. More than one hundred mutations of FOXL2 have been described to date. In agreement with the BPES phenotype, FOXL2 is expressed (though not exclusively) in the developing eyelids and in fetal and adult ovaries. Two mouse knock-out models have been produced. They recapitulate the BPES phenotype and have provided insights into the pathology. Loss-of-function mutations in FOXL2 are predicted to lead to BPES and POF, while hypomorphic mutations might lead to BPES without ovarian dysfunction. However, exceptions to the genotype-phenotype correlation have been described. To better understand the pathogenic effect of these mutations it is crucial to study the normal regulation of FOXL2 and its targets. We briefly address these aspects in this review and hope that basic research around FOXL2 will eventually lead to uncover new therapeutic avenues.
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PMID:The transcription factor FOXL2 in ovarian function and dysfunction. 2006 92

The FOXL2 forkhead transcription factor is expressed in ovarian granulosa cells, and mutated FOXL2 causes the blepharophimosis, ptosis and epicanthus inversus syndrome (BPES) and predisposes to premature ovarian failure. Inactivation of Foxl2 in mice demonstrated its indispensability for female gonadal sex determination and ovary development and revealed its antagonism of Sox9, the effector of male testis development. To help to define the regulatory activities of FOXL2, we looked for interacting proteins. Based on yeast two-hybrid screening, we found that FOXL2 interacts with PIAS1 and UBC9, both parts of the sumoylation machinery. We showed that human FOXL2 is sumoylated in transfected cell lines, and that endogenous mouse Foxl2 is comparably sumoylated. This modification changes its cellular localization, stability and transcriptional activity. It is intriguing that similar sumoylation and regulatory consequences have also been reported for SOX9, the male counterpart of FOXL2 in somatic gonadal tissues.
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PMID:The forkhead transcription factor Foxl2 is sumoylated in both human and mouse: sumoylation affects its stability, localization, and activity. 2020 45

The gene FOXL2 encodes a forkhead transcription factor whose mutations are responsible for the blepharophimosis ptosis epicanthus-inversus syndrome. This genetic disorder is characterized by eyelid and mild craniofacial abnormalities often in association with premature ovarian failure. FOXL2 orthologs are found throughout the animal phylum and its sequence is highly conserved in vertebrates. FOXL2 is one of the earliest ovarian markers and it offers, alongwith its targets, a model to study ovarian development and function. In this chapter, we review recent data concemingits mutations, targets, regulation and functions. Studies of the cellular consequences of FOXL2 mutations seem to indicate that aggregation is a common pathogenic mechanism. However, no reliable genotype/phenotype correlation has been established to predict the exact impact of point mutations in the coding region of FOXL2. FOXL2 has been suggested to be involved in the regulation of cholesterol homeostasis, steroid metabolism, apoptosis, reactive oxygen species detoxification and inflammation processes. Interestingly, all these processes are not equally affected by FOXL2 mutations. The elucidation of the impact of the FOXL2 function in the ovary will allow a better understanding of normal ovarian development and function as well as the pathogenic mechanisms underlying BPES.
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PMID:FOXL2: at the crossroads of female sex determination and ovarian function. 2042 27

FOXL2 is a gene encoding a forkhead transcription factor. Its mutations or misregulation have been shown to cause the blepharophimosis-ptosis-epicanthus inversus (BPES) syndrome and more recently have been associated with the development of Ovarian Granulosa Cell Tumors (OGCT). BPES is a genetic disorder involving mild craniofacial abnormalities often associated with premature ovarian failure. OGCTs are endocrine malignancies, accounting for 2-5% of ovarian cancers, the treatment of which is still challenging. In this review we summarize recent data concerning FOXL2 transcriptional targets and molecular partners, its post-translational modifications, its mutations and its involvement in newly discovered pathophysiological processes. In the ovary, FOXL2 is involved in the regulation of cholesterol and steroid metabolism, apoptosis, reactive oxygen species detoxification and cell proliferation. Interestingly, one of the main roles of FOXL2 is also to preserve the identity of ovarian granulosa cells even at the adult stage and to prevent their transdifferentiation into Sertoli-like cells. All these recent advances indicate that FOXL2 is central to ovarian development and maintenance. The elucidation of the impact of FOXL2 germinal and somatic mutations will allow a better understanding of the pathogenesis of BPES and of OGCTs.
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PMID:The transcription factor FOXL2: at the crossroads of ovarian physiology and pathology. 2176 50

Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare autosomal dominant disorder characterized by a complex dysgenesis of the eyelids and premature ovarian insufficiency. FOXL2 located at 3q22.3, encoding a forkhead transcription factor, is the only gene known to be responsible for BPES. We describe a patient diagnosed with BPES with atypical ovarian failure, characterized by normal levels of gonadotropins, who was found to have trisomy X as well as a translocation (3;11)(q22.3;q14.1). The translocation breakpoint at 3q22.3 is located upstream of the FOXL2 gene and most likely causes BPES by separating the FOXL2 transcription unit from its cis-regulatory sequences. By array analysis we detected mosaicism for the balanced and an unbalanced form of the translocation in blood cells. We propose mitotic recombination as the likely mechanism of the mosaicism formation. Mitotic recombination is a common phenomenon in human cells. Thus, we hypothesize that it may be one of the mechanisms responsible for cryptic imbalances and possible abnormal phenotypes in some carriers of balanced rearrangements.
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PMID:BPES with atypical premature ovarian insufficiency, and evidence of mitotic recombination, in a woman with trisomy X and a translocation t(3;11)(q22.3;q14.1). 2288 99

Forkhead box L2 (FOXL2) is a gene encoding a forkhead transcription factor preferentially expressed in the ovary, the eyelids and the pituitary gland. Its germline mutations are responsible for the blepharophimosis ptosis epicanthus inversus syndrome, which includes eyelid and mild craniofacial defects associated with primary ovarian insufficiency. Recent studies have shown the involvement of FOXL2 in virtually all stages of ovarian development and function, as well as in granulosa cell (GC)-related pathologies. A central role of FOXL2 is the lifetime maintenance of GC identity through the repression of testis-specific genes. Recently, a highly recurrent somatic FOXL2 mutation leading to the p.C134W subtitution has been linked to the development of GC tumours in the adult, which account for up to 5% of ovarian malignancies. In this review, we summarise data on FOXL2 modulators, targets, partners and post-translational modifications. Despite the progresses made thus far, a better understanding of the impact of FOXL2 mutations and of the molecular aspects of its function is required to rationalise its implication in various pathophysiological processes.
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PMID:FOXL2: a central transcription factor of the ovary. 2404 64

Blepharophimosis, ptosis, epicanthus-inversus syndrome (BPES) is an autosomal dominant genetic disorder characterized by narrow palpebral fissures and eyelid levator muscle defects. BPES is often associated to premature ovarian insufficiency (BPES type I). FOXL2, a member of the forkhead transcription factor family, is the only gene known to be mutated in BPES. Foxl2 is essential for maintenance of ovarian identity, but the developmental origin of the facial malformations of BPES remains, so far, unexplained. In this study, we provide the first detailed account of the developmental processes leading to the craniofacial malformations associated to Foxl2. We show that, during development, Foxl2 is expressed both by Cranial Neural Crest Cells (CNCCs) and by Cranial Mesodermal Cells (CMCs), which give rise to skeletal (CNCCs and CMCs) and muscular (CMCs) components of the head. Using mice in which Foxl2 is selectively inactivated in either CNCCs or CMCs, we reveal that expression of Foxl2 in CNCCs is essential for the development of extraocular muscles. Indeed, inactivation of Foxl2 in CMCs has only minor effects on muscle development, whereas its inactivation in CNCCs provokes a severe hypoplasia of the levator palpabrae superioris and of the superior and inferior oblique muscles. We further show that Foxl2 deletion in either CNCCs or CMCs prevents eyelid closure and induces subtle skeletal developmental defects. Our results provide new insights in the complex developmental origin of human BPES and could help to understand the origin of other ocular anomalies associated to this syndrome.
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PMID:Etiology of craniofacial malformations in mouse models of blepharophimosis, ptosis and epicanthus inversus syndrome. 2541 81

Blepharophimosis, ptosis, epicanthus inversus syndrome (BPES) is a rare autosomal dominant genetic disease characterized by a narrowed horizontal palpehral aperture, ptosis, epicanthus inversus and telecanthus with or without premature ovarian failure. Mutations in the forkhead transcription factor 2 (FOXL2) have been shown to be responsible for BPES. We performed direct sequencing of the FOXL2 gene for molecular investigation of a Chinese family with BPES. A novel duplication mutation (c.858_868dup), resulting in a truncated protein, was detected.
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PMID:A novel FOXL2 mutation in a Chinese family with blepharophimosis, ptosis, epicanthus inversus syndrome. 2708 23


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