Abstract:We report the genetic characterization of one family with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) type 1 and two families with BPES type 2 from a historically isolated population in northwest Colombia. Linkage and haplotype analyses indicate that BPES in these families is linked to 3q23. Mutation screening of FOXL2 in the family with BPES type 1 revealed a novel 394C --> T nonsense mutation which deletes the forkhead DNA binding domain. The two families with BPES type 2 both carry an in-fra… Show more
“…To date, a total of 106 unique intragenic FOXL2 mutations (i.e. different mutations that are unique to the world-wide collection of gene variants) have been identified in 206 unrelated BPES families from different ethnic origin [Bell et al, 2001;Cha et al, 2003;Crisponi et al, 2001Crisponi et al, , 2002De Baere et al, 2001Dollfus et al, 2003;Fokstuen et al, 2003;Kosaki et al, 2002;Kumar et al, 2004;Li et al, 2005;Nallathambi et al, 2007Nallathambi et al, , 2008Or et al, 2006;Raile et al, 2005;Ramírez-Castro et al, 2002;Tang et al, 2006;Udar et al, 2003;Vincent et al, 2005;Yamada et al, 2001] (this study). An overview of these mutations is presented in Supplementary Table S1 (available online at http://www.…”
Section: Mutation Spectrum Intragenic Foxl2 Mutations In Bpesmentioning
The FOXL2 gene is one of 10 forkhead genes, the mutations of which lead to human developmental disorders, often with ocular manifestations. Mutations in FOXL2 are known to cause blepharophimosis syndrome (BPES), an autosomal dominant eyelid malformation associated (type I) or not (type II) with ovarian dysfunction, leading to premature ovarian failure (POF). In addition, a few mutations have been described in patients with isolated POF. Here, we review all currently described FOXL2 sequence variations and genomic rearrangements in BPES and POF. Using a combined mutation detection approach, it is possible to identify the underlying genetic defect in a major proportion (88%) of typical BPES patients. Of all genetic defects found in our BPES cohort, intragenic mutations represent 81%. They include missense changes, frameshift and nonsense mutations, in-frame deletions, and duplications, that are distributed along the single-exon gene. Genomic rearrangements comprising both deletions encompassing FOXL2 and deletions located outside its transcription unit, represent 12% and 5% of all genetic defects in our BPES cohort, respectively. One of the challenges of genetic testing in BPES is the establishment of genotype-phenotype correlations, mainly with respect to the ovarian phenotype. Genetic testing should be performed in the context of genetic counseling, however, and should be systematically complemented by a multidisciplinary clinical follow-up. Another challenge for health care professionals involved in BPES is the treatment of the eyelid phenotype and the prevention or treatment of POF.
“…To date, a total of 106 unique intragenic FOXL2 mutations (i.e. different mutations that are unique to the world-wide collection of gene variants) have been identified in 206 unrelated BPES families from different ethnic origin [Bell et al, 2001;Cha et al, 2003;Crisponi et al, 2001Crisponi et al, , 2002De Baere et al, 2001Dollfus et al, 2003;Fokstuen et al, 2003;Kosaki et al, 2002;Kumar et al, 2004;Li et al, 2005;Nallathambi et al, 2007Nallathambi et al, , 2008Or et al, 2006;Raile et al, 2005;Ramírez-Castro et al, 2002;Tang et al, 2006;Udar et al, 2003;Vincent et al, 2005;Yamada et al, 2001] (this study). An overview of these mutations is presented in Supplementary Table S1 (available online at http://www.…”
Section: Mutation Spectrum Intragenic Foxl2 Mutations In Bpesmentioning
The FOXL2 gene is one of 10 forkhead genes, the mutations of which lead to human developmental disorders, often with ocular manifestations. Mutations in FOXL2 are known to cause blepharophimosis syndrome (BPES), an autosomal dominant eyelid malformation associated (type I) or not (type II) with ovarian dysfunction, leading to premature ovarian failure (POF). In addition, a few mutations have been described in patients with isolated POF. Here, we review all currently described FOXL2 sequence variations and genomic rearrangements in BPES and POF. Using a combined mutation detection approach, it is possible to identify the underlying genetic defect in a major proportion (88%) of typical BPES patients. Of all genetic defects found in our BPES cohort, intragenic mutations represent 81%. They include missense changes, frameshift and nonsense mutations, in-frame deletions, and duplications, that are distributed along the single-exon gene. Genomic rearrangements comprising both deletions encompassing FOXL2 and deletions located outside its transcription unit, represent 12% and 5% of all genetic defects in our BPES cohort, respectively. One of the challenges of genetic testing in BPES is the establishment of genotype-phenotype correlations, mainly with respect to the ovarian phenotype. Genetic testing should be performed in the context of genetic counseling, however, and should be systematically complemented by a multidisciplinary clinical follow-up. Another challenge for health care professionals involved in BPES is the treatment of the eyelid phenotype and the prevention or treatment of POF.
“…FOXL2 is a member of the forkhead/hepatocyte nuclear factor 3 family of transcription factors (15), which is characterized by the presence of a conserved winged helix domain that is essential for DNA binding as well as more divergent transactivation or transrepression domains (12,29,33). FOXL2 mutations in individuals with BPES type I create premature stop codons that are predicted to generate truncated proteins lacking the carboxyl (COOH) terminus alanine/proline-rich domain (15)(16)(17)44). Consistent with the BPES phenotype, FOXL2 is expressed selectively in the eyelids of developing mice (15) and in the mouse ovary (41).…”
is expressed in the ovary and acts as a transcriptional repressor of the steroidogenic acute regulatory (StAR) gene, a marker of granulosa cell differentiation. Human FOXL2 mutations that produce truncated proteins lacking the COOH terminus result in blepharophimosis/ptosis/epicanthus inversus (BPES) syndrome type I, which is associated with premature ovarian failure (POF). In this study, we investigated whether FOXL2's activity as a transcriptional repressor is regulated by phosphorylation. We found that FOXL2 is phosphorylated at a serine residue and, using yeast two-hybrid screening, identified LATS1 as a potential FOXL2-interacting protein.LATS1 is a serine/threonine kinase whose deletion in mice results in an ovarian phenotype similar to POF. Using coimmunoprecipitation and kinase assays, we confirmed that LATS1 binds to FOXL2 and demonstrated that LATS1 phosphorylates FOXL2 at a serine residue. Moreover, we found that FOXL2 and LATS1 are coexpressed in developing mouse gonads and in granulosa cells of small and medium follicles in the mouse ovary. Last, we demonstrated that coexpression with LATS1 enhances FOXL2's activity as a repressor of the StAR promoter, and this results from the kinase activity of LATS1. These results provide novel evidence that FOXL2 is phosphorylated by LATS1 and that this phosphorylation enhances the transcriptional repression of the StAR gene, a marker of granulosa cell differentiation. These data support our hypothesis that phosphorylation of FOXL2 may be a control mechanism regulating the rate of granulosa cell differentiation and hence, follicle maturation, and its dysregulation may contribute to accelerated follicular development and POF in BPES type I. large tumor suppressor gene 1 phosphorylation; transcriptional regulation; forkhead L2; granulosa cell; premature ovarian failure PREMATURE OVARIAN FAILURE (POF) is defined as a condition causing amenorrhea, hypoestrogenism, and elevated gonadotropins in women under 40 yr of age (1) and can be associated with failure to endow the follicle pool or an early loss of the fixed follicle pool following excess follicle recruitment and/or atresia. A genetic basis for selective cases of POF has been determined. Patients with blepharophimosis-ptosis-epicanthus inversus (BPES) syndrome type I exhibit POF in association with characteristic eyelid dysplasia, blepharophimosis, ptosis, and epicanthus inversus (60). Ovaries from BPES type I patients are histologically variable, ranging from the presence of some primordial follicles with atretic follicles to complete absence of follicles and scarring of the ovaries (23). The gene encoding the transcription factor forkhead L2 (FOXL2) (15) maps to the BPES locus on chromosome 3q22-3q23. FOXL2 is a member of the forkhead/hepatocyte nuclear factor 3 family of transcription factors (15), which is characterized by the presence of a conserved winged helix domain that is essential for DNA binding as well as more divergent transactivation or transrepression domains (12,29,33). FOXL2 mutations in indivi...
“…For mutants found in type I
BPES, various truncated forms of FOXL2 at the carboxy terminus due to frame shift
mutations leading to premature stop codons were cloned: Q53X, Q219X, I80T, I84S, and
Y274X, the latter was also reported to manifest type II BPES [12,13,14,15] (Fig. 1AFig.…”
Abstract. 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, 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.
FOXL2 is a member of the forkhead (FH) family of transcription factors known to be required for proper development of the ovary and eyelid [1]. FOXL2 is a single-exon gene that encodes a protein of 376 amino acids containing a DNA-binding FH domain and an alanine-rich region. Mutations in the FOXL2 gene cause the autosomal dominant genetic disorder blepharophimosis-ptosis-epicanthus inversus syndrome (BPES; MIM 110100) [2]. BPES type I patients have eyelid malformation associated with premature ovarian failure (POF). In contrast, type II BPES patients show defects in eyelid development, but affected individuals are fertile [2]. Although FOXL2 mRNA is expressed in fetal, juvenile, and adult mouse ovaries, undifferentiated granulosa cells (GCs) of small follicles have prevalent FOXL2 expression [3]. Female Foxl2 knockout mice are infertile and have defects in granulosa cell differentiation [4,5]. Conditional knockout of Foxl2 in adult mice results in somatic transdifferentiation of an adult ovary into a testis [4]. Also, more than 97% of adult-type ovarian GC tumors have a somatic point mutation (C134W) in the FOXL2 gene [6]. These human and mouse studies indicate that FOXL2 is an essential protein required for proper development and maintenance of the ovary. Although the mechanism by which FOXL2 orchestrates ovarian physiology is not completely understood, its role in regulating target genes involved in apoptosis, the cell cycle, and differentiation has been reported [7][8][9][10].In the present study, we investigated the functional differences of FOXL2 mutants found in BPES type I and II patients and observed compromised activities of mutant FOXL2 proteins that may at least partly contribute to the pathophysiology of ovarian dysfunction...
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