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PubMed2006

Reverse transcriptase template switching and false alternative transcripts.

Reverse transcriptase (RT) can switch from one template to another in a homology-dependent manner. In the study of eukaryotic transcripts, this propensity of RT can produce an artificially deleted cDNA, which can be wrongly interpreted as an alternative transcript. Here, we have investigated the presence of such template-switching artifacts in cDNA databases, by scanning a collection of human splice sites (Information for the Coordinates of Exons, ICE database). We have confirmed several cases at the experimental level. Artifacts represent a significant portion of apparently spliced sequences using noncanonical splice signals but are rare in the context of the whole database. However, care should be taken in the annotation of alternative transcripts, especially when the RT used is poorly thermostable and when the putative intron is flanked by direct repeats, which are the substrate for template switching.

Alternative Splicing↗
PubMed2006

Foxl2 function in ovarian development.

Foxl2 is a forkhead transcription factor essential for proper reproductive function in females. Human patients carrying mutations in the FOXL2 gene display blepharophimosis/ptosis/epicanthus inversus syndrome (BPES), an autosomal dominant disease associated with eyelid defects and premature ovarian failure in females. Recently, animal models for BPES have been developed that in combination with a catalogue of human FOXL2 mutations provide further insight into its molecular function. Mice homozygous mutant for Foxl2 display craniofacial malformations and female infertility. The analysis of the murine phenotype has revealed that Foxl2 is required for granulosa cell function. These ovarian somatic cells surround and nourish the oocyte and play an important role in follicle formation and activation. Mutations upstream of FOXL2 in humans, not affecting the coding sequence itself, have also been shown to cause BPES, which points to the existence of a distant regulatory element necessary for proper gene expression. The same regulatory sequences may be deleted in the goat polled intersex syndrome (PIS), in which FoxL2 expression is severely reduced. Sequence comparison of FoxL2 from several vertebrate species has shown that it is a highly conserved gene involved in ovary development. Thus, the detailed understanding of Foxl2 function and regulation and the identification of its transcriptional targets may open new avenues for the treatment of female infertility in the future.

Abnormalities, Multiple↗
PubMed2003

The gonadotropin releasing hormone (GnRH) receptor activating sequence (GRAS) is a composite regulatory element that interacts with multiple classes of transcription factors including Smads, AP-1 and a forkhead DNA binding protein.

Activin responsiveness of the murine GnRH receptor gene promoter is mediated at a regulatory element we termed the GnRH receptor activating sequence (GRAS). Here, we have sought to define the complex of transcription factors that interact at this element. Consistent with activin regulation at GRAS, gel shift analyses and yeast one-hybrid assays reveal Smad4 interaction at the 5' end of GRAS. While overexpression of Smad3 activates a GRAS reporter, Smad3 binding at GRAS was not detectable. A functional interaction of Smad3 at GRAS was, however, detectable in yeast expressing Smad4. Thus, Smad3 interaction at GRAS appears to be dependent on the presence of Smad4. Mutations located at the 3' end of GRAS do not affect Smad binding but eliminate functional activity. Thus, Smad binding alone cannot account for the functional attributes of GRAS. Consistent with this notion, we find that AP-1 binding is immediately juxtaposed to and, in fact, partially overlaps the Smad binding site. Finally, a recently identified member of the forkhead family of transcription factors, FoxL2, is also capable of interacting at GRAS. Furthermore, FoxL2 activation at GRAS is lost with mutation of either the 5' Smad binding site or a putative forkhead binding site located at the 3' end of the element. We suggest that GRAS is a composite regulatory element whose functional activity is dependent on the organization of a multi-protein complex consisting of Smads, AP-1 and a member of the forkhead family of DNA binding proteins.

Activins↗
PubMed2004

Conserved patterns of gene expression in mice and goats in the vicinity of the Polled Intersex Syndrome (PIS) locus.

The PIS mutation is a genomic ~12-kb deletion affecting long-range gene transcription and causing XX sex reversal and hornlessness in goats by simultaneous long-range action on two genes, gPISRT1 and gFOXL2. In this study, a comparative human/mouse analysis of the orthologous region was carriedout, permittingthe targeting of genes in the 1-Mb environment, and identification of previously unknown mouse orthologues for Pisrt1, Bpesc1 and Chr3syt, and a human orthologue for PISRT1. PCR primers were defined and made it possible to analyse tissue-specific gene expression in mice and goats for 10 and 8 genes, respectively. The profile of expression was analysed by principal component analysis (PCA). The results indicate that FAIM (Fas apoptotic inhibitory molecule) is expressed similarly to FOXL2 (the primary determinant of ovary development located 280 kb away from the PIS mutation). However, we could demonstrate in goats that the PIS mutation has no direct effect on FAIM expression. Therefore, FAIM could contribute to normal ovarian function by inhibiting the apoptotic effect of Fas in the ovary but it relies on other regulatory elements.

Animals↗
PubMed2003

Sporadic and familial blepharophimosis -ptosis-epicanthus inversus syndrome: FOXL2 mutation screen and MRI study of the superior levator eyelid muscle.

The analysis of the FOXL2 gene (3q23) in a series of two families and two sporadic cases affected with Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome (BPES) is presented. This study detected two novel FOXL2 mutations (missence and nonsens mutations) and confirmed the recurrence of a previously described duplication. Magnetic Resonance Imaging (MRI) of the orbit, in one family, showed absence or hypotrophy of the eyelid superior levator muscle suggesting a possible role of FOXL2 in the development of this extra-ocular muscle.

Adult↗
PubMed2001

A fork in the road to fertility.

Haploinsufficiency of FOXL2, a new forkhead transcription factor, causes blepharophimosis/ptosis/epicanthus inversus syndrome (BPES), a rare developmental disorder affecting the eyelid and sometimes the ovary. A new study implicates FOXL2 as the first human gene required for the maintenance of ovarian follicles. The discovery of FOXL2 may provide insight into the causes of idiopathic premature ovarian failure, a disease that burdens many infertile couples.

Blepharophimosis↗
PubMed2001

The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome.

In type I blepharophimosis/ptosis/epicanthus inversus syndrome (BPES), eyelid abnormalities are associated with ovarian failure. Type II BPES shows only the eyelid defects, but both types map to chromosome 3q23. We have positionally cloned a novel, putative winged helix/forkhead transcription factor gene, FOXL2, that is mutated to produce truncated proteins in type I families and larger proteins in type II. Consistent with an involvement in those tissues, FOXL2 is selectively expressed in the mesenchyme of developing mouse eyelids and in adult ovarian follicles; in adult humans, it appears predominantly in the ovary. FOXL2 represents a candidate gene for the polled/intersex syndrome XX sex-reversal goat.

Abnormalities, Multiple↗
PubMed2003

Mutational analysis of forkhead transcriptional factor 2 (FOXL2) in Korean patients with blepharophimosis-ptosis-epicanthus inversus syndrome.

We screened for mutations in the forkhead transcription factor gene, FOXL2, in Korean patients with sporadic or familial blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) by polymerase chain reaction-single-stranded conformation polymorphism (PCR-SSCP) and direct sequencing. Five of nine BPES families and three of seven sporadic cases were detected to have FOXL2 mutations. We identified four types of FOXL2 mutations, two of which are novel. A new 14 bp deletion (939-952del14) causing a frameshift from G235W and the extension of the predicted protein to 527 amino acids was detected in a BPES family patient. In addition, a novel 845C > A transversion, resulting in a nonsense mutation (S203X), was found in a sporadic case of BPES. The previously reported in-frame 30 bp duplication (909-938dup30) was the most common mutation and was found in eight patients of four BPES families and one sporadic case. A known 17 bp duplication (1080-1096dup17) was observed in a sporadic BPES case. We were unable to find a causal mutation in four BPES families and four sporadic cases. These results suggest that in a fraction of BPES patients, the genetic defect might be associated with a mutation in the non-coding region of the FOXL2 gene or in other genes.

Adolescent↗
PubMed2002

A novel mutation in the FOXL2 gene in a patient with blepharophimosis syndrome: differential role of the polyalanine tract in the development of the ovary and the eyelid.

Blepharophimosis/ptosis/epicanthus inversus syndrome (BPES) is an autosomal dominant disorder characterized by abnormalities of the eyelids. We herein report a 12-year-old girl with BPES who had bilateral blepharophimosis, ptosis, hypertelorism, and downslanting palpebral fissures. Mutation analysis revealed the insertion of a cytosine (dup 1036C) within a wild-type run of six cytosines. A comparison of the phenotypic outcomes of the previously described mutations and the dup 1036C mutation reported herein suggest that the outcome is largely dependent on the involvement of the polyalanine tract (residues 221 to 231). We suggest that the polyalanine tract may have a differential role in eyelid and ovarian development and function. Further work is required to clarify whether ovarian function can be predicted on the basis of genotype.

Blepharophimosis↗
PubMed2006

Familial blepharophimosis-like syndrome with esotropia, uveal coloboma, and short stature.

BACKGROUND: Interstitial deletion of Hsa 3q involves FOXL2, the gene responsible for blepharophimosis-ptosis-telecanthus-epicanthus inversus (BPES). Thought to be due to a contiguous gene syndrome, the recognizable phenotype of 3q interstitial deletion includes BPES facies and has not been associated with other loci. OBJECTIVE: To describe a familial syndrome that resembles the interstitial deletion of 3q clinically, but does not map to the FOXL2 region. METHODS: Clinical evaluation of family members and linkage analysis. RESULTS: Three affected siblings with a phenotype resembling that seen in 3q interstitial deletion were studied in addition to their clinically unaffected parents. Linkage analysis excluded FOXL2 as underlying the distinct phenotype, observed with > 99% confidence. CONCLUSIONS: The relevant locus in the current family, although remote from FOXL2, is likely important to the FOXL2 functional pathway. The phenotype observed in 3q interstitial deletion may be due to severe disruption of FOXL2 rather than to a contiguous gene syndrome.

Blepharophimosis↗
PubMed2003

FOXL2 and BPES: mutational hotspots, phenotypic variability, and revision of the genotype-phenotype correlation.

Blepharophimosis syndrome (BPES), an autosomal dominant syndrome in which an eyelid malformation is associated (type I) or not (type II) with premature ovarian failure (POF), has recently been ascribed to mutations in FOXL2, a putative forkhead transcription factor gene. We previously reported 22 FOXL2 mutations and suggested a preliminary genotype-phenotype correlation. Here, we describe 21 new FOXL2 mutations (16 novel ones) through sequencing of open reading frame, 5' untranslated region, putative core promoter, and fluorescence in situ hybridization analysis. Our study shows the existence of two mutational hotspots: 30% of FOXL2 mutations lead to polyalanine (poly-Ala) expansions, and 13% are a novel out-of-frame duplication. In addition, this is the first study to demonstrate intra- and interfamilial phenotypic variability (both BPES types caused by the same mutation). Furthermore, the present study allows a revision of the current genotype-phenotype correlation, since we found exceptions to it. We assume that for predicted proteins with a truncation before the poly-Ala tract, the risk for development of POF is high. For mutations leading to a truncated or extended protein containing an intact forkhead and poly-Ala tract, no predictions are possible, since some of these mutations lead to both types of BPES, even within the same family. Poly-Ala expansions may lead to BPES type II. For missense mutations, no correlations can be made yet. Microdeletions are associated with mental retardation. We conclude that molecular testing may be carefully used as a predictor for POF risk in a limited number of mutations.

5' Untranslated Regions↗
PubMed2005

Deletions involving long-range conserved nongenic sequences upstream and downstream of FOXL2 as a novel disease-causing mechanism in blepharophimosis syndrome.

The expression of a gene requires not only a normal coding sequence but also intact regulatory regions, which can be located at large distances from the target genes, as demonstrated for an increasing number of developmental genes. In previous mutation studies of the role of FOXL2 in blepharophimosis syndrome (BPES), we identified intragenic mutations in 70% of our patients. Three translocation breakpoints upstream of FOXL2 in patients with BPES suggested a position effect. Here, we identified novel microdeletions outside of FOXL2 in cases of sporadic and familial BPES. Specifically, four rearrangements, with an overlap of 126 kb, are located 230 kb upstream of FOXL2, telomeric to the reported translocation breakpoints. Moreover, the shortest region of deletion overlap (SRO) contains several conserved nongenic sequences (CNGs) harboring putative transcription-factor binding sites and representing potential long-range cis-regulatory elements. Interestingly, the human region orthologous to the 12-kb sequence deleted in the polled intersex syndrome in goat, which is an animal model for BPES, is contained in this SRO, providing evidence of human-goat conservation of FOXL2 expression and of the mutational mechanism. Surprisingly, in a fifth family with BPES, one rearrangement was found downstream of FOXL2. In addition, we report nine novel rearrangements encompassing FOXL2 that range from partial gene deletions to submicroscopic deletions. Overall, genomic rearrangements encompassing or outside of FOXL2 account for 16% of all molecular defects found in our families with BPES. In summary, this is the first report of extragenic deletions in BPES, providing further evidence of potential long-range cis-regulatory elements regulating FOXL2 expression. It contributes to the enlarging group of developmental diseases caused by defective distant regulation of gene expression. Finally, we demonstrate that CNGs are candidate regions for genomic rearrangements in developmental genes.

Animals↗
PubMed2001

Two families with blepharophimosis/ptosis/epicanthus inversus syndrome have mutations in the putative forkhead transcription factor FOXL2.

Blepharophimosis/ptosis/epicanthus inversus syndrome (BPES) is an autosomal dominant disorder that is characterized by distinctive eyelid abnormalities. Two clinical subtypes have been described in which type I, but not type II, is associated with premature ovarian failure. Both types of BPES are linked to 3q22-23, and the gene has recently been identified as the putative forkhead transcription factor FOXL2. We report mutation screening of FOXL2 in two families with this condition. The two mutations detected were frameshift mutations resulting from a small insertion or duplication within the gene. Both mutations would result in the production of novel carboxyl terminii, one terminating the predicted protein earlier than the wild type, and the other giving rise to a larger protein product, assuming these proteins or their mRNA were not degraded. Based on the present data, this would suggest that the first family should be type I and the second, type II. Although there is evidence of infertility in the first family, all 3 females in the youngest generation have normal pelvic ultrasound and hormone levels, suggesting that the divide between types I and II may not be as distinct as has been suggested.

Blepharophimosis↗
PubMed2001

Spectrum of FOXL2 gene mutations in blepharophimosis-ptosis-epicanthus inversus (BPES) families demonstrates a genotype--phenotype correlation.

Mutations in FOXL2, a forkhead transcription factor gene, have recently been shown to cause blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) types I and II, a rare genetic disorder. In BPES type I a complex eyelid malformation is associated with premature ovarian failure (POF), whereas in BPES type II the eyelid defect occurs as an isolated entity. In this study, we describe the identification of novel mutations in the FOXL2 gene in BPES types I and II families, in sporadic BPES patients, and in BPES families where the type could not be established. In 67% of the patients studied, we identified a mutation in the FOXL2 gene. In total, 21 mutations (17 of which are novel) and one microdeletion were identified. Thirteen of these FOXL2 mutations are unique. In this study, we demonstrate that there is a genotype--phenotype correlation for either types of BPES by the finding that mutations predicted to result in a truncated protein either lacking or containing the forkhead domain lead to BPES type I. In contrast, duplications within or downstream of the forkhead domain, and a frameshift downstream of them, all predicted to result in an extended protein, cause BPES type II. In addition, in 30 unrelated patients with isolated POF no causal mutations were identified in FOXL2. Our study provides further evidence that FOXL2 haploinsufficiency may cause BPES types I and II by the effect of a null allele and a hypomorphic allele, respectively. Furthermore, we propose that in a fraction of the BPES patients the genetic defect does not reside within the coding region of the FOXL2 gene and may be caused by a position effect.

Alleles↗
PubMed2004

Foxl2 disruption causes mouse ovarian failure by pervasive blockage of follicle development.

FOXL2 mutations cause gonadal dysgenesis or premature ovarian failure (POF) in women, as well as eyelid/forehead dysmorphology in both sexes (the 'blepharophimosis-ptosis-epicanthus inversus syndrome', BPES). Here we report that mice lacking Foxl2 recapitulate relevant features of human BPES: males and females are small and show distinctive craniofacial morphology with upper eyelids absent. Furthermore, in mice as in humans, sterility is confined to females. Features of Foxl2 null animals point toward a new mechanism of POF, with all major somatic cell lineages failing to develop around growing oocytes from the time of primordial follicle formation. Foxl2 disruption thus provides a model for histogenesis and reproductive competence of the ovary.

Animals↗
PubMed2005

Foxl2 is required for commitment to ovary differentiation.

Genetic control of female sex differentiation from a bipotential gonad in mammals is poorly understood. We find that mouse XX gonads lacking the forkhead transcription factor Foxl2 form meiotic prophase oocytes, but then activate the genetic program for somatic testis determination. Pivotal Foxl2 action thus represses the male gene pathway at several stages of female gonadal differentiation. This suggests the possible continued involvement of sex-determining genes in maintaining ovarian function throughout female reproductive life.

Animals↗