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Query: UNIPROT:P06889 (Mol)
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Blepharophimosis syndrome (BPES) is an autosomal dominant disorder of craniofacial development, the features of which are small palpebral fissures (blepharophimosis), drooping eyelids (ptosis) and a skin fold arising from the lower eyelid (epicanthus inversus). The chromosomal localization and identity of the BPES locus is not known with certainty. In the current paper, DNA samples from three individuals with a clinical history of BPES, two with interstitial deletions (cases 1 and 2) and one with a balanced translocation (case 3) all involving chromosome 3q23, were analyzed. Allele loss studies using short tandem repeat markers in cases 1 and 2 suggested that the region between the markers D3S1292 and D3S1306 was deleted in both cases. Subsequently, the derived chromosomes resulting from the translocation in case 3 were segregated in interspecific somatic cell hybrids. Analysis of the resultant hybrids showed that D3S1615 was retained in the derived chromosome 3, whereas D3S1316 was retained in the derived chromosome 4. In neither case was the marker present in the reciprocal hybrid. These results indicate that the BPES critical region lies in the D3S1615-D3S1316 interval.
Hum Mol Genet 1995 May
PMID:Definition of the blepharophimosis, ptosis, epicanthus inversus syndrome critical region at chromosome 3q23 based on the analysis of chromosomal anomalies. 763 59

Blepharophimosis syndrome (BPES, blepharophimosis eyelid syndrome) is a distinctive congenital eyelid malformation which can occur sporadically or be inherited in an autosomal dominant fashion. Previous reports have described associated cytogenetic abnormalities on chromosome 3q. We have ascertained and sampled two BPES families with apparent autosomal dominant inheritance and have tested for linkage with 17 polymorphic markers on 3q. Multipoint analysis generated a maximum LOD score of 3.23 using the markers RHO, ACPP and D3S1238. No evidence of genetic heterogeneity was observed. These studies provide the first non-cytogenetic evidence that a defective gene responsible for BPES is located on 3q22.
Hum Mol Genet 1995 Mar
PMID:Blepharophimosis syndrome is linked to chromosome 3q. 779

Homeodomain (HD) proteins are transcription regulators controlling a variety of cell fates. The HD region characterizing this protein family is a domain of 60 amino acid residues that recognizes and binds a site in the regulatory region of the target gene. It has been suggested that regions outside the HD may determine the specific functions of the various HD proteins by forming additional contacts with DNA sequences or by interactions with other proteins. We have identified a 14 amino acid motif within the C-terminal region of the protein encoded by the RIEG1 gene that is conserved among several HD proteins. Overlapping expression of the genes encoding these proteins during craniofacial development suggested that they might interact with a common factor. In order to identify additional genes possessing this motif we screened a human craniofacial cDNA library with oligoprobes. A novel gene was identified, exhibiting the most homology to murine Og12x (formerly OG12) and the recently reported human SHOX gene. Human OG12X and murine Og12x are highly homologous and the OG12X and Og12x proteins are 100% identical. In situ hybridization on mouse embryos ranging from 9 to 16 days post-coitum localized murine Og12x mRNA in the heart, otic region, maxillary and mandibular components of the first branchial arch, nasal processes, eyelid, midbrain, medulla oblongata, limbs, dorsal root ganglia and genital tubercle. OG12X was mapped to human chromosome 3q22-26 and murine Og12x to the syntenic region on mouse chromosome 3. Based upon the expression pattern of its mouse cognate, OG12X represents a candidate for the blepharophimosis (BPES) and Cornelia de Lange syndromes previously mapped to this region.
Hum Mol Genet 1998 Mar
PMID:A new human homeobox gene OGI2X is a member of the most conserved homeobox gene family and is expressed during heart development in mouse. 946 98

Premature ovarian failure (POF) is an heterogeneous syndrome. Among genetic causes, X monosomy as in Turner syndrome or X deletions and translocations are known to be responsible for POF. The genes involved in ovarian function, located on the X chromosome are still unknown. On the other hand, autosomal abnormalities have been identified in POF patients such as mutations of the FSH gene, the LH and FSH receptor genes, chromosome 3q containing the blepharophimosis gene, the ATM gene (Ataxia-telangiectasia gene). Mutations in the AIRE gene (responsible for APECED syndrome) can involve ovarian insufficiency. It is likely that studies on the function of the protein AIRE might improve our knowledge on follicular development. Furthermore, different mouse models of ovarian failure such as mouse lacking connexins or mice lacking GDF9 (growth derived factor 9), might increase our knowledge of ovarian failure. In the future, a better knowledge of the cellular and biochemical components involved in folliculogenesis and apoptosis should elucidate the mechanisms of POF.
Mol Cell Endocrinol 1998 Oct 25
PMID:Genes and premature ovarian failure. 992 2

Preadipocyte factor 1 (Pref-1/Dlk1) inhibits in vitro adipocyte differentiation and has been recently reported to be a paternally expressed imprinted gene at human chromosome 14q32. Studies on human chromosome 14 deletions and maternal uniparental disomy (mUPD) 14 suggest that misexpression of a yet-to-be-identified imprinted gene or genes present on chromosome 14 causes congenital disorders. We generated Pref-1 knockout mice to assess the role of Pref-1 in growth and in vivo adipogenesis and to determine the contribution of Pref-1 in mUPD. Pref-1-null mice display growth retardation, obesity, blepharophimosis, skeletal malformation, and increased serum lipid metabolites. Furthermore, the phenotypes observed in Pref-1-null mice are present in heterozygotes that harbor a paternally inherited, but not in those with a maternally inherited pref-1-null allele. Our results demonstrate that Pref-1 is indeed paternally expressed and is important for normal development and for homeostasis of adipose tissue mass. We also suggest that Pref-1 is responsible for most of the symptoms observed in mouse mUPD12 and human mUPD14. Pref-1-null mice may be a model for obesity and other pathologies of human mUPD14.
Mol Cell Biol 2002 Aug
PMID:Mice lacking paternally expressed Pref-1/Dlk1 display growth retardation and accelerated adiposity. 1210 Dec 50

Premature ovarian failure (POF) is a heterogeneous disorder whose aetiology is still unknown. Recently, the autosomal FOXL2 gene, highly expressed in the adult ovary, has been correlated with the disorder. FOXL2 mutations, causing a truncation of the FOXL2 protein in the forkhead domain or in the poly-Ala tract lead to blepharophimosis-ptosis-epicanthus-inversus syndrome associated with POF (BPES I). Interestingly, in two out of 70 idiopathic POF patients, a 30 bp deletion (898-927del) and a missense mutation (1009T-->A) were identified. To further evaluate the correlation between POF and FOXL2 mutations, 120 phenotypically normal women affected by POF were analysed by direct sequencing of the FOXL2 coding region. The analysis did not reveal any mutation in the 240 analysed chromosomes, indicating that mutations in the FOXL2 coding region are rarely associated with non-syndromic POF.
Mol Hum Reprod 2004 Aug
PMID:Mutations in the coding region of the FOXL2 gene are not a major cause of idiopathic premature ovarian failure. 1518 Nov 79

XX sex reversal syndromes not involving Sry provide an opportunity to identify and study genes important for sexual development. The polled intersex syndrome (PIS) in goats, which shares some features with blepharophimosis, ptosis, epicanthus inversus syndrome (BPES) in humans, exemplifies such syndromes. BPES is caused by defects in the forkhead transcription factor gene FOXL2, while PIS is caused by a large deletion of goat chromosome 1q43 that affects transcription of the genes Pisrt1 and Foxl2. Pisrt1 is a non-translated gene that has a sexually dimorphic expression pattern in goats. Here, we describe the structure and expression of the mouse Pisrt1 locus, to investigate its likely role in ovarian development more broadly in mammals. This gene showed some sequence similarity, and was found in a similar genomic context, to its goat and human orthologues. Expression analyses indicated that Pisrt1 is transcribed, and its mRNA polyadenylated and exported to the cytoplasm, but no significant open reading frames were found in a 1.5kb mouse genomic region corresponding to goat Pisrt1. Pisrt1 transcripts were expressed very broadly among tissues of the developing mouse embryo, and at similar levels in male and female gonads at each stage examined, as determined by in situ hybridisation and RT-PCR. This profile of expression suggests that Pisrt1 is unlikely to contribute to sex-specific events during gonadal development in mice and that divergent pathways of ovarian development operate among different mammalian species.
Mol Genet Metab
PMID:Pisrt1, a gene implicated in XX sex reversal, is expressed in gonads of both sexes during mouse development. 1613 5

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.
Mol Genet Metab 2006 Jul
PMID:Foxl2 function in ovarian development. 1664 86

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.
Genet Test Mol Biomarkers 2009 Apr
PMID:Mutations of the transcription factor FOXL2 gene in Chinese patients with blepharophimosis-ptosis-epicanthus inversus syndrome. 1937 Dec 27

Mutations of FOXL2 are responsible for the Blepharophimosis-Ptotsis-Epicantus-inversus Syndrome (BPES), involving complex eyelid malformations often associated with premature ovarian failure (POF). Loss-of-function mutations are expected to lead to BPES associated with POF, whereas hypomorphic mutations would lead to BPES without ovarian dysfunction. However, multiple exceptions to the genotype-phenotype correlation have been described and missense mutations in the forkhead domain can lead to either type of BPES. This renders almost impossible the prediction of a POF condition from a given genotype. Moreover, no clear-cut correlation between nuclear and/or cytoplasmic aggregation or cytoplasmic retention of mutant FOXL2 forms and the BPES type has been established thus far. Here, we dissect the molecular and functional effects of 10 FOXL2 mutants, known to induce BPES associated with POF or not. We found a correlation between the transcriptional activity of FOXL2 variants on two different reporter promoters and the type of BPES. We used this functional classification framework to explore the behavior of 18 missense mutations leading to BPES of unknown type. The reporters used enabled us to assess the risk of POF associated with these mutations. Moreover, we document a previously overlooked correlation between subcellular mislocalization and aggregation of mutant FOXL2 and the type of BPES, known or predicted using our reporter assays. Thus, intranuclear aggregation and cytoplasmic mislocalization of mutant FOXL2 may be considered as loose predictors of ovarian dysfunction. The functional classification tool described here is a first step towards circumventing the lack of a clear-cut genotype-phenotype correlation in BPES.
Hum Mol Genet 2009 Sep 01
PMID:Towards a functional classification of pathogenic FOXL2 mutations using transactivation reporter systems. 1951 49


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