Blepharophimosis-ptosis-epicanthus Inversus Syndrome Type Research Articles

Deletion of cis-regulatory Element in FOXL2 Promoter in a Chinese Family of Type II Blepharophimosis-ptosis-epicanthus Inversus Syndrome with Polydactyly.

Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a relatively uncommon autosomal-dominant genetic disorder, primarily attributed to mutations in the forkhead box L2 (FOXL2) gene. Albeit the involvement of protein-coding regions of FOXL2 has been observed in the majority of BPES cases, whether deficiencies in regulatory elements lead to the pathogenesis remains poorly understood. Herein, an autosomal-dominant BPES type II family was included. Peripheral venous blood has been collected, and genomic DNA has been extracted from leukocytes. A whole exome sequencing analysis has been performed and analyzed (Deposited in NODE database: OER422653). The promoter region of FOXL2 was amplified using polymerase chain reaction (PCR). The luciferase reporter assay was performed to identify the activity of this region. In this study, we present a Chinese family diagnosed with type II BPES, characterized by the presence of small palpebral fissures, ptosis, telecanthus, and epicanthus inversus. Notably, all male individuals within the family display polydactyly. A 225-bp deletion in the 556-bp 5'-upstream to transcription start site of FOXL2 , decorated by multiple histone modifications, was identified in affected members of the family. This deletion significantly decreased FOXL2 promoter activity, as measured by the luciferase assay. Conclusively, a novel 255-bp-deletion of the FOXL2 promoter was identified in Chinese families with BPES. Our results expand the spectrum of known FOXL2 mutations and provide additional insight into the genotype-phenotype relationships of the BPES pathogenesis. In addition, this study indicates the important role of genetic screening of cis-regulatory elements in testing heritable diseases.

Functional Studies of Novel FOXL2 Variants in Chinese Families With Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome.

The blepharophimosis–ptosis–epicanthus inversus syndrome (BPES) is a rare autosomal dominant disease mainly caused by FOXL2 variants. This genetic disorder is usually characterized by eyelid malformation and ovarian dysfunction. However, no reliable genotype/phenotype correlations have been established considering the ovarian phenotype. Here, we detected 15 FOXL2 variants including nine novel ones from 7 families and 8 sporadic cases, which expanded the spectrum of FOXL2 variants and identified a potential clinical cause. Functional studies, with respect to the effect of FOXL2 on the StAR promoter, showed that non-sense variants that lead to protein truncation before the polyalanine tract and missense variants [c.307C > T; p.(Arg103Cys), c.311A > C; p.(His104Pro), c.320G > A; p.(Ser107Asn), and c.335T > A; p.(Phe112Tyr)] within the central portion of the FOXL2 forkhead domain significantly affect its suppressor activity. Such changes may explain the mechanism underlying a more severe phenotype, more likely to result in BPES type I. Furthermore, the missenses variants c.307C > T; p.(Arg103Cys), c.311A > C; p.(His104Pro), and c.320G > A; p.(Ser107Asn) were not able to transactivate OSR2, which is consistent with the eyelid malformation in these patients. The results from our cohort have expanded the spectrum of FOXL2 variants and have provided insights into genotype/phenotype correlations.

Premature ovarian insufficiency as a variable feature of blepharophimosis, ptosis, and epicanthus inversus syndrome associated with c.223C\u2009>\u2009T p.(Leu75Phe) FOXL2 mutation: a case report

BackgroundFOXL2 gene mutations cause blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) and may be associated with premature ovarian insufficiency (POI). Two types of BPES were described in the literature. BPES type 2 is a simple association of inherited developmental defects of the eyelid area, while in type 1 female patients additionally suffer from POI. The following case study is the first report of endocrine impairments typical for menopausal transition in young female with NG_012454.1:g.138665342G > A, c.223C > T p.(Leu75Phe), mutation in FOXL2 gene. This mutation has been reported in the literature before, however until now, it was never linked to BPES type 1.Case presentationAn 18-year-old nulliparous woman suspected of secondary amenorrhea was referred to our Endocrinology Outpatient Clinic. Blood tests revealed decreased levels of AMH (anti-Mullerian hormone) and increased levels of gonadotropins, suggesting menopausal transition. Her past medical history was remarkable for several ophthalmic defects that has required surgical interventions. BPES syndrome had not been suspected before, although the patient had reported a similar phenotype occurring in her father, sister and half-sister. Venous blood samples were collected from the female proband and from her three family members. Whole-exome sequencing and deep amplicon sequencing were performed. A potential pathogenic variant in the FOXL2 gene was revealed. Namely, the c.223C > T p.(Leu75Phe) missense variant was detected.ConclusionsThe authors found mutations, c.223C > T p.(Leu75Phe) in the FOXL2 gene in a young woman with hormonal disorders suggesting menopausal transition. These results indicate that the possibility of different phenotypes should be considered in patients with a similar genetic mutation.

Analysis of FOXL2 gene mutation and genotype-phenotype correlation in a Chinese pedigree affected with blepharophimosis-ptosis-epicanthus inversus syndrome

To detect FOXL2 gene mutation in a Chinese pedigree affected with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) type I, and to explore its genotype-phenotype correlation. Peripheral blood samples were obtained from 3 patients and 19 healthy members from the pedigree for the isolation of genomic DNA. All exons and flanking sequences of the FOXL2 gene were amplified by PCR with 7 pairs of overlapping primers and sequenced. DNA sequencing indicated that the BPES phenotype in this pedigree was caused by a hotspot c.843_859dup17 mutation. The same mutation was not found among the healthy members of the pedigree. The c.843_859dup17 frameshift mutation probably underlies the BPES type I in this Chinese pedigree, which may manifest as either BEPS type I or type II.

Abstract QS43: Blepharophimosis Ptosis Epicanthus Inversus Syndrome Caused by a ZC3H13 Gene Mutation

PURPOSE: Blepharophimosis Ptosis Epicanthus Inversus Syndrome (BPES) is a rare craniofacial autosomal dominant disorder characterized by severe bilateral ptosis, telecanthus, epicanthus inverses, belpharophimosis and orbital dysmorphology. BPES type 1 is accompanied by ovarian failure and attendant infertility, while type 2 manifests only eyelid and orbital involvement. While BPES is often associated with a dominantly inherited mutation in the forkhead transcription factor FOXL2 (3q23), we sought to capitalize on next generation whole exome sequencing to decipher the cause of BPES in a pedigree lacking a FOXL2 mutation. METHODS: A male patient with BPES was identified at the Yale-New Haven Hospital. Following informed consent, clinical data and blood samples from both affected and unaffected family members were obtained. Genomic DNA was extracted from whole blood samples and subjected to exome capture followed by next generation sequencing. Sequence reads were mapped to the human reference genome. Variants with minor allele frequencies in reference databases were selected and annotated for impact on the encoded protein and for conservation of the reference base and amino acid residue among orthologs across phylogeny. Sanger sequencing was employed to verify candidate mutations. In addition, all FOXL2 exons were subjected to Sanger sequencing to verify sequence status. RESULTS: A four-generation BPES pedigree was identified demonstrating autosomal dominant inheritance. In affected individuals, next generation whole exome sequencing identified a common non-sense mutation in ZC3H13 (13q14.13), which was confirmed by Sanger sequencing. A cytosine to thymine (C>T) alteration resulted in the conversion of arginine 1513 to a premature stop codon (R1513X). The variant 13:46538114 C / T was not found in dbSNP with an ExAC allele frequency of 1.651e-05. The amino acid residue arginine 1513 is evolutionarily conserved from Neurospora crassa (red bread mold) to Homo sapiens. All FOXL2 exons lacked disease-causing alterations. Conclusions: ZC3H13 is a putative tumor suppressor gene encoding a zinc finger CCCH-type containing protein. It localizes to nuclear speckles and is predicted to play a role in mRNA splicing and cell cycle progression. Our data suggest that ZC3H13 mutations represent an additional dominant subtype of BPES and point to a novel role for ZC3H13 in craniofacial development and disease pathogenesis. D.M. Balkin: None. C. Nelson-Williams: None. B.J. Sumpio: None. D.A. Scott: None. P. Le Pabic: None. T.F. Schilling: None. R.P. Lifton: None. D. Narayan: None.

A Novel FOXL2 Mutation Implying Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome Type I

Background/Aims: Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare autosomal dominant disease caused by FOXL2 gene mutations, and it is clinically characterized by an eyelid malformation associated (type I) or not (type II) with premature ovarian failure (POF). Functional study of novel mutations is especially critical for female patients, as it may allow the prediction of infertility and early planning of an appropriate therapy. Methods: A clinical and molecular genetic investigation was performed in all members of a Chinese family with BPES. Genomic DNA was extracted, and the FOXL2 coding region was sequenced. Subcellular localization was performed by confocal microscopy. Transactivation studies were performed by real-time PCR, dual luciferase reporter assays and electrophoretic mobility shift assays. Results: A novel deletion mutation (C.634_641 del, CCCATGC) between the forkhead domain and the polyalanine domain was found, resulting in a frameshift mutation and a truncated protein. Functional studies showed a strong cytoplasmic mislocalization and abnormal transactivation activity, implying a type I kind mutation with a large chance of infertility. Conclusion: This study identifies that this mutation indicates the probability of developing into POF and shows the importance and necessity of early recognition of BPES type through mutation testing for female patients. Prompt personalized therapy and follow-up is of great clinical significance for female patients carrying this kind of mutation.

Identification of a novel FOXL2 mutation in a single family with both types of blepharophimosis‑-ptosis-epicanthus inversus syndrome.

Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare autosomal dominant disease, which has been divided into two types according to whether it involves premature ovarian failure (POF). Mutations in forkhead box L2 (FOXL2) have been identified in the majority of patients with BPES. The present study aimed to identify the causative mutation in FOXL2 in a Chinese family with both types of BPES. Clinical data and genomic DNA were collected from a single Chinese family with BPES. All the coding exons and adjacent regions of FOXL2 were screened in one affected member to detect the causative mutation using Sanger sequencing. The detected mutation was also screened in available family members and in 100 normal control chromosomes. In total, seven family members were recruited in the present study, including four affected and three unaffected members. The patient (II:5) exhibited typical features of typeII BPES, characterized by a narrowed horizontal palpehral aperture, ptosis, epicanthus inversus and telecanthus without POF, whereas the patient's three daughters (III:1,III:2 and III:3) were diagnosed with type I BPES, in which a complex eyelid malformation was accompanied with POF. A novel heterozygous mutation in FOXL2 (c.844_860dup17, p.His291Argfs*71) was found in the four affected members, which was absent in the remaining three unaffected members and in the 100 control chromosomes. This novel duplicate mutation (c.844_860dup17, p.His291Argfs*71) in FOXL2 was identified in a Chinese family with both types of BPES. These findings expand current knowledge of the mutation spectrum of the FOXL2 gene and confirmed the intra‑family phenotypic heterogeneity of BPES.

Functional Analysis of a Novel FOXL2 Indel Mutation in Chinese Families with Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome Type I.

Background: Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is an autosomal dominant disease with a low incidence rate. Indel mutations in the forkhead box L2 (FOXL2) gene cause two types of BPES that are distinguished by the presence (type I) or absence (type II) of premature ovarian failure (POF). The purpose of this study was to identify a possible deletion in FOXL2 in Chinese families with BPES and to clarify its relationship with POF.Methods: An autosomal dominant Chinese BPES family with four generations was enrolled in this study. Peripheral venous blood was collected from all affected patients, and genomic DNA was extracted from leukocytes. The whole coding sequence and nearby 5' untranslated region (UTR) and 3'UTR of the FOXL2 gene were amplified using polymerase chain reaction (PCR) with three sets of overlapping primers, followed by sequencing analyses. The sequencing results were analysed using SeqMan software. Based on the patients' clinical manifestations and analysis of the identified indel mutation, we found that the mutation disturbed interactions between FOXL2 and the StAR gene. Furthermore, through subcellular localisation and functional studies, we observed significant mislocalisation of the mutant protein; the mutant protein was found in the cytoplasm, while the wild-type protein was found in the nucleus. Loss of function was confirmed by transcriptional activity assays, quantitative real-time PCR, and electrophoretic mobility shift assays.Results: All affected patients presented with clinical features of BPES type I, including small palpebral fissures, ptosis, telecanthus, and epicanthus inversus with POF. A novel FOXL2 heterozygous indel mutation, c.19_95del, a 77-bp deletion that disrupts FOXL2 protein structure, was identified in all affected members of the family. In addition, this indel mutation significantly increased StAR mRNA expression by disrupting the ability of the FOXL2 protein to bind to the StAR promoter and act as a repressor of this gene.Conclusions: A novel FOXL2 indel mutation was identified in Chinese families with BPES. Our results expand the spectrum of known FOXL2 mutations and provide additional insight into the structure-function relationships of the FOXL2 protein. Furthermore, this novel mutation resulted in the dysfunction of FOXL2 as a transcription factor, blocking its ability to bind to the promoter region of the StAR gene, resulting in POF in the affected patient.

Etiology of craniofacial malformations in mouse models of blepharophimosis, ptosis and epicanthus inversus syndrome.

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.

Differential Apoptotic and Proliferative Activities of Wild-type FOXL2 and Blepharophimosis-ptosis-epicanthus Inversus Syndrome (BPES)-associated Mutant FOXL2 Proteins

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, TNF-R1, 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.

Functional study on a novel missense mutation of the transcription factor FOXL2 causes blepharophimosis-ptosis-epicanthus inversus syndrome (BPES)

Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare autosomal dominant disease caused by FOXL2 gene mutations. However, only one missense mutation has been found in family with BPES type I. Here, we report a novel missense mutation in the forkhead domain of the FOXL2 gene (c.340A > G, NM_023067) resulted in the replacement of lysine by glutamic acid at amino acid position 114 of the FOXL2 protein (p.K114E, NP_075555) that was identified in a Chinese family with BPES type I, members of which displayed clinical symptoms such as shortened palpebral fissures, drooping eyelids, a vertical skin fold arising from the lower eyelid, and premature ovarian failure (POF) in affected females. Based on the patients' clinical features and computational analysis of this missense mutation in a three-dimensional structural model, we hypothesised that the mutation might disturb the intermolecular contacts between FOXL2 and the StAR gene. The disturbance of this interaction might contribute to the POF observed in BPES type I patients. We performed subcellular localisation and functional studies and as expected, observed significant nuclear aggregation and cytoplasmic mislocalization of the mutant type protein and loss-of-function was confirmed by electrophoretic mobility shift assays, transcriptional activity assays and quantitative real-time polymerase chain reaction. This functional study on a novel missense mutation has important implications for the molecular analysis of this gene.

FOXL2 mutations in Taiwanese patients with blepharophimosis, ptosis, epicanthus inversus syndrome

Blepharophimosis, ptosis, epicanthus inversus syndrome (BPES) is an autosomal dominant developmental disorder that includes an eyelid malformation associated with (type I) or without (type II) premature ovarian failure (POF). Mutations in the forkhead transcription factor 2 (FOXL2) gene, a member of winged/forkhead transcription factor family, are responsible for both types of BPES. The purpose of this study was to identify mutations in FOXL2 in Taiwanese patients with BPES. The karyotype and genomic DNA was prepared from the leukocytes of peripheral venous blood samples. The coding and flanking region sequences of FOXL2 were analyzed by directed or cloning sequencing. The karyotypes of these patients did not show significant variation, especially on the 3q23 region. Two mutations in FOXL2 were identified in two familial cases. One was c.855-871dup (17-bp insertion) associated with POF. The other was c.384G>A (TGG>TGA), a novel mutation that resulted in non-sense changes of the encoded protein, i.e., p.W128X. Our results expand the spectrum of FOXL2 mutations and confirm the mutation hotspot in FOXL2 in Taiwanese BPES patients.

A new FOXL2 gene mutation in a woman with premature ovarian failure and sporadic blepharophimosis-ptosis-epicanthus inversus syndrome

To describe a new FOXL2 gene mutation in a woman with sporadic blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) and hypergonadotropic hypogonadism. Case report. University medical center. A 28-year-old woman. Clinical evaluation, hormone assays, gene mutation research. FOXL2 gene mutation. The patient with hypergonadotropic hypogonadism was diagnosed with BPES due to a new FOXL2 gene mutation. Blepharophimosis-ptosis-epicanthus inversus syndrome is a rare disorder associated with premature ovarian failure (POF). The syndrome is an autosomal dominant trait that causes eyelid malformations and POF in affected women. Mutations in FOXL2 gene, located in chromosome 3, are related to the development of BPES with POF (BPES type I) or without POF (BPES type II). This report demonstrates a previously undescribed de novo mutation in the FOXL2 gene-a thymidine deletion, c.627delT (g.864delT)-in a woman with a sporadic case of BPES and POF. This mutation leads to truncated protein production that is related to a BPES type I phenotype. This report shows the importance of family history and genetic analysis in the evaluation of patients with POF and corroborates the relationship between mutations on the FOXL2 gene and ovarian insufficiency.

Human forkhead L2 represses key genes in granulosa cell differentiation including aromatase, P450scc, and cyclin D2

FOXL2 is expressed in granulosa cells (GC) of small and medium ovarian follicles, functions as a repressor of the human steroidogenic acute regulatory gene, a marker of a GC differentiation, and its mutation is associated with premature ovarian failure (POF) in women with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), type I. We now report that FOXL2 also represses the transcription of aromatase, P450scc, and cyclin D2, three other key genes involved in GC proliferation, differentiation, and steroidogenesis, and that a FOXL2 mutation found in patients with BPES type I, also fails to repress aromatase transcription, further supporting a role for FOXL2 in follicle maturation.

Identification of copy number variants associated with BPES-like phenotypes

Blepharophimosis-Ptosis-Epicanthus inversus syndrome (BPES) is a well-characterized rare syndrome that includes an eyelid malformation associated with (type I) or without premature ovarian failure (type II). Patients with typical BPES have four major characteristics: blepharophimosis, ptosis, epicanthus inversus and telecanthus. Mutations in the FOXL2 gene, encoding a forkhead transcription factor, are responsible for the majority of both types of BPES. However, many patients with BPES-like features, i.e., having at least two major characteristics of BPES, have an unidentified cause. Here, we report on a group of 27 patients with BPES-like features, but without an identified genetic defect in the FOXL2 gene or flanking region. These patients were analyzed with whole-genome high-density arrays in order to identify copy number variants (CNVs) that might explain the BPES-like phenotype. In nine out of 27 patients (33%) CNVs not previously described as polymorphisms were detected. Four of these patients displayed psychomotor retardation as an additional clinical characteristic. In conclusion, we demonstrate that BPES-like phenotypes are frequently caused by CNVs, and we emphasize the importance of whole-genome copy number screening to identify the underlying genetic causes of these phenotypes.

Blepharophimosis–ptosis–epicanthus inversus syndrome (BPES)

Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare inherited condition that includes characteristic eyelid malformations and sometimes reduced fertility in females. Genetic studies have implicated mutations in the forkhead transcription factor FOXL2 as responsible for BPES. We report a female and her father with BPES type I, who presented the 1092-1108dup17 mutation in the FOXL2 gene. Molecular studies and the typical clinical features of BPES should allow the dermatologist to reach an early diagnosis and permit the treatment of eyelid alterations and the investigation of infertility.

Mutation analysis of the FOXL2 gene in Chinese patients with blepharophimosis–ptosis–epicanthus inversus syndrome

Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is an autosomal dominant disorder characterized by blepharophimosis, ptosis and epicanthus inversus. Based on the presence and absence of premature ovarian failure, two clinical types have been distinguished. Both types of BPES have been mapped to chromosome 3q23 and are mostly due to mutations of a forkhead transcription factor FOXL2 gene which locates at this region. We screened for FOXL2 mutations in Chinese patients with BPES. A novel mutation (g.901-930dup30) which could result in an expansion of the polyalanine tract was found in two BPES type II families and one sporadic case. In addition, a new g.952delC mutation was identified in two patients from a BPES family of undetermined type. The previously reported g.892C>T (p.Q219X) was also found in 12 patients from a large BPES family of type I. No mutations were detected in three other BPES families and three sporadic cases. So we speculate that in a fraction of the BPES patients the genetic defect may represent a change in gene dosage or a rearrangement outside the transcription unit of FOXL2.

A new heterozygous mutation of the FOXL2 gene is associated with a large ovarian cyst and ovarian dysfunction in an adolescent girl with blepharophimosis/ptosis/epicanthus inversus syndrome

Blepharophimosis/ptosis/epicanthus inversus syndrome (BPES), an autosomal dominant syndrome in which eyelid malformation is associated with (type I BPES) or without premature ovarian failure (type II BPES). Mutations of a putative winged helix/forkhead transcription factor FOXL2 account for both types of BPES. We report on a 16-year-old adolescent girl with blepharophimosis and ptosis. Subsequently she developed oligomenorrhea, secondary amenorrhea for 6 months, and an extremely large cyst of one ovary. The cyst contained 8 l of cyst fluid and histopathology displayed a large corpus luteum cyst. Following laparotomy, gonadotropin levels were elevated (LH 17.2 U/l, FSH 29.4 U/l) and estradiol levels decreased (67 pmol/l). Because of clinical aspects of BPES and abnormal ovarian function we suspected a mutation of her FOXL2 gene and found a new in-frame mutation (904_939dup36) on one allele, leading to a 12 alanine expansion within the polyalanine domain. We conclude that the FOXL2 mutation 904_939dup36 may account not only for blepharophimosis and ptosis but also for ovarian dysfunction and growth of the large corpus luteum cyst. In contrast to known FOXL2 mutations with polyalanine expansions and association with BPES type II, clinical aspects of our girl may indicate some degree of ovarian dysfunction that might finally lead to BPES type I with premature ovarian failure.

Mutations in FOXL2 underlying BPES (types 1 and 2) in Colombian families.

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-frame 30 bp duplication that leads to the elongation of a polyalanine tract. This duplication has been previously reported in Europe, where recurrent mutation has been demonstrated in unrelated familial and sporadic BPES cases. The recurrent nature of this duplication seems to relate to the secondary structure of this DNA region. The genotype-phenotype correlation seen in the Colombian families is consistent with the recent proposal that BPES type 1 is caused by truncating mutations leading to haploinsufficiency, while BPES type 2 is due to mutations generating elongated protein products.

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.