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Sexual Development : Genetics,... 2022FOXL2 encodes a transcription factor that regulates a wide array of target genes including those involved in sex development, eyelid development, ovarian function and... (Review)
Review
FOXL2 encodes a transcription factor that regulates a wide array of target genes including those involved in sex development, eyelid development, ovarian function and maintenance, genomic integrity as well as cellular pathways such as cell-cycle progression, proliferation, and apoptosis. The role of FOXL2 has been widely studied in humans and animals. Consistent with its role in ovarian and eyelid development, over 100 germline variants in FOXL2 are associated with blepharophimosis, ptosis, and epicanthus inversus syndrome in humans, an autosomal dominant condition characterised by ovarian dysgenesis/premature ovarian insufficiency, as well as defective eyelid development. Reflecting its role in apoptosis and proliferation, a somatic variant in FOXL2 causes adult granulosa cell tumours in humans. Despite being widely studied and having clear relevance to human disease, much remains unknown about the genes FOXL2 regulates and how it exerts its wide-reaching effect on multiple organs. This review focuses on FOXL2 and its varied roles as a transcription factor in sex determination, ovarian maintenance and function, eyelid development, genome integrity, and cell regulation, followed by discussion of the in vivo disruption of FOXL2 in humans and other species.
Topics: Adult; Animals; Female; Humans; Blepharophimosis; Eyelids; Forkhead Box Protein L2; Mutation; Primary Ovarian Insufficiency
PubMed: 34727551
DOI: 10.1159/000519836 -
Journal of Ovarian Research Feb 2023Premature ovarian insufficiency refers to the loss of ovarian function before 40 years of age. The etiology is heterogeneous, and genetic factors account for 20-25% of...
BACKGROUND
Premature ovarian insufficiency refers to the loss of ovarian function before 40 years of age. The etiology is heterogeneous, and genetic factors account for 20-25% of cases. However, how to transform genetic findings to clinical molecular diagnose remains a challenge. To identify potential causative variations for POI, a next generation sequencing panel with 28 known causative genes of POI was designed, and a large cohort of 500 Chinese Han patients was screened directly. Pathogenic evaluation of the identified variants and the phenotype analysis were performed according to monogenic or oligogenic variants.
RESULTS
A total of 14.4% (72/500) of the patients carried 61 pathogenic or likely pathogenic variants in 19 of the genes in the panel. Interestingly, 58 variants (95.1%, 58/61) were firstly identified in patients with POI. FOXL2 harbored the highest occurrence frequency (3.2%, 16/500), among whom presented with isolated ovarian insufficiency instead of blepharophimosis-ptosis-epicanthus inversus syndrome. Moreover, luciferase reporter assay confirmed variant p.R349G, which account for 2.6% of POI cases, impaired the transcriptional repressive effect of FOXL2 on CYP17A1. The novel compound heterozygous variants in NOBOX and MSH4 were confirmed by pedigree haplotype analysis, and digenic heterozygous variants in MSH4 and MSH5 were firstly identified. Furthermore, nine patients (1.8%, 9/500) with digenic or multigenic pathogenic variants presented with delayed menarche, early onset of POI and high prevalence of primary amenorrhea compared with those with monogenic variation(s).
CONCLUSIONS
The genetic architecture of POI has been enriched through the targeted gene panel in a large cohort of patients with POI. Specific variants in pleiotropic genes may result in isolated POI rather than syndromic POI, whereas oligogenic defects might have cumulative deleterious effects on the severity of POI phenotype.
Topics: Humans; Female; Primary Ovarian Insufficiency; Ovarian Diseases; Menopause, Premature; Phenotype; High-Throughput Nucleotide Sequencing
PubMed: 36793102
DOI: 10.1186/s13048-023-01104-6 -
Genes Mar 2021Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is a craniofacial disorder caused by heterozygous variants of the forkhead box L2 () gene. It shows... (Review)
Review
Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is a craniofacial disorder caused by heterozygous variants of the forkhead box L2 () gene. It shows autosomal dominant inheritance but can also occur sporadically. Depending on the mutation, two phenotypic subtypes have been described, both involving the same craniofacial features: type I, which is associated with premature ovarian failure (POF), and type II, which has no systemic features. The genotype-phenotype correlation is not fully understood, but it has been hypothesised that type I BPES involves more severe loss of function variants spanning the whole gene. Type II BPES has been linked to frameshift mutations that result in elongation of the protein rather than complete loss of function. A mutational hotspot has been identified within the poly-alanine domain, although the exact function of this region is still unknown. However, the BPES subtype cannot be determined genetically, necessitating informed genetic counselling and careful discussion of family planning advice in view of the associated POF particularly as the patient may still be a child. Following puberty, female patients should be referred for ovarian reserve and response assessment. Oculofacial features can be managed with surgical intervention and regular monitoring to prevent amblyopia.
Topics: Blepharophimosis; Female; Forkhead Box Protein L2; Frameshift Mutation; Humans; Loss of Function Mutation; Male; Phenotype; Primary Ovarian Insufficiency; Protein Domains; Skin Abnormalities; Urogenital Abnormalities
PubMed: 33806295
DOI: 10.3390/genes12030364 -
Genes Apr 2021MED12 is a member of the Mediator complex that is involved in the regulation of transcription. Missense variants in MED12 cause FG syndrome, Lujan-Fryns syndrome, and... (Review)
Review
MED12 is a member of the Mediator complex that is involved in the regulation of transcription. Missense variants in MED12 cause FG syndrome, Lujan-Fryns syndrome, and Ohdo syndrome, as well as non-syndromic intellectual disability (ID) in hemizygous males. Recently, female patients with de novo missense variants and de novo protein truncating variants in MED12 were described, resulting in a clinical spectrum centered around ID and Hardikar syndrome without ID. The missense variants are found throughout MED12, whether they are inherited in hemizygous males or de novo in females. They can result in syndromic or nonsyndromic ID. The de novo nonsense variants resulting in Hardikar syndrome that is characterized by facial clefting, pigmentary retinopathy, biliary anomalies, and intestinal malrotation, are found more N-terminally, whereas the more C-terminally positioned variants are de novo protein truncating variants that cause a severe, syndromic phenotype consisting of ID, facial dysmorphism, short stature, skeletal abnormalities, feeding difficulties, and variable other abnormalities. This broad range of distinct phenotypes calls for a method to distinguish between pathogenic and non-pathogenic variants in MED12. We propose an isogenic iNeuron model to establish the unique gene expression patterns that are associated with the specific MED12 variants. The discovery of these patterns would help in future diagnostics and determine the causality of the MED12 variants.
Topics: Abnormalities, Multiple; Agenesis of Corpus Callosum; Anus, Imperforate; Blepharophimosis; Blepharoptosis; Cholestasis; Cleft Palate; Constipation; Craniofacial Abnormalities; Heart Defects, Congenital; Humans; Intellectual Disability; Marfan Syndrome; Mediator Complex; Mental Retardation, X-Linked; Muscle Hypotonia; Phenotype; Retinitis Pigmentosa
PubMed: 33925166
DOI: 10.3390/genes12050663 -
Hormone Research in Paediatrics 2012FOXL2 encodes a forkhead transcription factor that plays important roles in the ovary during development and in post-natal, adult life. Here, we focus on the clinical... (Review)
Review
FOXL2 encodes a forkhead transcription factor that plays important roles in the ovary during development and in post-natal, adult life. Here, we focus on the clinical consequences of FOXL2 impairment in human disease. In line with other forkhead transcription factors, its constitutional genetic defects and a somatic mutation lead to developmental disease and cancer, respectively. More than 100 unique constitutional mutations and regulatory defects have been found in blepharophimosis syndrome (BPES), a complex eyelid malformation associated (type I) or not (type II) with premature ovarian failure (POF). In agreement with the BPES phenotype, FOXL2 is expressed in the developing eyelids and in fetal and adult ovaries. Two knock-out mice and at least one natural animal model, the Polled Intersex Syndrome goat, are known. They recapitulate the BPES phenotype and have provided many insights into the ovarian pathology. Only a few constitutional mutations have been described in nonsyndromic POF. Moreover, a recurrent somatic mutation p.C134W was found to be specific for adult ovarian granulo-sa cell tumors. Functional studies investigating the consequences of FOXL2 mutations or regulatory defects have shed light on the molecular pathogenesis of the aforementioned conditions, and contributed considerably to genotype-phenotype correlations. Recently, a conditional knock-out of Foxl2 in the mouse induced somatic transdifferentiation of ovary into testis in adult mice, suggesting that Foxl2 has an anti-testis function in the adult ovary. This changed our view on the ovary and testis as terminally differentiated organs in adult mammals. Finally, this might have potential implications for the understanding and treatment of frequent conditions such as POF and polycystic ovary syndrome.
Topics: Animals; Blepharophimosis; Female; Forkhead Box Protein L2; Forkhead Transcription Factors; Gene Deletion; Genetic Testing; Granulosa Cell Tumor; Humans; Ovarian Neoplasms; Primary Ovarian Insufficiency
PubMed: 22248822
DOI: 10.1159/000335236 -
Ceska a Slovenska Oftalmologie :... 2016To report the ocular phenotype of blepharophimosis-ptosis-epicanthus inversus syndrome (BPES).
PURPOSE
To report the ocular phenotype of blepharophimosis-ptosis-epicanthus inversus syndrome (BPES).
METHODS
Ophthalmological examination of a 36 year-old proband and detailed family history evaluation, including assessment of available facial photographs of affected relatives, was performed.
RESULTS
There were four affected males and one female in three generations. The proband underwent two surgical eyelid procedures in childhood. Upon our examination, he had symmetrical ptosis with shorter eye lids, and incomplete medial canthal closure. The skin in the inner canthi was scarred, and the medial lower lids slightly everted, leading to malapposition of lacrimal punctae. There was no epicanthus inversus, however it was impossible to determine the status prior to the eyelid surgeries. The best corrected visual acuity was 0.66 and 0.33, in the right and left eye, respectively. The rest of the ocular examination was normal. There was no strabismus. Based on inspection of photographs taken prior to eyelid surgeries, the typical signs of BPES were also present in a son and a nephew of the proband. Photographs of the affected brother were not available, but family history indicated that he had BPES and underwent in his childhood two eye lid surgeries. Atypical ocular phenotype of the probands mother has been published previously.
CONCLUSIONS
Ophthalmologists need to be aware about the phenotype of BPES, with the potential for visual impairment, and the need for personalized management in the affected families.Key words: blepharophimosis-ptosis-epicanthus inversus, phenotype, FOXL2.
Topics: Adult; Blepharophimosis; Blepharoplasty; Eyelids; Female; Humans; Male; Pedigree; Phenotype; Skin Abnormalities; Syndrome; Urogenital Abnormalities; Vision Disorders; Visual Acuity
PubMed: 28224805
DOI: No ID Found