Blepharophimosis, Ptosis, and Epicanthus Inversus Syndrome (FOXL2)
| Dred_ID | RD00024 |
| OMIM ID | 110100 |
| Disease name | Blepharophimosis, Ptosis, and Epicanthus Inversus Syndrome |
| Alternative names | BPES, Type I, Included BPES, Type II, Included BPES with Ovarian Failure, Included BPES without Ovarian Failure, Included BPES with Duane Retraction Syndrome, Included BPES, Type I, Autosomal Recessive, Included |
| Category | Genetic diseases, Rare diseases, Eye diseases, Reproductive diseases, Endocrine diseases, Fetal diseases |
| Phenotype | NIH Rare Diseases: 53 Blepharophimosis, ptosis and epicanthus inversus syndrome type 1 (BPES I) is a condition, present at birth, that mainly effects the development of the eyelids. People with this condition have narrowing of the eye opening (blepharophimosis), droopy eyelids (ptosis), an upward fold of the skin of the lower eyelid near the inner corner of the eye (epicanthus inversus), and an increased distance between the inner corners of the eyes (telecanthus). Because of these eyelid malformations, the eyelids cannot open fully, and vision may be limited. Blepharophimosis syndrome type 1 also causes premature ovarian failure (POF). This condition is caused by mutations in the FOXL2 gene and is inherited in an autosomal dominant pattern.
OMIM: Blepharophimosis syndrome (BPES) is a complex eyelid malformation invariably characterized by four major features: blepharophimosis, ptosis, epicanthus inversus, and telecanthus. BPES type I includes the four major features and premature ovarian failure (POF); BPES type II includes only the four major features. Other ophthalmic manifestations associated with BPES include lacrimal duct anomalies, amblyopia, strabismus, and refractive errors. Minor features include a broad nasal bridge, low-set ears, and a short philtrum. Individuals with BPES and an intragenic disease-causing mutation are expected to have normal intelligence. |
| Miscellaneouse | OMIM: two types - one with premature ovarian failure (bpes type 1) and one without pof (bpes type 2) |
| Prevalence | N/A [source: MalaCards] |
| Inheritance | Autosomal dominant |
| Anticipation | N/A |
| Evidence | Strong |
| Gene symbol | FOXL2 |
| Alias symbols | BPES; PFRK; POF3; BPES1; PINTO |
| Gene name | forkhead box L2 |
| Gene map locus | 3q23; chr3:138,944,224-138,947,137(-) |
| Ensembl Gene ID | ENSG00000183770 |
| Gene expression and Gene Ontology | BioGPS |
| Protein expression | Human Protein Atlas |
| Gene sequence | Sequence |
| Variation | ClinVar, dbSNP | Gene conservation | Gene Conservation from UCSC Genome Browser |
| Gene Description | This gene encodes a forkhead transcription factor. The protein contains a fork-head DNA-binding domain and may play a role in ovarian development and function. Expansion of a polyalanine repeat region and other mutations in this gene are a cause of blepharophimosis syndrome and premature ovarian failure 3. [provided by RefSeq, Jul 2016] |
| Repeat unit | GCG |
| Normal repeat copies | 14 |
| Pathogenic repeat copies | ≥22 |
| Gene | FOXL2 |
| Repeat location | CDS |
| Chromosome locus | chr3:138946018-138946044 (-) |
| Repeat conservation | Repeat Conservation from UCSC Genome Browser |
| Toxic cause | Protein |
| Possible toxicity | To study the effects of the homozygous polyAla expansion FOXL2–Ala19, we have undertaken localization studies in COS-7 cells, a frequently used cellular model for aggregation analysis. Specifically, we performed single transfection experiments to overexpress the wild type FOXL2–Ala14, and expanded Ala19 and Ala24 proteins fused to the green fluorescent protein (GFP), as we have described (Caburet et al. 2004). FOXL2–Ala14 and Ala24 recapitulated our previous findings and the most prominent hallmark of the expression of FOXL2–Ala19–GFP was the strong cytoplasmic fluorescence in about 15% of transfected cells. This might be due to misfolding that prevents protein translocation into the nucleus. However, we failed to detect significant aggregation in our conditions (light microscopy resolution). Cytoplasmic retention was significantly higher than for the wild-type protein but much lower than that of FOXL2–Ala24. This observation, together with the recessive character of the Ala19 expansion in the context of craniofacial development, suggests that it is a hypomorphic allele that has kept substantial activity. Thus, in the heterozygotes, total FOXL2 activity would attain a threshold ensuring normal eyelid development while in the homozygotes this activity would be insufficient. This analysis suggests that protein mislocalization to the cytoplasm is partially responsible for the molecular pathogenesis of intermediate FOXL2 polyAla expansions, even if obvious aggregates are not detectable. [By PMID: 17089161] |
| Pathway annotation | Reactome, KEGG |
| PMID | 17089161 |
| Authors | Nallathambi J, Moumné L, De Baere E, Beysen D, Usha K, Sundaresan P, Veitia RA |
| Title | A novel polyalanine expansion in FOXL2: the first evidence for a recessive form of the blepharophimosis syndrome (BPES) associated with ovarian dysfunction |
| Journal | Hum Genet. 121(1):107-12 |
| Year | 2007 |
| PMID | 18158309 |
| Authors | Moumné L, Dipietromaria A, Batista F, Kocer A, Fellous M, Pailhoux E, Veitia RA |
| Title | Differential aggregation and functional impairment induced by polyalanine expansions in FOXL2, a transcription factor involved in cranio-facial and ovarian development |
| Journal | Hum Mol Genet. 17(7):1010-9 |
| Year | 2008 |