A recurrent polyalanine expansion in the transcription factor FOXL2 induces extensive nuclear and cytoplasmic protein aggregation

Caburet, Sandrine; Démarez, Alice; Moumné, Lara; Fellous, Marc; Baere, Elfride De; Veitia, Reiner A.

doi:10.1136/jmg.2004.024356

Cited by 88 publications

(77 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This mutation is responsible for a shift in the protein location from the nucleus, where it is normally located, to the cytoplasm, and induces a strong tendency to aggregation. 31 In our study, the same type of alanine duplication was found in 2 distinct families (1 of them Portuguese and the other Brazilian) and in 1 Brazilian sporadic case. This genetic defect is, in fact, recurrent and has been reported in distinct families with different geographic and ethnic backgrounds.…”

Section: Discussionsupporting

confidence: 78%

Lacrimal Gland Involvement in Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome

et al. 2017

View full text Add to dashboard Cite

Purpose: To describe the involvement of the lacrimal gland (LG) in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES).Design: Observational, cross-sectional study. Participants: Twenty-one patients with BPES (10 female, 11 male) aged on average 15 years (range, 2e39 years), from 3 Brazilian medical centers and 1 Portuguese medical center.Methods: Patients had their ocular surface evaluated with slit-lamp biomicroscopy, and tear production quantified with the Schirmer test I. The LG volumes were measured on computed tomography (CT) scans in the BPES sample and in a group of age-matched subjects imaged for nonorbital diseases. Sixteen patients were screened for mutations in the FOXL2 gene.Main Outcome Measures: Lacrimal meniscus height, Schirmer test I, presence of superficial punctate keratopathy (SPK), LG volume, and molecular analysis of the FOXL2 gene.Results: Absence of LG was detected bilaterally in 9 patients (42.8%) and unilaterally in 2 patients (9.5%). When considering only patients with measurable LG, the median volume was 0.22 cm 3 in the right eye (range, 0.06e0.36 cm 3 ) and 0.24 cm 3 in the left eye (range, 0.08e0.34 cm 3 ). These values were significantly lower than those for the age-matched controls (median ¼ 0.54 right eye and 0.53 left eye; P < 0.05). There was a significant association between deficiency of tear production and LG volume reduction and agenesis. Molecular analysis of the FOXL2 gene revealed the presence of 8 distinct mutations, 4 of them novel ones. A significant reduction of LG size or agenesis was associated with mutations affecting protein size (due to underlying changes in the stop codon location) or the DNA-binding forkhead domain (Fisher exact test, P ¼ 0.021). In 3 probands, the underlying genetic defect was not found.Conclusions: This is the first study reporting LG volumes in BPES, describing a significant number of patients with LG agenesis. The association between alacrima and BPES is not incidental, and a thorough evaluation of tear production is recommended especially if ptosis surgery is planned. Ophthalmology 2017;124:399-406 ª

show abstract

Section: Discussionsupporting

confidence: 78%

Lacrimal Gland Involvement in Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Although the physiological function of this polyalanine tract remains unknown, its expansion from 14 to 24 residues accounts for 30% of the reported mutations in BPES patients (De Baere et al 2003). The 14 to 24 expansion induces extensive nuclear and cytoplasmic FOXL2 protein aggregation (Caburet et al 2004). Until now, two FOXL2 target genes have been described in two different tissues, the gonadotropin releasing hormone receptor (GnRHR) gene in the pituitary (Ellsworth et al 2003) and the steroidogenic acute regulatory (StAR) gene in the adult ovary (Pisarska et al 2004).…”

Section: Introductionmentioning

confidence: 99%

FOXL2 activates P450 aromatase gene transcription: towards a better characterization of the early steps of mammalian ovarian development

Pannetier

Fabre²,

Batista³

et al. 2006

Journal of Molecular Endocrinology

229

173

View full text Add to dashboard Cite

Previous studies have equated FOXL2 as a crucial actor in the ovarian differentiation process in different vertebrate species. Its transcriptional extinction in the polled intersex syndrome (PIS) leads primarily to a drastic decrease of aromatase (CYP19) expression in the first steps of goat ovarian development. In this study, we provide a better characterization of early ovarian development in goat, and we provide experimental evidence demonstrating that FOXL2 represents a direct transcriptional activator of the CYP19 gene through its ovarian-specific promoter 2. Moreover, the ovarian location of FOXL2 and CYP19 proteins, together with their expression profiles in the female gonads, stress the involvement of FOXL2 co-factor(s) for regulating CYP19 transcription. Expressional analyses show that activin-A can be considered as a strong candidate for being one of these FOXL2 co-factors. Finally, we discuss evidence for a role of activin and estrogens in somatic and germinal cell proliferation occurring before germ cell meiosis. This period, of 20 days in goat, seems to have no equivalent in mouse. This species-specific difference could explain the phenotype discrepancy observed between XX goat PIS −/− and XX mouse Foxl2 −/− .

show abstract

“…Moreover, even when the protein can localize in the nucleus, it aggregates and cannot interact with its target promoters. Interestingly, co-expression of the WT and the mutant construct induced a partial retention of the normal protein in the aggregates, suggesting a possible dominant negative effect of the expanded protein (Caburet et al, 2004). This deserves further analyses.…”

Section: Mutations Affecting the Foxl2 Locusmentioning

confidence: 85%

The mutations and potential targets of the forkhead transcription factor FOXL2

Moumné

Batista

Benayoun

et al. 2008

Molecular and Cellular Endocrinology

View full text Add to dashboard Cite

Abstract.Mutations of FOXL2, a gene encoding a forkhead transcription factor, have been shown to cause the blepharophimosis-ptosis-epicanthus inversus (BPES) syndrome. This genetic disorder is characterized by eyelid and mild craniofacial abnormalities that can appear associated with premature ovarian failure. FOXL2 is one of the earliest ovarian markers and it offers, along with its targets, an excellent model to study ovarian development and function in normal and pathological conditions. In this review we summarize recent data concerning FOXL2, its mutations and its potential targets. Indeed, many mutations have been described in the coding sequence of FOXL2. Among them, polyAlanine expansions and premature nonsense mutations have been shown to induce protein aggregation. In the context of the ovary, FOXL2 has been suggested to be involved in the regulation of cholesterol and steroid metabolism, apoptosis, reactive oxygen species detoxification and inflammation processes. The elucidation of the impact of FOXL2 mutations on its function will allow a better understanding of the pathogenic mechanisms underlying the BPES phenotype.

show abstract

A recurrent polyalanine expansion in the transcription factor FOXL2 induces extensive nuclear and cytoplasmic protein aggregation

Cited by 88 publications

References 21 publications

Lacrimal Gland Involvement in Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome

Lacrimal Gland Involvement in Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome

FOXL2 activates P450 aromatase gene transcription: towards a better characterization of the early steps of mammalian ovarian development

The mutations and potential targets of the forkhead transcription factor FOXL2

Contact Info

Product

Resources

About