FOXL2 and BPES: Mutational Hotspots, Phenotypic Variability, and Revision of the Genotype-Phenotype Correlation

Abstract

Blepharophimosis syndrome (BPES), an autosomal dominant syndrome in which an eyelid malformation is associated (type I) or not (type II) with premature ovarian failure (POF), has recently been ascribed to mutations in FOXL2, a putative forkhead transcription factor gene. We previously reported 22 FOXL2 mutations and suggested a preliminary genotype-phenotype correlation. Here, we describe 21 new FOXL2 mutations (16 novel ones) through sequencing of open reading frame, 5' untranslated region, putative core promoter, and fluorescence in situ hybridization analysis. Our study shows the existence of two mutational hotspots: 30% of FOXL2 mutations lead to polyalanine (poly-Ala) expansions, and 13% are a novel out-of-frame duplication. In addition, this is the first study to demonstrate intra- and interfamilial phenotypic variability (both BPES types caused by the same mutation). Furthermore, the present study allows a revision of the current genotype-phenotype correlation, since we found exceptions to it. We assume that for predicted proteins with a truncation before the poly-Ala tract, the risk for development of POF is high. For mutations leading to a truncated or extended protein containing an intact forkhead and poly-Ala tract, no predictions are possible, since some of these mutations lead to both types of BPES, even within the same family. Poly-Ala expansions may lead to BPES type II. For missense mutations, no correlations can be made yet. Microdeletions are associated with mental retardation. We conclude that molecular testing may be carefully used as a predictor for POF risk in a limited number of mutations.

Forkhead transcription factors in ovarian function

“…There is a certain variance in the clinical spectrum associated with FOXL2 mutations, with infertility ranging from primary amenorrhea to irregular menses followed by POF and ovarian appearance varying from ostensibly normal to streak gonads (De Baere et al 2001). Depending on the type and position of the mutation within the FOXL2 coding sequence, a putative genotype-phenotype correlation could be derived: mutations closer toward the N-terminus, leading to the production of a truncated FOXL2 protein, most likely lead to loss of function and cause both ovarian failure and eyelid abnormalities (BPES type I), whereas extensions such as frameshifts or duplications represent hypomorphic alleles and result in BPES type II (De Baere et al 2003, 2009, Beysen et al 2009). Figure 1 The forkhead transcription factor family.…”

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

“…Another feature of FOXL2 is the presence of a polyalanine domain of 14 alanines, located to the C-terminus with respect to the DNA binding domain. 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).…”

Potential targets of FOXL2, a transcription factor involved in craniofacial and follicular development, identified by transcriptomics

“…Expression of murine Foxl2 has also been reported in the pituitary (5), which is suggestive of an implication in the hypothalamuspituitary-ovarian axis. The expansion of the polyalanine domain of FOXL2 from 14 to 24 residues accounts for 30% of the reported mutations in the ORF (6). This mutation induces the formation of intranuclear aggregates and mislocalization of the protein due to cytoplasmic aggregation or retention (7).…”