FOXL2 and BPES: mutational hotspots, phenotypic variability, and revision of the genotype-phenotype correlation.
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.
De Baere
Elfride
E
Department of Medical Genetics, Ghent University Hospital, Ghent, Belgium. Elfride.DeBaere@rug.ac.be
Beysen
Diane
D
Oley
Christine
C
Lorenz
Birgit
B
Cocquet
Julie
J
De Sutter
Paul
P
Devriendt
Koen
K
Dixon
Michael
M
Fellous
Marc
M
Fryns
Jean-Pierre
JP
Garza
Arturo
A
Jonsrud
Christoffer
C
Koivisto
Pasi A
PA
Krause
Amanda
A
Leroy
Bart P
BP
Meire
Françoise
F
Plomp
Astrid
A
Van Maldergem
Lionel
L
De Paepe
Anne
A
Veitia
Reiner
R
Messiaen
Ludwine
L
D020121:5' Untranslated Regions; D016569:Blepharophimosis / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors; D020440:Gene Duplication; D005799:Genes, Dominant; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D009690:Nucleic Acid Conformation; D016366:Open Reading Frames; D010375:Pedigree; D010641:Phenotype; D011401:Promoter Regions, Genetic; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics*
D020121:5' Untranslated Regions; D004268:DNA-Binding Proteins; C421604:FOXL2 protein, human; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors; D014157:Transcription Factors