Back to Search
Start Over
FOXL2 and BPES: Mutational Hotspots, Phenotypic Variability, and Revision of the Genotype-Phenotype Correlation
- Source :
- American journal of human genetics, 72(2), 478-487. Cell Press, American Journal of Human Genetics, 72, 478-487. Cell Press
- Publication Year :
- 2003
- Publisher :
- Elsevier BV, 2003.
-
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.
- Subjects :
- Forkhead Box Protein L2
Male
Genotype
Mutation, Missense
Blepharophimosis
Biology
medicine.disease_cause
Open Reading Frames
Gene Duplication
Report
Genetic variation
Gene duplication
Genetics
medicine
Humans
Missense mutation
Genetics(clinical)
Child
Promoter Regions, Genetic
Gene
Genetics (clinical)
Genes, Dominant
Mutation
Genetic Variation
Forkhead Transcription Factors
Syndrome
medicine.disease
Pedigree
DNA-Binding Proteins
Phenotype
Forkhead box L2
Child, Preschool
Nucleic Acid Conformation
Female
5' Untranslated Regions
Transcription Factors
Subjects
Details
- ISSN :
- 00029297
- Volume :
- 72
- Database :
- OpenAIRE
- Journal :
- The American Journal of Human Genetics
- Accession number :
- edsair.doi.dedup.....a568d163f9b297d2ca212198fe31854f