Missense mutation outside the forkhead domain of FOXL2 causes a severe form of BPES type II

Mol Vis. 2012;18:211-8. Epub 2012 Jan 26.

Abstract

Purpose: Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a developmental disease characterized by a complex eyelid malformation associated or not with premature ovarian failure (POF). BPES is essentially an autosomal dominant disease, due to mutations in the forkhead box L2 (FOXL2) gene, encoding a forkhead transcription factor. More than one hundred unique FOXL2 mutations have been described in BPES in different populations, many of which are missense mutations in the forkhead domain. Here, we report on a very severe form of BPES resulting from a missense mutation outside the forkhead domain.

Methods: A clinical and molecular genetic investigation was performed in affected and unaffected members of an Iranian family with BPES. The FOXL2 coding region was sequenced in an index case. Targeted mutation testing was performed in 8 family members.

Results: We have identified a heterozygous FOXL2 missense mutation c.650C→G (p.Ser217Cys) co-segregating with disease in members of a three-generation family with BPES type II. Only few missense mutations have been reported outside the forkhead domain so far. They were all found in mild BPES, in line with in vitro studies demonstrating mostly normal localization and normal or increased transactivation properties of the mutant proteins. Unlike previous studies, affected members of the family studied here showed a severe BPES phenotype, with bilateral amblyopia due to uncorrected ptosis.

Conclusions: This is the first study demonstrating a severe BPES phenotype resulting from a FOXL2 missense mutation outside the forkhead domain, expanding our knowledge about the phenotypic consequences of missense mutations outside the forkhead domain in BPES.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Blepharophimosis / genetics*
  • Blepharophimosis / pathology
  • DNA Mutational Analysis
  • Female
  • Forkhead Box Protein L2
  • Forkhead Transcription Factors / genetics*
  • Genes, Dominant
  • Genetic Linkage
  • Genotype
  • Heterozygote
  • Humans
  • Iran
  • Male
  • Molecular Sequence Data
  • Mutation, Missense*
  • Pedigree
  • Phenotype
  • Protein Structure, Tertiary
  • Severity of Illness Index
  • Skin Abnormalities / genetics*
  • Skin Abnormalities / pathology

Substances

  • FOXL2 protein, human
  • Forkhead Box Protein L2
  • Forkhead Transcription Factors

Supplementary concepts

  • Blepharophimosis syndrome type 2