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J Med Genet 39:916-921 doi:10.1136/jmg.39.12.916
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Evolution and expression of FOXL2

  1. J Cocquet1,*,
  2. E Pailhoux2,
  3. F Jaubert3,
  4. N Servel2,
  5. X Xia4,
  6. M Pannetier2,
  7. E De Baere5,
  8. L Messiaen5,
  9. C Cotinot2,
  10. M Fellous1,*,
  11. R A Veitia1,*
  1. 1INSERM E0021, Génomique et Développement, Immunogénétique Humaine, Institut Pasteur, 25 rue du Dr Roux, 75724 Paris, France
  2. 2Biologie du Développement et Biotechnologies, INRA - Jouy en Josas, France
  3. 3Service d’Anatomie Pathologique, Hopital Necker-Enfants Malades, Paris, France
  4. 4Bioinformatics Laboratory, HKU-Pasteur Research Centre, Pokfulam, Hong Kong
  5. 5Department of Medical Genetics, Ghent University Hospital, Ghent, Belgium
  1. Correspondence to:
 Dr R A Veita, U361 Reproduction et Physiopathologie Obstétricale, Hôpital Cochin, Pavillon Baudelocque, 123 Bd de Port-Royal, 75014 Paris, France;
 veitia{at}cochin.inserm.fr

    Mutations in the FOXL2 gene have recently been shown to cause the blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), a rare genetic disease (MIM 110100).1 In type I BPES eyelid abnormalities are associated with premature ovarian failure (POF), while in type II BPES only the eyelid malformation is observed.2FOXL2 is the first human autosomal gene whose dominant mutations have been shown to be involved in POF. The eyelid malformation in both BPES types is inherited as a dominant trait and we have recently argued that ovarian failure in type II BPES is a recessive trait.3

    FOXL2 is a single exon gene of 2.7 kb. The predicted protein of 376 amino acids belongs to the large family of forkhead/winged helix transcription factors, containing a characteristic 100 amino acid DNA binding forkhead domain. Many members are known to be involved in vertebrate embryogenesis4 and some have been implicated in inherited developmental human disorders.5 Apart from the forkhead domain, the FOXL2 protein also contains a polyalanine (poly-Ala) tract whose role has not yet been elucidated. Recurrent mutations leading to its expansion cause type II BPES and account for 30% of the deleterious alterations detected in the open reading frame (ORF).6,7 These alleles have been considered as hypomorphic (residual activity) in the context of the ovary.1,6

    Northern blot analysis and RNA in situ hybridisation have shown that FOXL2 is expressed in developing mouse eyelids and in adult ovarian follicular cells.1

    Here we have performed a comparative sequence analysis of FOXL2 in order to study the evolution of the FOXL2 coding region. We have estimated the synonymous (Ks) and non-synonymous (Ka) substitution rates in the ORF of several species, human, goat, mouse and pufferfish. In addition, to determine the subcellular localisation of the FOXL2 protein and its …