Spectrum of FOXL2 gene mutations in blepharophimosis-ptosis-epicanthus inversus (BPES) families demonstrates a genotype-phenotype correlation

Elfride De Baere, Michael J. Dixon, Kent W. Small, Ethylin W. Jabs, Bart P. Leroy, Koenraad Devriendt, Yves Gillerot, Geert Mortier, Françoise Meire, Lionel Van Maldergem, Winnie Courtens, Helle Hjalgrim, Shangzhi Huang, Inge Liebaers, Nicole Van Regemorter, Philippe Touraine, Verayuth Praphanphoj, Alain Verloes, Nitin Udar, Vivek YelloreMeenal Chalukya, Svetlana Yelchits, Anne De Paepe, Frédérique Kuttenn, Marc Fellous, Reiner Veitia, Ludwine Messiaen

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219 Scopus citations


Mutations in FOXL2, a forkhead transcription factor gene, have recently been shown to cause blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) types I and II, a rare genetic disorder. In BPES type I a complex eyelid malformation is associated with premature ovarian failure (POF), whereas in BPES type II the eyelid defect occurs as an isolated entity. In this study, we describe the identification of novel mutations in the FOXL2 gene in BPES types I and II families, in sporadic BPES patients, and in BPES families where the type could not be established. In 67% of the patients studied, we identified a mutation in the FOXL2 gene. In total, 21 mutations (17 of which are novel) and one microdeletion were identified. Thirteen of these FOXL2 mutations are unique. In this study, we demonstrate that there is a genotype-phenotype correlation for either types of BPES by the finding that mutations predicted to result in a truncated protein either lacking or containing the forkhead domain lead to BPES type I. In contrast, duplications within or downstream of the forkhead domain, and a frameshift downstream of them, all predicted to result in an extended protein, cause BPES type II. In addition, in 30 unrelated patients with isolated POF no causal mutations were identified in FOXL2. Our study provides further evidence that FOXL2 haploinsufficiency may cause BPES types I and II by the effect of a null allele and a hypomorphic allele, respectively. Furthermore, we propose that in a fraction of the BPES patients the genetic defect does not reside within the coding region of the FOXL2 gene and may be caused by a position effect.

Original languageEnglish (US)
Pages (from-to)1591-1600
Number of pages10
JournalHuman Molecular Genetics
Issue number15
StatePublished - Jul 15 2001

ASJC Scopus subject areas

  • Genetics


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