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A recurrent polyalanine expansion in the transcription factor FOXL2 induces extensive nuclear and cytoplasmic protein aggregation
  1. S Caburet1,
  2. A Demarez1,
  3. L Moumné1,
  4. M Fellous1,
  5. E De Baere2,
  6. R A Veitia1
  1. 1INSERM E0021 Génomique fonctionnelle du Développement, Hôpital Cochin, 123 bd du Port Royal, Bâtiment Baudelocque, 75014 Paris, France
  2. 2Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
  1. Correspondence to:
 Reiner A Veitia
 INSERM E0021, Hôpital Cochin, Pavillon Baudelocque, 123 Bd de Port Royal, 75014 Paris, France;


Blepharophimosis syndrome is an autosomal dominant disease characterised by eyelid malformations, associated or not with premature ovarian failure. It is caused by mutations in the FOXL2 gene, which encodes a forkhead transcription factor containing a polyalanine (polyAla) domain of 14 alanines. Expansions of the polyAla tract from 14 to 24 residues account for 30% of the reported mutations and lead mainly to isolated palpebral defects. We have transfected COS-7 cells with DNA constructs driving the expression of the wildtype and mutant FOXL2 proteins fused to the green fluorescent protein. The polyAla expansion was found to induce the formation of intranuclear aggregates and a mislocalisation of the protein due to extensive cytoplasmic aggregation. These findings were confirmed by immunofluorescence. Co-transfection experiments suggest that the wildtype and mutant proteins can co-aggregate. We propose that the mechanism for the molecular pathogenesis of the polyAla expansions of FOXL2 may be its mislocalisation concomitant with its inclusion into nuclear aggregates. This may diminish the pool of active protein. Potential effects of aggregation on cell viability are under study.

  • BPES, blepharophimosis ptosis epicanthus inversus syndrome
  • DMEM, Dulbecco’s modified Eagle’s medium
  • DNE, dominant negative effect
  • FCS, fetal calf serum
  • GFP, green fluorescent protein
  • OPMD, oculopharyngeal muscular dystrophy
  • ORF, open reading frame
  • PABPN1, poly(A)-binding protein nuclear 1
  • PBS, phosphate buffered saline
  • dominant negative effect
  • FOXL2
  • polyalanine expansion
  • protein aggregation
  • transcription factor

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  • This study was supported by Fund for Scientific Research (FWO-Flanders) grant KAN No. RAV and MF are supported by INSERM and the University of Paris VII. SC is supported by the GIS-Institut des maladies rares.

  • Conflict of interest: none declared.