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Human Molecular Genetics Advance Access published online on October 11, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi383
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received August 9, 2005
Revised October 5, 2005
Accepted October 5, 2005

Article

Deletions in the polyAlanine-containing transcription factor FOXL2 lead to intranuclear aggregation

Lara Moumné 1, Marc Fellous 1, and Reiner A. Veitia 1*

1 INSERM U709 Génomique et Epigénétique des Pathologies Placentaires and Université Denis Diderot/Paris VII., Hôpital Cochin. Pavillon Baudelocque., 123 Bd de Port Royal, 75014 Paris

* To whom correspondence should be addressed.
Reiner A. Veitia, E-mail: veitia{at}cochin.inserm.fr


  Abstract

Mutations of FOXL2, a gene encoding a forkhead transcription factor, have been shown to cause the blepharophimosis-ptosis epicanthus inversus syndrome (BPES). This genetic disorder is characterized by eyelid and craniofacial abnormalities associated or not with premature ovarian failure. We have previously shown that mutant FOXL2 with an expanded polyAlanine tract forms large aggregates both in the nucleus and the cytoplasm of transfected cells, whereas the wild-type protein localizes in the nucleus in a rather diffuse manner. Premature stop codons in FOXL2 have been considered so far as null alleles. However, we demonstrate here that such nonsense mutations may lead to the production of N-terminally truncated proteins by re-initiation of translation downstream of the stop codon. Surprisingly, the truncated proteins strongly aggregate in the nucleus, partially localize in the cytoplasm and retain a fraction of the wild-type protein. We also show that a complete deletion of the polyAlanine tract of FOXL2 induces a significant intranuclear aggregation. Our results enlarge the spectrum of mutations inducing FOXL2 aggregation.


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