title: Deletions in the polyAlanine-containing transcription factor FOXL2 lead to intranuclear aggregation.
abstract: Mutations of FOXL2, a gene encoding a forkhead transcription factor, have been shown to cause the blepharophimosis-ptosis-epicanthus inversus syndrome. 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 (polyAla) tract forms large aggregates both in the nucleus and in 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 polyAla tract of FOXL2 induces a significant intranuclear aggregation. Our results enlarge the spectrum of mutations inducing FOXL2 aggregation.
authors.affiliation: INSERM U709 Génomique et Epigénétique des Pathologies Placentaires and Universités Paris V & VII, Paris 75014, France.
authors.forename: Lara
authors.initials: L
authors.lastname: Moumné
authors.forename: Marc
authors.initials: M
authors.lastname: Fellous
authors.forename: Reiner A
authors.initials: RA
authors.lastname: Veitia
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002467:Cell Nucleus / Q000737:chemistry; D002478:Cells, Cultured; D018389:Codon, Nonsense / Q000235:genetics; D003593:Cytoplasm / Q000737:chemistry; D005141:Eyelid Diseases / Q000235:genetics; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D010455:Peptides / Q000235:genetics*; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D017384:Sequence Deletion; D012995:Solubility
chemical_list: D018389:Codon, Nonsense; C421604:FOXL2 protein, human; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors; D018832:Molecular Chaperones; D010455:Peptides; D012333:RNA, Messenger; C019529:polyalanine