title: Differential functional effects of novel mutations of the transcription factor FOXL2 in BPES patients.
abstract: Mutations of the transcription factor FOXL2, involved in cranio-facial and ovarian development lead to the Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome (BPES) in human. Here, we describe nine mutations in the open reading frame of FOXL2. Six of them are novel: c.292T>A (p.Trp98Arg), c.323T>C (p.Leu108Pro), c.650C>G (p.Ser217Cys) and three frameshifts. We have performed localization and functional studies for three of them. We have observed a strong cytoplasmic mislocalization induced by the missense mutation p.Leu108Pro located in the forkhead (FKH) domain of FOXL2. In line with this, transcriptional activity assays confirmed the loss-of-function induced by this variant. Interestingly, the novel mutation p.Ser217Cys, mapping between the FKH and the polyalanine domain of FOXL2 and producing a mild eyelid phenotype, led to normal localization and transactivation. We have also modeled the structure of the FKH domain to explore the potential structural impact of the mutations reported here and other previously reported ones. This analysis shows that mutants can be sorted into two classes: those that potentially alter protein-protein interactions and those that might disrupt the interactions with DNA. Our findings reveal new insights into the molecular effects of FOXL2 mutations, especially those affecting the FKH binding domain. (c) 2008 Wiley-Liss, Inc.
authors.affiliation: Department of Genetics, Dr. G.Venkataswamy Eye Research Institute, Aravind Medical Research Foundation, Aravind Eye Hospital, Madurai 625020, India.
authors.forename: Jeyabalan
authors.initials: J
authors.lastname: Nallathambi
authors.forename: Paul
authors.initials: P
authors.lastname: Laissue
authors.forename: Frank
authors.initials: F
authors.lastname: Batista
authors.forename: Bérénice A
authors.initials: BA
authors.lastname: Benayoun
authors.forename: Corinne
authors.initials: C
authors.lastname: Lesaffre
authors.forename: Lara
authors.initials: L
authors.lastname: Moumné
authors.forename: Pj Eswari
authors.initials: PE
authors.lastname: Pandaranayaka
authors.forename: Kim
authors.initials: K
authors.lastname: Usha
authors.forename: Sankaran
authors.initials: S
authors.lastname: Krishnaswamy
authors.forename: Periasamy
authors.initials: P
authors.lastname: Sundaresan
authors.forename: Reiner A
authors.initials: RA
authors.lastname: Veitia
mesh_terms: D000818:Animals; D016569:Blepharophimosis / Q000235:genetics*; D019556:COS Cells; D002648:Child; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D005260:Female; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000502:physiology*; D016368:Frameshift Mutation; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D016649:Primary Ovarian Insufficiency / Q000235:genetics; D017434:Protein Structure, Tertiary
chemical_list: C421604:FOXL2 protein, human; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors