title: Expanding the phenotype associated with FOXG1 mutations and in vivo FoxG1 chromatin-binding dynamics.
abstract: Mutations in the Forkhead box G1 (FOXG1) gene, a brain specific transcriptional factor, are responsible for the congenital variant of Rett syndrome. Until now FOXG1 point mutations have been reported in 12 Rett patients. Recently seven additional patients have been reported with a quite homogeneous severe phenotype designated as the FOXG1 syndrome. Here we describe two unrelated patients with a de novo FOXG1 point mutation, p.Gln46X and p.Tyr400X, respectively, having a milder phenotype and sharing a distinctive facial appearance. Although FoxG1 action depends critically on its binding to chromatin, very little is known about the dynamics of this process. Using fluorescence recovery after photobleaching, we showed that most of the GFP-FoxG1 fusion protein associates reversibly to chromatin whereas the remaining fraction is bound irreversibly. Furthermore, we showed that the two pathologic derivatives of FoxG1 described in this paper present a dramatic alteration in chromatin affinity and irreversibly bound fraction in comparison with Ser323fsX325 mutant (associated with a severe phenotype) and wild type Foxg1 protein. Our observations suggest that alterations in the kinetics of FoxG1 binding to chromatin might contribute to the pathological effects of FOXG1 mutations.
authors.affiliation: Medical Genetics, Department of Biotechnology, University of Siena, Siena, Italy.
authors.forename: R
authors.initials: R
authors.lastname: De Filippis
authors.forename: L
authors.initials: L
authors.lastname: Pancrazi
authors.forename: K
authors.initials: K
authors.lastname: Bjørgo
authors.forename: A
authors.initials: A
authors.lastname: Rosseto
authors.forename: T
authors.initials: T
authors.lastname: Kleefstra
authors.forename: E
authors.initials: E
authors.lastname: Grillo
authors.forename: A
authors.initials: A
authors.lastname: Panighini
authors.forename: F
authors.initials: F
authors.lastname: Cardarelli
authors.forename: I
authors.initials: I
authors.lastname: Meloni
authors.forename: F
authors.initials: F
authors.lastname: Ariani
authors.forename: M A
authors.initials: MA
authors.lastname: Mencarelli
authors.forename: J
authors.initials: J
authors.lastname: Hayek
authors.forename: A
authors.initials: A
authors.lastname: Renieri
authors.forename: M
authors.initials: M
authors.lastname: Costa
authors.forename: F
authors.initials: F
authors.lastname: Mari
mesh_terms: D000328:Adult; D015153:Blotting, Western; D002648:Child; D002843:Chromatin / Q000378:metabolism*; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics; D005260:Female; D036681:Fluorescence Recovery After Photobleaching; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D030342:Genetic Diseases, Inborn / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D007621:Karyotyping; D008856:Microscopy, Fluorescence; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D017354:Point Mutation / Q000235:genetics; D013577:Syndrome
chemical_list: D002843:Chromatin; C090173:FOXG1 protein, human; D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins