title: Intracellular distribution of a speech/language disorder associated FOXP2 mutant.
abstract: Although a mutation (R553H) in the forkhead box (FOX)P2 gene is associated with speech/language disorder, little is known about the function of FOXP2 or its relevance to this disorder. In the present study, we identify the forkhead nuclear localization domains that contribute to the cellular distribution of FOXP2. Nuclear localization of FOXP2 depended on two distally separated nuclear localization signals in the forkhead domain. A truncated version of FOXP2 lacking the leu-zip, Zn2+ finger, and forkhead domains that was observed in another patient with speech abnormalities demonstrated an aggregated cytoplasmic localization. Furthermore, FOXP2 (R553H) mainly exhibited a cytoplasmic localization despite retaining interactions with nuclear transport proteins (importin alpha and beta). Interestingly, wild type FOXP2 promoted the transport of FOXP2 (R553H) into the nucleus. Mutant and wild type FOXP2 heterodimers in the nucleus or FOXP2 R553H in the cytoplasm may underlie the pathogenesis of the autosomal dominant speech/language disorder.
authors.affiliation: Division of Development, Department of Human Inherited Metabolic Disease, National Institute of Neuroscience, Ogawahigashi-machi 4-1-1, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Akifumi
authors.initials: A
authors.lastname: Mizutani
authors.forename: Ayumi
authors.initials: A
authors.lastname: Matsuzaki
authors.forename: Mariko Y
authors.initials: MY
authors.lastname: Momoi
authors.forename: Eriko
authors.initials: E
authors.lastname: Fujita
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tanabe
authors.forename: Takashi
authors.initials: T
authors.lastname: Momoi
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D019556:COS Cells; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D002522:Chlorocebus aethiops; D003593:Cytoplasm / Q000378:metabolism*; D019281:Dimerization; D051858:Forkhead Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D007806:Language Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013050:Spectrometry, Fluorescence; D013064:Speech Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014162:Transfection
chemical_list: C465448:FOXP2 protein, human; D051858:Forkhead Transcription Factors; D050505:Mutant Proteins; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins