title: Molecular pathology of expanded polyalanine tract mutations in the Aristaless-related homeobox gene.
abstract: The Aristaless-related homeobox gene (ARX) is one of the major genes causing X-linked mental retardation. We have been interested in the pathogenic mechanism of expanded polyalanine tract mutations in ARX. We showed that the c.304ins(GCG)7 mutation causing an increase from 16 to 23 alanines increased the propensity of ARX protein aggregation and a shift from nuclear to cytoplasmic localization. We proposed that mislocalization of ARX via cytoplasmic aggregation and subsequent degradation leads to a partial loss of function, contributing to the pathogenesis. We identified importin 13 (IPO13), a mediator of nuclear import for a variety of proteins, as a novel ARX interacting protein. We predicted that the transport of ARX by IPO13 from the cytoplasm to the nucleus might be disrupted by expanded polyalanine tract mutations, but our data showed that in both yeast and mammalian cells these mutant ARX proteins were still able to interact with IPO13. We established the nuclear localization regions of the ARX homeodomain that were required for the interaction with IPO13 and correct localization of the full-length ARX transcription factor to the nucleus.
authors.affiliation: Department of Genetic Medicine, Women's and Children's Hospital, Adelaide 5006, Australia. cheryl.shoubrdge@adelaide.edu.au
authors.forename: Cheryl
authors.initials: C
authors.lastname: Shoubridge
authors.forename: Desiree
authors.initials: D
authors.lastname: Cloosterman
authors.forename: Emma
authors.initials: E
authors.lastname: Parkinson-Lawerence
authors.forename: Douglas
authors.initials: D
authors.lastname: Brooks
authors.forename: Jozef
authors.initials: J
authors.lastname: Gécz
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D016923:Cell Death / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D028884:Karyopherins / Q000378:metabolism; D038901:X-Linked Intellectual Disability / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008969:Molecular Sequence Data; D009154:Mutation; D016716:PC12 Cells; D010455:Peptides / Q000235:genetics*; D051381:Rats; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: C469264:ARX protein, human; D018398:Homeodomain Proteins; D028884:Karyopherins; D010455:Peptides; D014157:Transcription Factors; C019529:polyalanine