title: The DISC1 promoter: characterization and regulation by FOXP2.
abstract: Disrupted in schizophrenia 1 (DISC1) is a leading candidate susceptibility gene for schizophrenia, bipolar disorder and recurrent major depression, which has been implicated in other psychiatric illnesses of neurodevelopmental origin, including autism. DISC1 was initially identified at the breakpoint of a balanced chromosomal translocation, t(1;11) (q42.1;14.3), in a family with a high incidence of psychiatric illness. Carriers of the translocation show a 50% reduction in DISC1 protein levels, suggesting altered DISC1 expression as a pathogenic mechanism in psychiatric illness. Altered DISC1 expression in the post-mortem brains of individuals with psychiatric illness and the frequent implication of non-coding regions of the gene by association analysis further support this assertion. Here, we provide the first characterization of the DISC1 promoter region. Using dual luciferase assays, we demonstrate that a region -300 to -177 bp relative to the transcription start site (TSS) contributes positively to DISC1 promoter activity, while a region -982 to -301 bp relative to the TSS confers a repressive effect. We further demonstrate inhibition of DISC1 promoter activity and protein expression by forkhead-box P2 (FOXP2), a transcription factor implicated in speech and language function. This inhibition is diminished by two distinct FOXP2 point mutations, R553H and R328X, which were previously found in families affected by developmental verbal dyspraxia. Our work identifies an intriguing mechanistic link between neurodevelopmental disorders that have traditionally been viewed as diagnostically distinct but which do share varying degrees of phenotypic overlap.
authors.affiliation: Medical Genetics Section, Molecular Medicine Centre, MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK.
authors.forename: Rosie M
authors.initials: RM
authors.lastname: Walker
authors.forename: Alison E
authors.initials: AE
authors.lastname: Hill
authors.forename: Alice C
authors.initials: AC
authors.lastname: Newman
authors.forename: Gillian
authors.initials: G
authors.lastname: Hamilton
authors.forename: Helen S
authors.initials: HS
authors.lastname: Torrance
authors.forename: Susan M
authors.initials: SM
authors.lastname: Anderson
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Ogawa
authors.forename: Pelagia
authors.initials: P
authors.lastname: Derizioti
authors.forename: Jérôme
authors.initials: J
authors.lastname: Nicod
authors.forename: Sonja C
authors.initials: SC
authors.lastname: Vernes
authors.forename: Simon E
authors.initials: SE
authors.lastname: Fisher
authors.forename: Pippa A
authors.initials: PA
authors.lastname: Thomson
authors.forename: David J
authors.initials: DJ
authors.lastname: Porteous
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Evans
mesh_terms: D001714:Bipolar Disorder / Q000235:genetics; D045744:Cell Line, Tumor; D003865:Major Depressive Disorder / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D009419:Nerve Tissue Proteins / Q000235:genetics*; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D012559:Schizophrenia / Q000235:genetics
chemical_list: C412476:DISC1 protein, human; C465448:FOXP2 protein, human; D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins