The DISC1 promoter: characterization and regulation by FOXP2

Rosie M. Walker, Alison E. Hill, Alice C. Newman, Gillian Hamilton, Helen S. Torrance, Susan M. Anderson, Fumiaki Ogawa, Pelagia Derizioti, Jerome Nicod, Sonja C. Vernes, Simon E. Fisher, Pippa A. Thomson, David J. Porteous, Kathryn L. Evans

Research output: Contribution to journalArticle

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.
Original languageEnglish
Pages (from-to)2862-2872
Number of pages11
JournalHuman Molecular Genetics
Volume21
Issue number13
DOIs
Publication statusPublished - 20 Mar 2012

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Keywords

  • phentoype
  • mutation
  • bipolar disorder
  • genes
  • languages
  • luciferases
  • mental disorders
  • point mutation
  • promoter regions
  • schizophrenia
  • speech
  • transcription initiation site
  • transfection
  • translocation
  • brain
  • transcription factor
  • major depressive disorder
  • recurrent
  • disc1 gene
  • balanced chromosomal translocation
  • neurodevelopmental disorders
  • childhood appraxia of speech
  • heart sound p2

Cite this

Walker, R. M., Hill, A. E., Newman, A. C., Hamilton, G., Torrance, H. S., Anderson, S. M., Ogawa, F., Derizioti, P., Nicod, J., Vernes, S. C., Fisher, S. E., Thomson, P. A., Porteous, D. J., & Evans, K. L. (2012). The DISC1 promoter: characterization and regulation by FOXP2. Human Molecular Genetics, 21(13), 2862-2872. https://doi.org/10.1093/hmg/dds111