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  The DISC1 promoter: Characterization and regulation by FOXP2

Walker, R. M., Hill, A. E., Newman, A. C., Hamilton, G., Torrance, H. S., Anderson, S. M., et al. (2012). The DISC1 promoter: Characterization and regulation by FOXP2. Human Molecular Genetics, 21, 2862-2872. doi:10.1093/hmg/dds111.

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Walker_et_al_Hum_Mol_Gen_2012.pdf (Publisher version), 434KB
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 Creators:
Walker, Rosie M.1, Author
Hill, Alison E.2, Author
Newman, Alice C.1, Author
Hamilton, Gillian1, 3, Author
Torrance, Helen S.1, Author
Anderson, Susan M.1, Author
Ogawa, Fumiaki1, Author
Derizioti, Pelagia4, 5, Author           
Nicod, Jérôme5, Author
Vernes, Sonja C.4, 6, Author           
Fisher, Simon E.4, 5, 6, Author           
Thomson, Pippa A.1, 7, Author
Porteous, David J.1, 7, Author
Evans, Kathryn L.1, 7, Author
Affiliations:
1Medical Genetics Section, Molecular Medicine Centre, MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh, Western General Hospital, ou_persistent22              
2Medical Research Council Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, ou_persistent22              
3Centre for Integrative Physiology, The University of Edinburgh, School of Biomedical Sciences, ou_persistent22              
4Language and Genetics Department, MPI for Psycholinguistics, Max Planck Society, ou_792549              
5Wellcome Trust Centre for Human Genetics, University of Oxford, ou_persistent22              
6Donders Institute for Brain, Cognition and Behaviour, External Organizations, ou_55236              
7Centre for Cognitive Ageing and Cognitive Epidemiology, Medical Genetics Section, Molecular Medicine Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, ou_persistent22              

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 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 characterisation of the DISC1 promoter region. Using dual luciferase assays, we demonstrate that a region -300bp to -177bp relative to the transcription start site (TSS) contributes positively to DISC1 promoter activity, whilst a region -982bp to -301bp relative to the TSS confers a repressive effect. We further demonstrate inhibition of DISC1 promoter activity and protein expression by 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 (DVD). 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.

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Language(s): eng - English
 Dates: 2012-01-262012-03-152012-03-202012
 Publication Status: Issued
 Pages: -
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 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1093/hmg/dds111
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Title: Human Molecular Genetics
Source Genre: Journal
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Publ. Info: Oxford, England : IRL Press
Pages: - Volume / Issue: 21 Sequence Number: - Start / End Page: 2862 - 2872 Identifier: ISSN: 0964-6906
CoNE: https://pure.mpg.de/cone/journals/resource/954925581153