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Lack of functional promoter polymorphisms in genes involved in glutamate neurotransmission

Smith, Susan Kay, Hoogendoorn, Bastiaan ORCID:, Guy, Carol, Coleman, Sharon Louise, O'Donovan, Michael Conlon ORCID: and Buckland, Paul Robert 2003. Lack of functional promoter polymorphisms in genes involved in glutamate neurotransmission. Psychiatric Genetics 13 (4) , pp. 193-199. 10.1097/00041444-200312000-00001

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Objectives: The regulation of genes involved in glutamatergic function is thought to be a critical for many central nervous system processes including memory, learning, synaptic maintenance, and many pathological states. As part of a larger survey into the key regulatory elements in genes of neuro-psychiatric interest, we sought to identify the promoter regions of genes in this broad family, and to identify sequence variants that alter gene expression. Methods: Mutation analysis was carried out on the promoters of 20 genes encoding 13 glutamate receptor subunits, four transporters and three metabolizing enzymes using denaturing high performance liquid chromatography. Thirty-nine different promoter haplotypes were cloned into a luciferase reporter gene vector and tested for differences in their ability to drive transcription in both HEK293t and TE671 cell lines. Results: We have identified a total of 48 sequence variants in six glutamate receptor subunits, four glutamate transporters and two enzymes. Interestingly, seven promoter sequences gave three or more haplotypes from a single individual, indicating gene duplication. No differences in expression greater than 1.35-fold were found between haplotypes originating from the same or paralogous genes. Conclusion: The lack of common functional polymorphisms in any of these promoters indicates that expression of glutamate receptors and transporters is unusually tightly controlled, and suggests the possibility that non-coding polymorphisms in these genes are rare and may be unlikely to contribute in a major way to neuro-psychiatric phenotypes. This study represents the world's largest survey of the any group of promoters yet performed for any gene system.

Item Type: Article
Date Type: Publication
Status: Published
Schools: MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Subjects: R Medicine > R Medicine (General)
Publisher: Lippincott Williams & Wilkins
ISSN: 0955-8829
Last Modified: 12 Dec 2022 08:55

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