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  • Original Research Article
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Identification of genomic organisation, sequence variants and analysis of the role of the human dishevelled 1 gene in late onset Alzheimer's disease

Molecular Psychiatry volume 7, pages 104–109 (2002)Cite this article

Abstract

Alzheimer's disease (AD) is a disorder characterised by a progressive deterioration in memory and other cognitive functions. Neurofibrillary tangles (NFT) are a major pathological hallmark of AD, these are aggregations of paired helical filaments (PHF) comprised of the hyperphosphorylated microtubule associated protein tau. Several kinases, such as glycogen synthase kinase 3 beta (GSK3β) and c-Jun N-terminal kinase (JNK), phosphorylate tau at sites that are phosphorylated in PHF. Dishevelled 1 (DVL1) is thought to act as a positive regulator of the wnt signalling pathway, and inhibits GSK3β activity preventing β-catenin degradation and thus allowing wnt target gene expression. JNK activation is also regulated by DVL1, however it is unclear if this is via the wnt signalling pathway. These observations suggest a central role for DVL1 in tau phosphorylation and AD and led us to investigate DVL1 as a candidate gene for this disorder. We determined the genomic structure of the DVL1 gene by sequencing and data mining and searched for sequence variations in the coding sequences and flanking introns. The DVL1 gene spans a region of approximately 13.8 kb (not including the 5′ untranslated region) and is encoded by 15 exons. Analysis of over 4.3 kb of sequence, including 98% of exonic sequences and introns 2, 3, 6, 7, 9, 10, 11 and 12, revealed there to be six rare (≤6%) sequence variations. None of these had any association with late onset AD. This would suggest that polymorphic variations in the coding sequences of DVL1 are not important in AD. However further analysis of regulatory regions may lead to the identification of other sequence variations which may be implicated in AD.

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Acknowledgements

This study was supported by the Wellcome Trust (049542/Z). The authors wish to thank Dr Clive Holmes for the use of the clinical and genotypic data for the Camberwell Dementia Case Register. Samples from participants in the MRC trial of assessment and management of elderly people in the community (MRC Elderly Study) were collected in collaboration with the trial investigators: Professor Astrid Fletcher, London School of Hygiene & Tropical Medicine (Principal investigator) and co-investigators Dr Dee Jones, University of Wales College of Medicine and Professor Chris Bulpitt, Imperial College. We also thank Aaron Jeffries for his Unix skills.

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  1. Department of Neuroscience, Institute of Psychiatry, London, SE5 8AF, UK

    C Russ, S Lovestone & J F Powell

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Correspondence to J F Powell.

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Russ, C., Lovestone, S. & Powell, J. Identification of genomic organisation, sequence variants and analysis of the role of the human dishevelled 1 gene in late onset Alzheimer's disease. Mol Psychiatry 7, 104–109 (2002). https://doi.org/10.1038/sj.mp.4000941

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