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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

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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 (2002) 7, 104–109 2002 Nature Publishing Group All rights reserved 1359-4184/02 $15.00 www.nature.com/mp ORIGINAL RESEARCH ARTICLE Identification of genomic organisation, sequence variants and analysis of the role of the human dishevelled 1 gene in late onset Alzheimer’s disease C Russ, S Lovestone and JF Powell Department of Neuroscience, Institute of Psychiatry, London SE5 8AF, UK Keywords: polymorphism; genomic; DVL1; association; kinases, such as c-Jun N-terminal kinase (JNK), and SNP glycogen synthase kinase 3 beta (GSK3␤) have been Alzheimer’s disease (AD) is a disorder characterised by shown to phosphorylate tau in vitro, in cell at sites that a progressive deterioration in memory and other cogni- are phosphorylated in PHF.4–7 JNK and GSK3␤ are tive functions. Neurofibrillary tangles (NFT) are a major regulated by the dishevelled 1 gene (DVL1), the latter pathological hallmark of AD, these are aggregations of as part of the wnt signalling pathways.8–11 Activation paired helical filaments (PHF) comprised of the hyper- of the wnt signalling pathway is thought to cause DVL1 phosphorylated microtubule associated protein tau. to inactivate GSK3␤ through complex-formation with Several kinases, such as glycogen synthase kinase 3 ␤ ␤ adenomatous poliposis coli (APC), axin and -catenin beta (GSK3 ) and c-Jun N-terminal kinase (JNK), phos- proteins,8 whereas JNK is activated by DVL1.10,11 The phorylate tau at sites that are phosphorylated in PHF. Dishevelled 1 (DVL1) is thought to act as a positive mechanism by which this JNK activation occurs is regulator of the wnt signalling pathway, and inhibits unclear, however, it has been demonstrated that a DEP GSK3␤ activity preventing ␤-catenin degradation and (dishevelled, egl-10 and pleckstrin) protein binding thus allowing wnt target gene expression. JNK acti- domain found at the C-terminal of DVL1 is essential vation is also regulated by DVL1, however it is unclear for JNK activation.10 It has been suggested that the wnt if this is via the wnt signalling pathway. These obser- signalling pathway is altered in AD,8,9 therefore DVL1 vations suggest a central role for DVL1 in tau phos- is a very strong candidate gene for AD. Furthermore a phorylation and AD and led us to investigate DVL1 as recent genome scan has shown suggestive linkage (LOD a candidate gene for this disorder. We determined the score 1.33, markers D1S548 and D1S1592) to the distal genomic structure of the DVL1 gene by sequencing and end of chromosome 1 p to AD, where DVL1 is data mining and searched for sequence variations in the located.12 coding sequences and flanking introns. The DVL1 gene 13 spans a region of approximately 13.8 kb (not including DVL1 is a cytoplasmic phosphoprotein encoding a the 5Ј untranslated region) and is encoded by 15 exons. 670-amino acid polypeptide mapping to chromosome Analysis of over 4.3 kb of sequence, including 98% of 1p36.14 In Drosophila it regulates cell proliferation, act- exonic sequences and introns 2, 3, 6, 7, 9, 10, 11 and 12, ing as a transducer molecule for developmental pro- revealed there to be six rare (Յ6%) sequence variations. cesses, including segmentation and neuroblast speci- None of these had any association with late onset AD. fication.14 DVL1 is part of a multi-gene family of This would suggest that polymorphic variations in the proteins that contain three highly conserved species of coding sequences of DVL1 are not important in AD. protein binding domains: an N-terminal DIX However further analysis of regulatory regions may lead (dishevelled and axin) domain; a central PDZ (PSD-95, to the identification of other sequence variations which may be implicated in AD. discs-large and ZO-1) domain; and a DEP domain. Molecular Psychiatry (2002) 7, 104–109. DOI: 10.1038/ DVL1 is highly expressed in both adult and fetal sj/mp/4000941 tissues such as skeletal muscle and pancreas but is also found in the brain and neural tube.14 In contrast to JNK Late onset Alzheimer’s disease (AD) is the most com- activation, all three protein binding domains are mon form of progressive neurodegenerative dementia required for GSK3␤ inactivation and thus ␤-catenin afflicting 5–10% of the population aged over 65 years.1 upregulation.10,15 AD is characterised by two major neuropathological A chromosomal deletion that includes the DVL1 features, neuritic plaques and neurofibrillary tangles gene causes severe morphological abnormalities in (NFT). NFT are intraneuronal inclusions of paired heli- children.16 However knockout mice lacking DVL1 are cal filaments (PHF), mostly comprised of highly phos- viable, fertile, and structurally normal but show abnor- phorylated microtubule associated protein tau. Tau mal social behaviour and several neurological promotes microtubule (MT) assemble in vitro2 and defects.17 Recent studies demonstrated that over- stabilises MT in vivo3 and it is thought that phos- expression of mouse DVL1 causes inhibition of GSK3␤ phorylation inhibits these processes and leads to PHF mediated tau phosphorylation.18 Furthermore Strovel formation. Several mitogen activated protein (MAP) et al19 demonstrated the inability of producing stable Role of DVL1 in late onset AD C Russ et al 105 cell lines overexpressing DVL1. They showed that We examined each SNP in larger sample populations DVL1 causes cell death due to the induction of of ADs and controls to determine whether these alter- apoptosis in an APC-dependent manner. This led us ations were potential disease-related or non-patho- to hypothesise that a subtle variation in the coding or genic. Statistical analysis showed that all of the poly- regulatory region of DVL1 may have an influence later morphisms examined are in Hardy–Weinberg in life and in AD. equilibrium. Haplotype analysis showed that SNPs We therefore sought to sequence the DVL1 gene 98876 G/A and 102296 C/T were in strong linkage dis- including some of its introns in a series of AD cases equilibrium (DЈ = 1.00, df = 3, P Ͻ 10−7). When compar- and controls to identify polymorphisms and then ing ADs to controls no statistically significant associ- investigate these in AD. ation of any SNP was found for individual alleles (see We systematically sequenced 1979 bp of the DVL1 Table 3) and genotypes (data not shown). coding sequence and 2337 bp of the non-coding As the APOE ⑀4 allele has repeatedly been associated sequence in 24 control and 24 AD samples to identify with risk for AD, this association should be seen in our differences between the two populations. Sequencing Caucasian AD case-control sample. Indeed, statistical and BLAST20 analysis of the cDNA (Acc. No. analysis of the sample showed there to be a highly sig- AF006011) sequence against the NCBI (National Centre nificant association between APOE ⑀4 allele frequency for Biotechnology Information) htgs (unfinished high and AD (0.36) vs controls (0.16) (P = 0.001; OR = 3.02, throughput genomic sequences) nucleotide database, CI 1.44–6.40).22,23 As all SNPs were found to be rare led us to determine the genomic structure of the DVL1 (Յ6%), we did not perform any further statistical gene (see Figure 1 and Table 1). DVL1 is encoded by analysis of the sample, such as stratification by APOE 15 exons similar to that of the mouse DVL1 gene21 rang- ⑀4 status, sex, age of onset and ‘probable’ or ‘poss- ing in size from 68 bp (exon 10) to 374 bp (exon 15) ible’ AD. spanning a region of approximately 13.8 kb (not To ensure that our analyses were specific to DVL1 including the 5Ј untranslated region) with the largest we performed radiation hybrid mapping24 (data not and smallest introns being 6139 bp (intron 1) and 69 bp shown) using several primer pairs. This revealed link- (intron 7) respectively. We fully sequenced exons 2–14 age of our PCR fragments to chromosome 1p36 with and partially sequenced exons 1 and 15. Due to sequen- LOD scores greater than 7, therefore confirming the cing primer design constraints, the first 21 bp of exon specificity of our investigation. No other chromosomal 1 and the last 12 bp of exon 15 were not sequenced. location showed any significant linkage. We also fully sequenced introns 2, 3, 6, 7, 9, 10, 11, 12 In this study we have elucidated the genomic organ- and partially sequenced other introns. The other isation of the human DVL1 gene and have investigated introns and the 5Ј and 3Ј untranslated region were not the frequency of polymorphisms in the DVL1 gene and sequenced due to time constraint. The coding sequence analysed their possible involvement in AD. Statistical we elucidated is identical to the Semenov sequence analysis showed there to be no significant association (Acc.No. AAB65242). The DIX domain is located in between any of the detected polymorphisms and AD. exons 1–3, the PDZ domain is in exons 7–10 and the However, control populations are an intrinsic problem DEP domain is encoded by exons 12 and 13. in AD genetic studies and this is as true for the control Sequencing analysis detected six single nucleotide group we used as for those used in other studies. We polymorphisms (SNPs). We identified a rare silent included only controls with no evidence of cognitive coding SNP in exon 1 at codon 22 position nt 69 C/T impairment (MMSE Ͼ 25) but it remains possible that (relative to Acc.No. AF006011) with rare allele fre- we included a few individuals in the early, perhaps quency of 1%. Furthermore we identified five rare non- presymptomatic, stages of dementia. However it is coding SNPs at positions nt 98876 G/A (intron 2), nt unlikely that this would have affected our results.
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