The MAPT H1c risk haplotype is associated with increased expression of tau and especially of 4 repeat containing transcripts

Myers, Amanda; Pittman, Alan; Zhao, Alice; Rohrer, Kristen; Kaleem, Mona; Marlowe, Lauren; Lees, Andrew J.; Leung, Doris G.; McKeith, Ian G.; Perry, Robert H.; Morris, Christopher M.; Trojanowski, John Q.; Clark, Christopher M.; Karlawish, Jason; Arnold, S. E.; Forman, Mark S.; Deerlin, Vivianna M. Van; Silva, Rohan de; Hardy, John

doi:10.1016/j.nbd.2006.10.018

Cited by 235 publications

(211 citation statements)

References 19 publications

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“…We showed in vivo in post-mortem brain that the H1c haplotype is associated with increased MAPT transcription and inclusion of exon 10 [12]. In general, these studies strongly suggest that the basis of the risk due to the H1 haplotype is due to increased levels of tau protein with cis-modulation of [12]. The reporter assay was consistent with the view that rs242557 was a key part of promoter variability and a driver of the increased risk in PSP [12].…”

Section: Introductionsupporting

confidence: 84%

“…In general, these studies strongly suggest that the basis of the risk due to the H1 haplotype is due to increased levels of tau protein with cis-modulation of [12]. The reporter assay was consistent with the view that rs242557 was a key part of promoter variability and a driver of the increased risk in PSP [12]. Moreover, in a recently completed genomewide association study (GWAS) ) [9].…”

Section: Introductionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 53%

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Tau gene promoter rs242557 and allele-specific protein binding

Anaya¹,

Lees²,

Silva³

2011

Translational Neuroscience

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The H1 haplotype clade of the tau gene (MAPT) is associated with increased risk of the sporadic disorders, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) and to a lesser extent, Parkinson’s disease (PD). The H1c sub-haplotype drives this association in PSP and CBD, and is also weakly associated with Alzheimer’s disease (AD), suggesting involvement in common pathogenic pathway(s). The rs242557 single-nucleotide polymorphism (SNP) that defines H1c resides in a highly conserved repressor domain in the MAPT promoter. Previously, in cellular reporter assays, we showed significant rs242557 allele-specific differences in transcriptional repression, with the H1c-specific rs242557/A allele contributing a significantly higher MAPT promoter activity compared to the non-H1c rs242557/G allele. With evidence of allele-specific differences in protein binding to this repressor domain, we set out to identify those proteins that bind to this region. Electrophoretic mobility shift assay (EMSA) analysis strongly suggested allele-specific differences in protein affinities. In order to identify nuclear proteins that differentially bind to this repressor domain, we carried out a promoter-trap assay and analysed the bound proteins by SDS-PAGE and HPLC ESI-QTOF mass spectrometry. We identified 37 proteins and used bioinformatic tools such as STRING and Reactome to analyse and stratify the results. These included U2AF65, hnRNPU, PTBP1, hnRNPD0, U5 snRNP 116, ALY, HMGB2, H1 and actin and provide the basis for further studies of the role of the MAPT repressor domain and the binding proteins in regulating MAPT gene transcription and splicing.

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Section: Introductionsupporting

confidence: 84%

Section: Introductionsupporting

confidence: 76%

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Tau gene promoter rs242557 and allele-specific protein binding

Anaya¹,

Lees²,

Silva³

2011

Translational Neuroscience

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“…Even in the context of AD, the active contribution of Tau was highlighted by animal models, suggesting that Tau is required for the induction of Ab-induced toxicity (Roberson et al 2007). In fact, an increased Tau level alone suffices as a risk factor, as demonstrated for the H1c haplotype (Myers et al 2007). This provides a rationale for the quest for Tau-lowering drugs.…”

Section: Tau and Admentioning

confidence: 93%

Biochemistry and Cell Biology of Tau Protein in Neurofibrillary Degeneration

Mandelkow

2012

Cold Spring Harbor Perspectives in Medicine

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636

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Tau represents the subunit protein of one of the major hallmarks of Alzheimer disease (AD), the neurofibrillary tangles, and is therefore of major interest as an indicator of disease mechanisms. Many of the unusual properties of Tau can be explained by its nature as a natively unfolded protein. Examples are the large number of structural conformations and biochemical modifications ( phosphorylation, proteolysis, glycosylation, and others), the multitude of interaction partners (mainly microtubules, but also other cytoskeletal proteins, kinases, and phosphatases, motor proteins, chaperones, and membrane proteins). The pathological aggregation of Tau is counterintuitive, given its high solubility, but can be rationalized by short hydrophobic motifs forming b structures. The aggregation of Tau is toxic in cell and animal models, but can be reversed by suppressing expression or by aggregation inhibitors. This review summarizes some of the structural, biochemical, and cell biological properties of Tau and Tau fibers. Further aspects of Tau as a diagnostic marker and therapeutic target, its involvement in other Tau-based diseases, and its histopathology are covered by other chapters in this volume.

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“…These extensive investigations have revealed that two main nonrecombining MAPT locus haplotypes (H1 and H2) can be distinguished. The H1 haplotype and/or subhaplotypes play a general role in the development of sporadic tauopathies (Laws et al, 2007;Myers et al, 2007). It has also become obvious that there are notable differences in the geographical distribution of the MAPT-related haplotypes.…”

Section: Introductionmentioning

confidence: 99%

H1 tau haplotype-related genomic variation at 17q21.3 as an Asian heritage of the European Gypsy population

et al. 2008

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In this study, we examine the frequency of a 900 kb inversion at 17q21.3 in the Gypsy and Caucasian populations of Hungary, which may reflect the Asian origin of Gypsy populations. Of the two haplotypes (H1 and H2), H2 is thought to be exclusively of Caucasian origin, and its occurrence in other racial groups is likely to reflect admixture. In our sample, the H1 haplotype was significantly more frequent in the Gypsy population (89.8 vs 75.5%, Po0.001) and was in Hardy-Weinberg disequilibrium (P ¼ 0.017). The 17q21.3 region includes the gene of microtubule-associated protein tau, and this result might imply higher sensitivity to H1 haplotype-related multifactorial tauopathies among Gypsies.

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The MAPT H1c risk haplotype is associated with increased expression of tau and especially of 4 repeat containing transcripts

Cited by 235 publications

References 19 publications

Tau gene promoter rs242557 and allele-specific protein binding

Tau gene promoter rs242557 and allele-specific protein binding

Biochemistry and Cell Biology of Tau Protein in Neurofibrillary Degeneration

H1 tau haplotype-related genomic variation at 17q21.3 as an Asian heritage of the European Gypsy population

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