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P3–312: Functional consequences of tau haplotype and subhaplotypes in human brains
Author(s) -
Loy Clement T.,
Kwok John B.,
Blair Ian P.,
Hallupp Marianne,
Todd Elizabeth,
Schofield Peter R.
Publication year - 2006
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2006.05.1582
Subject(s) - haplotype , tauopathy , biology , tau protein , genetics , gene , microbiology and biotechnology , single nucleotide polymorphism , snp , genotype , alzheimer's disease , disease , neurodegeneration , medicine , pathology
Background: The Microtubule-Associated Protein Tau gene has a complex genetic architecture. Primary haplotype and subhaplotypes of the Tau gene are associated with a range of neurodegenerative diseases, but the pathogenic mechanism remains unclear. Objective: We studied Tau gene expression in cerebellae of subjects with no evidence of tauopathy, as a model to investigate the biology behind regulation of Tau gene expression. Methods: We examined 93 frozen brain samples with no evidence of tauopathy, Parkinson’s Disease or Alzheimer’s Disease. Tau transcripts from the constitutively spliced Exon 7 sequence were amplified and expression measured by real-time PCR (SYBR-Green chemistry). Total Tau mRNA level for each sample was measured twice, normalised by comparison with GAPDH, and adjusted against the mean value of the H1/H1 subset in each run. The primary Tau haplotype was determined in two ways: by using Baker’s original description and by examining the -373 G/C SNP in the promoter region. The H1B subhaplotype, defined by SNP rs242557, was examined by restriction enzyme digest with RsaI after amplification. The H1C subhaplotype, defined by SNP rs2471738, was examined by restriction enzyme digest with HinfI after amplification. The H1’ promoter subhaplotype was determined by direct DNA sequencing. Results: Primary Tau haplotypes determined using the two methods were found to be in complete concordance. 53, 36 and 4 brain samples were found to have the H1/H1, H1/H2 and H2/H2 genotypes, respectively. The H1 Tau haplotype was associated with significantly higher Tau expression (p 0.00036). Tau expression in H1/H1 samples was 3.82 times that of H2/H2 samples (p 0.00096). The H1B, H1C and H1’ subhaplotypes were not associated with Tau expression levels after taking into account the primary haplotype effect and Bonferroni correction. Conclusions: This is the first study to provide in vivo evidence that the H1 haplotype increases Tau gene expression in the human brain. This suggests that increased Tau gene expression may be one mechanism causing increased disease susceptibility among people with the H1 Tau haplotype. Disease risk associated with Tau subhaplotypes may also involve other pathogenic mechanisms, such as alteration in Tau gene splicing, and the ratio of 3& 4-repeat Tau.