O2–02–02: The H1c risk haplotype of the MAPT gene is over–expressed in human temporal cortex relative to the other common alleles of MAPT
Year: 2006
Type: article
Study design: Observational Study
Abstract: MAPT is located in a 2 Mb block at 17q21 where there is a common inversion. This inversion creates two major haplotypes: H1 and H2. We found that while there was no recombination between H1 and H2, there was a normal pattern of linkage disequilibrium within the H1 clade, creating two main sub–haplotypes (H1b and H1c) and one rare sub–haplotype (H1e). The H1c haplotype was associated with increased risk for both PSP and AD. Currently, we are trying to understand how H1c increases risk for disease. There is extensive alternative splicing of MAPT, and increased inclusion of exon 10 creates a form of Tau which is more prone to aggregate (4R). Thus, there is the possibility that there are variants on the H1c background which alter splicing to more pathogenic forms of Tau. Alternatively, a recent study demonstrated that altering the expression of Tau could improve memory and performance in a mouse model. Therefore, the other possibility is that variability on the H1c background changes expression of MAPT. We have used RNAs prepped from the same set of brains in which we found the H1c association in AD to investigate the regulation of MAPT. The relative levels of transcript were quantified using RT–PCR. MAPT haplotype homozygotes were assessed by the delta delta CT method. H1H2 heterozygotes were assessed by allele–specific PCR. For both homozygotes and heterozygotes, probes were designed to both amplify all transcripts, as well as exclusively amplifying 4R tau isoforms. We found that there was approximately 3 fold increase in total tau transcript for the H1c homozygotes relative to the H2a homozygotes. This increase was even more pronounced when only 4R isoforms were examined. There was an approximate 4% increase in expression in H1c/H2 heterozygotes compared with either H1b/H2 or H1e/H2 heterozygotes looking at all isoforms. This rose to 8% when only 4R transcripts were assessed. We feel these results demonstrate that within the brain there is both a splicing and expression effect of the H1c haplotype.
Source: Alzheimer s & Dementia
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2580077064