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A molecular genetic study of the tau locus in neurodegeneration

Pittman, AM; (2006) A molecular genetic study of the tau locus in neurodegeneration. Doctoral thesis , UCL (University College London). Green open access

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Tau is a microtubule-associated protein and is deposited as neurofibrillary tangles in the group of neurodegenerative diseases collectively known as the tauopathies including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and frontotemporal dementia with parkinsonism linked to chromosome 17 with tau pathology (FTDP-17T). The pathological tau is hyperphosphorylated and has a reduced microtubule binding capacity. The identification of missense and splice site mutations in the tau gene (MAPI) causing FTDP-17T affirmed a central role for tau dysfunction in this neurodegenerative disease. PSP is usually a sporadic disorder of late adult life, with no family history or MAPT mutations in the majority of cases. However, it has been shown that common genetic variation at the MAPT locus is an important genetic risk factor for sporadic PSP. This finding has been consistently and independently replicated. There are two major MAPT haplotypes at 17q21.31 designated HI and H2. It is the over-representation of HI that is associated with PSP and in this work the extent of the H1/H2 MAPT non recombining haplotypes was mapped to cover a region of approximately 2 million base pairs of perfect linkage disequilibrium. In order to explore the functional and pathogenic basis of the HI haplotype, a systematic framework of genetic analysis was employed for a high resolution association study of the MAPT gene with PSP. Multiple common variants of the HI haplotype were identified and one common haplotype, Hlc, showed preferential association with PSP above all others. Candidate causal variants were identified on this haplotype background and were tested for their effects on MAPT promoter driven expression using luciferase reporter assays. The functional SNP loci that were identified reside in evolutionarily conserved islands and the SNP variants that give rise to higher MAPT promoter driven expression were significantly over- represented in PSP. Thus, increased MAPT expression could at least in part explain the association of the locus with PSP. The region of 17q21.31 also shows complex genomic architecture containing low- copy repeats (LCRs) that are responsible for an ancient parcentric inversion that corresponds to the HI and H2 lineages. A de novo microdeletion encompassing the MAPT gene was identified in three individuals with moderate to severe learning disabilities. In this work, a in depth haplotype analysis in these triad families with respect to H1 and H2 haplotypes unambiguously revealed that in two of the cases the parental origins of the deletion were heterozygous carriers for the H1/H2 inversion. A mechanism of inversion mediated non-allelic homologous recombination between the MAPT 17q21.31 LCRs was proposed to explain the generation of the deletion.

Type: Thesis (Doctoral)
Title: A molecular genetic study of the tau locus in neurodegeneration
Identifier: PQ ETD:593370
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest. Third party copyright material has been removed from the ethesis. Images identifying individuals have been redacted or partially redacted to protect their identity.
URI: https://discovery.ucl.ac.uk/id/eprint/1446044
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