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Human Molecular Genetics Advance Access originally published online on April 28, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 12 1267-1274
DOI: 10.1093/hmg/ddh138
Human Molecular Genetics, Vol. 13, No. 12 © Oxford University Press 2004; all rights reserved

The structure of the tau haplotype in controls and in progressive supranuclear palsy

Alan M. Pittman1,2,{dagger}, Amanda J. Myers3,{dagger}, Jaime Duckworth3, Leslie Bryden3, Melissa Hanson3, Patrick Abou-Sleiman2, Nicholas W. Wood2, John Hardy1,3, Andrew Lees1,2 and Rohan de Silva1,2,*

1Reta Lila Weston Institute of Neurological Studies, University College London, Windeyer Building, 46 Cleveland Street, London W1T 4JF, UK, 2Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London WC1N 3BG, UK and 3Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Building 10, Bethesda, MD 20892, USA

Received February 18, 2004; Accepted April 7, 2004

The group of neurodegenerative diseases collectively known as tauopathies are characterized by hallmark lesions consisting of fibrillar aggregates of the microtubule-associated protein, tau (MAPT). Mutations of the tau gene (MAPT) are the cause of frontotemporal dementia with parkinsonism linked to chromosome 17, giving tau a central role in the pathogenic process. The chromosomal region containing MAPT has been shown to evolve into two major haplotypes, H1 and H2, which are defined by linkage disequilibrium (LD) between several polymorphisms over the entire MAPT gene. Studies to date suggest a complete absence of recombination between these two haplotypes. The more common haplotype H1 is over-represented in patients with progressive supranuclear palsy (PSP) and corticobasal degeneration. Using single nucleotide polymorphisms, we mapped LD in the regions flanking MAPT and have established the maximum extent of the haplotype block on chromosome 17q21.31 as a region covering ~2 Mb. This gene-rich region extends centromerically beyond the corticotrophin releasing hormone receptor 1 gene (CRHR1) to a region of ~400 kb, where there is a complete loss of LD. The telomeric end is defined by an ~150 kb region just beyond the WNT3 gene. We show that the entire, fully extended H1 haplotype is associated with PSP, which implicates several other genes in addition to MAPT, as candidate pathogenic loci.

* To whom correspondence should be addressed. Tel: +44 2076799266; Fax: +44 2076799429; Email: rsilva{at}ion.ucl.ac.uk


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