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Acta Neuropathologica
Published in: Acta Neuropathologica 2/2014

01-02-2014 | Original Paper

Novel mutation in MAPT exon 13 (p.N410H) causes corticobasal degeneration

Authors: Naomi Kouri, Yari Carlomagno, Matthew Baker, Amanda M. Liesinger, Richard J. Caselli, Zbigniew K. Wszolek, Leonard Petrucelli, Bradley F. Boeve, Joseph E. Parisi, Keith A. Josephs, Ryan J. Uitti, Owen A. Ross, Neill R. Graff-Radford, Michael A. DeTure, Dennis W. Dickson, Rosa Rademakers

Published in: Acta Neuropathologica | Issue 2/2014

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Abstract

In order to determine the frequency of microtubule-associated protein tau gene (MAPT) mutations and rare variants in CBD, we performed a systematic sequence analysis of MAPT coding and 3′ untranslated region (3′UTR) in a large cohort of autopsy-confirmed CBD patients (N = 109). This identified a novel MAPT mutation in exon 13, p.N410H, in a case that is neuropathologically indistinguishable from sporadic CBD. On immunoblot, the p.N410H mutation carrier had the same insoluble tau profile as seen in CBD. Additionally, tau expression analysis in brain tissue found a significant increase in the 4R/3R tau mRNA ratio (P = 0.04), indicating that p.N410H disrupts tau isoform homeostasis. Biochemically, recombinant tau protein with p.N410H showed a marked increase in tau filament formation compared to wild-type tau (P < 0.001), had a 19.2 % decrease in rate of microtubule assembly (P < 0.05), and a 10.3 % reduction in the extent of total microtubule polymerization (P < 0.01). Sequence analysis of the complete MAPT 3′UTR in autopsy-confirmed CBD cases further identified two rare variants with nominally significant association with CBD. An ATC nucleotide insertion (“MAPTv8”) was found in 4.6 % of CBD patients compared to 1.2 % of controls (P = 0.031, OR = 3.71), and rs186977284 in 4.6 % CBD patients, but only 0.9 % of controls (P = 0.04, OR = 3.58). Rs186977284 was also present in 2.7 % of a large cohort of autopsy-confirmed PSP patients (N = 566) and only 0.9 % of an additional control series (P = 0.034, OR = 3.08), extending the association to PSP. Our findings show that mutations in MAPT can cause CBD and MAPT non-coding variants may increase the risk of complex 4R tauopathies.
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Metadata
Title
Novel mutation in MAPT exon 13 (p.N410H) causes corticobasal degeneration
Authors
Naomi Kouri
Yari Carlomagno
Matthew Baker
Amanda M. Liesinger
Richard J. Caselli
Zbigniew K. Wszolek
Leonard Petrucelli
Bradley F. Boeve
Joseph E. Parisi
Keith A. Josephs
Ryan J. Uitti
Owen A. Ross
Neill R. Graff-Radford
Michael A. DeTure
Dennis W. Dickson
Rosa Rademakers
Publication date
01-02-2014
Publisher
Springer Berlin Heidelberg
Published in
Acta Neuropathologica / Issue 2/2014
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI
https://doi.org/10.1007/s00401-013-1193-7

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