Journal
ACTA NEUROPATHOLOGICA
Volume 127, Issue 2, Pages 271-282Publisher
SPRINGER
DOI: 10.1007/s00401-013-1193-7
Keywords
Corticobasal degeneration; Progressive supranuclear palsy; Tauopathy; Microtubule-associated protein tau; TDP-43; MAPT mutations
Categories
Funding
- Irene and Abe Pollin Fund for CBD
- Mayo Foundation (Jacoby Professorship of Alzheimer Research)
- NIH [P50-AG016574, P50-NS072187, P01-AG003949, R01-AG037491, R01-DC010367]
- CurePSP
- NINDS [NS078086, P50 NS072187]
- NIH/NINDS [P50 NS072187]
- Mayo Clinic Center for Regenerative Medicine
- Dystonia Medical Research Foundation
- The Michael J. Fox Foundation for Parkinson's Research
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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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