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

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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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Acknowledgments

The authors would like to thank the patients and their families for support of this research. We would also like to thank Mariely De Jesus-Hernandez for sequencing assistance, Monica Castanedes Casey, Linda Rousseau, and Virginia Phillips for histological and immunohistochemistry assistance, and Beth Marten for logistic and administrative support in collecting material for this study. This work was funded by the Irene and Abe Pollin Fund for CBD. DWD is supported by the Mayo Foundation (Jacoby Professorship of Alzheimer Research) and NIH grants: P50-AG016574, P50-NS072187 and P01-AG003949. The Society for Progressive Supranuclear Palsy Brain Bank is supported by CurePSP. OAR is supported by NINDS NS078086 and P50 NS072187. ZKW is partially supported by the NIH/NINDS P50 NS072187, Mayo Clinic Center for Regenerative Medicine, Dystonia Medical Research Foundation, The Michael J. Fox Foundation for Parkinson’s Research, and the gift from Carl Edward Bolch, Jr. and Susan Bass Bolch. KAJ is supported by the NIH grants R01-AG037491 and R01-DC010367.

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Authors and Affiliations

  1. Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA

    Naomi Kouri, Yari Carlomagno, Matthew Baker, Amanda M. Liesinger, Leonard Petrucelli, Owen A. Ross, Michael A. DeTure, Dennis W. Dickson & Rosa Rademakers

  2. Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA

    Naomi Kouri

  3. Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA

    Richard J. Caselli

  4. Department of Neurology, Mayo Clinic, Jacksonville, FL, USA

    Zbigniew K. Wszolek, Ryan J. Uitti & Neill R. Graff-Radford

  5. Department of Neurology, Mayo Clinic, Rochester, MN, USA

    Bradley F. Boeve & Keith A. Josephs

  6. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

    Joseph E. Parisi

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  1. Naomi Kouri
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Correspondence to Rosa Rademakers.

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Kouri, N., Carlomagno, Y., Baker, M. et al. Novel mutation in MAPT exon 13 (p.N410H) causes corticobasal degeneration. Acta Neuropathol 127, 271–282 (2014). https://doi.org/10.1007/s00401-013-1193-7

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  • DOI: https://doi.org/10.1007/s00401-013-1193-7

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