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

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

Research output: Contribution to journalArticle

49 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)271-282
Number of pages12
JournalActa neuropathologica
Volume127
Issue number2
DOIs
StatePublished - Feb 2014

Keywords

  • Corticobasal degeneration
  • MAPT mutations
  • Microtubule-associated protein tau
  • Progressive supranuclear palsy
  • TDP-43
  • Tauopathy

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Fingerprint Dive into the research topics of 'Novel mutation in MAPT exon 13 (p.N410H) causes corticobasal degeneration'. Together they form a unique fingerprint.

  • Cite this