Different mutations at V363 MAPT codon are associated with atypical clinical phenotypes and show unusual structural and functional features

Giacomina Rossi, Antonio Bastone, Elena Piccoli, Michela Morbin, Giulia Mazzoleni, Valeria Fugnanesi, Marten Beeg, Elena Del Favero, Laura Cantù, Simona Motta, Ettore Salsano, Davide Pareyson, Alessandra Erbetta, Antonio Emanuele Elia, Francesca Del Sorbo, Vincenzo Silani, Claudia Morelli, Mario Salmona, Fabrizio Tagliavini

Research output: Contribution to journalArticlepeer-review


Microtubule-associated protein tau gene ( MAPT) is one of the major genes linked to frontotemporal lobar degeneration, a group of neurodegenerative diseases clinically, pathologically, and genetically heterogeneous. In particular, MAPT mutations give rise to the subgroup of tauopathies. The pathogenetic mechanisms underlying the MAPT mutations so far described are the decreased ability of tau protein to promote microtubule polymerization (missense mutations) or the altered ratio of tau isoforms (splicing mutations), both leading to accumulation of hyperphosphorylated filamentous tau protein. Following a genetic screening of patients affected by frontotemporal lobar degeneration, we identified 2 MAPT mutations, V363I and V363A, leading to atypical clinical phenotypes, such as posterior cortical atrophy. We investigated invitro features of the recombinant mutated tau isoforms and revealed unusual functional and structural characteristics such as an increased ability to promote microtubule polymerization and a tendency to form oligomeric instead of filamentous aggregates. Thus, we disclosed a greater than expected complexity of abnormal features of mutated tau isoforms. Overall our findings suggest a high probability that these mutations are pathogenic.

Original languageEnglish
Pages (from-to)408-417
Number of pages10
JournalNeurobiology of Aging
Issue number2
Publication statusPublished - Feb 2014


  • Fibrils
  • Frontotemporal lobar degeneration
  • FTLD
  • MAPT gene
  • Microtubules
  • Mutation
  • Oligomers
  • Pathogenicity
  • PCA
  • PNFA
  • PSP
  • Tau

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)
  • Ageing
  • Developmental Biology
  • Geriatrics and Gerontology


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