title: Different mutations at V363 MAPT codon are associated with atypical clinical phenotypes and show unusual structural and functional features.
abstract: 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 in vitro 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.
authors.affiliation: Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy. Electronic address: grossi@istituto-besta.it.
authors.forename: Giacomina
authors.initials: G
authors.lastname: Rossi
authors.forename: Antonio
authors.initials: A
authors.lastname: Bastone
authors.forename: Elena
authors.initials: E
authors.lastname: Piccoli
authors.forename: Michela
authors.initials: M
authors.lastname: Morbin
authors.forename: Giulia
authors.initials: G
authors.lastname: Mazzoleni
authors.forename: Valeria
authors.initials: V
authors.lastname: Fugnanesi
authors.forename: Marten
authors.initials: M
authors.lastname: Beeg
authors.forename: Elena
authors.initials: E
authors.lastname: Del Favero
authors.forename: Laura
authors.initials: L
authors.lastname: Cantù
authors.forename: Simona
authors.initials: S
authors.lastname: Motta
authors.forename: Ettore
authors.initials: E
authors.lastname: Salsano
authors.forename: Davide
authors.initials: D
authors.lastname: Pareyson
authors.forename: Alessandra
authors.initials: A
authors.lastname: Erbetta
authors.forename: Antonio Emanuele
authors.initials: AE
authors.lastname: Elia
authors.forename: Francesca
authors.initials: F
authors.lastname: Del Sorbo
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Silani
authors.forename: Claudia
authors.initials: C
authors.lastname: Morelli
authors.forename: Mario
authors.initials: M
authors.lastname: Salmona
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Tagliavini
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D003062:Codon / Q000235:genetics*; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D058105:Polymerization; D020033:Protein Isoforms; D024801:Tauopathies / Q000235:genetics; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D003062:Codon; C054369:MAPT protein, human; D020033:Protein Isoforms; D016875:tau Proteins
keywords: FTLD; Fibrils; Frontotemporal lobar degeneration; MAPT gene; Microtubules; Mutation; Oligomers; PCA; PNFA; PSP; Pathogenicity; Tau