title: New mutations in MAPT gene causing frontotemporal lobar degeneration: biochemical and structural characterization.
abstract: Frontotemporal lobar degeneration (FTLD) can be sporadic or familial. The genes encoding the microtubule-associated protein tau (MAPT) and progranulin (GRN) are the most relevant genes so far known causing the hereditary forms. Following genetic screening of patients affected by FTLD, we identified 2 new MAPT mutations, P364S and G366R, the former in a sporadic case. In the study we report the clinical and genetic features of the patients carrying these mutations, and the functional effects of the mutations, analyzed in vitro in order to investigate their pathogenic character. Both mutations resulted in reduced ability of tau to promote microtubule polymerization; the P364S protein variant also showed a high propensity to aggregate into filaments. These results suggest a high probability that these mutations are pathogenic. Our findings highlight the importance of genetic analysis also in sporadic forms of FTLD, and the role of in vitro studies to evaluate the pathologic features of new mutations.
authors.affiliation: Division of Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy. 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: Giulia
authors.initials: G
authors.lastname: Mazzoleni
authors.forename: Michela
authors.initials: M
authors.lastname: Morbin
authors.forename: Andrea
authors.initials: A
authors.lastname: Uggetti
authors.forename: Giorgio
authors.initials: G
authors.lastname: Giaccone
authors.forename: Sarah
authors.initials: S
authors.lastname: Sperber
authors.forename: Marten
authors.initials: M
authors.lastname: Beeg
authors.forename: Mario
authors.initials: M
authors.lastname: Salmona
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Tagliavini
mesh_terms: D000368:Aged; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005192:Family Health; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D007558:Italy; D008279:Magnetic Resonance Imaging; D008297:Male; D008870:Microtubules / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C054369:MAPT protein, human; D020033:Protein Isoforms; D016875:tau Proteins