title: A novel MAPT mutation associated with the clinical phenotype of progressive nonfluent aphasia.
abstract: A number of mutations in microtubule associated protein tau gene (MAPT), causing frontotemporal lobar degeneration (FTLD) with tau pathology, are located in the four-repeated microtubule (MT) binding domains and affect the ability of tau to bind MTs. Here, we describe a novel variant lying in the second MT domain, found in a female patient diagnosed clinically with progressive nonfluent aphasia (PNFA), with a positive family history for dementia. At 65 years, she started developing progressive language deficits, characterized by expression difficulties and word coordination impairment. She came to our attention at 67 years. Her MMSE score was 22/30. A Brain CT scan showed mild diffuse cortical atrophy, ventricles' asymmetry (left > right), and very mild signs of chronic vasculopathy. Cerebrospinal fluid analysis showed normal amyloid-β₄₂, tau, and P-tau levels. She was diagnosed with PNFA according to current diagnostic criteria. A novel exon 10 MAPT variant was identified (g.123798G > A), which leads to an amino acidic change (p.Gly304Ser) in the second MT microtubule binding domain. In silico analysis predicted that this variant is damaging on protein structure and function. Additional 168 FTLD patients and 503 controls screened (1342 chromosomes) did not carry the variant, suggesting that it is a mutation rather than a polymorphism. The amino acid change likely compromises the ability of tau to properly regulate the dynamic behavior of microtubules.
authors.affiliation: Department of Neurological Sciences, University of Milan, IRCCS Fondazione Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Villa
authors.forename: Laura
authors.initials: L
authors.lastname: Ghezzi
authors.forename: Anna M
authors.initials: AM
authors.lastname: Pietroboni
authors.forename: Chiara
authors.initials: C
authors.lastname: Fenoglio
authors.forename: Francesca
authors.initials: F
authors.lastname: Cortini
authors.forename: Maria
authors.initials: M
authors.lastname: Serpente
authors.forename: Claudia
authors.initials: C
authors.lastname: Cantoni
authors.forename: Elisa
authors.initials: E
authors.lastname: Ridolfi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Marcone
authors.forename: Luisa
authors.initials: L
authors.lastname: Benussi
authors.forename: Roberta
authors.initials: R
authors.lastname: Ghidoni
authors.forename: Francesca
authors.initials: F
authors.lastname: Jacini
authors.forename: Andrea
authors.initials: A
authors.lastname: Arighi
authors.forename: Giorgio G
authors.initials: GG
authors.lastname: Fumagalli
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mandelli
authors.forename: Giuliano
authors.initials: G
authors.lastname: Binetti
authors.forename: Stefano
authors.initials: S
authors.lastname: Cappa
authors.forename: Nereo
authors.initials: N
authors.lastname: Bresolin
authors.forename: Elio
authors.initials: E
authors.lastname: Scarpini
authors.forename: Daniela
authors.initials: D
authors.lastname: Galimberti
mesh_terms: D000368:Aged; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008609:Mental Status Schedule; D009483:Neuropsychological Tests; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D057178:Primary Progressive Nonfluent Aphasia / Q000235:genetics* / Q000473:pathology; D000077153:Progranulins; D014057:Tomography, X-Ray Computed / Q000379:methods; D016875:tau Proteins / Q000235:genetics*
chemical_list: C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; C054369:MAPT protein, human; D000077153:Progranulins; D016875:tau Proteins