A novel MAPT mutation associated with the clinical phenotype of progressive nonfluent aphasia
Document Type
Article
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.
Medical Subject Headings
Aged; Brain (diagnostic imaging, pathology); DNA Mutational Analysis; Family Health; Female; Humans; Intercellular Signaling Peptides and Proteins (genetics); Male; Mental Status Schedule; Neuropsychological Tests; Phenotype; Polymorphism, Single Nucleotide (genetics); Primary Progressive Nonfluent Aphasia (genetics, pathology); Progranulins; Tomography, X-Ray Computed (methods); tau Proteins (genetics)
Publication Date
1-1-2011
Publication Title
Journal of Alzheimer's disease : JAD
E-ISSN
1875-8908
Volume
26
Issue
1
First Page
19
Last Page
26
PubMed ID
21558644
Digital Object Identifier (DOI)
10.3233/JAD-2011-102124
Recommended Citation
Villa, Chiara; Ghezzi, Laura; Pietroboni, Anna M.; Fenoglio, Chiara; Cortini, Francesca; Serpente, Maria; Cantoni, Claudia; Ridolfi, Elisa; Marcone, Alessandra; Benussi, Luisa; Ghidoni, Roberta; Jacini, Francesca; Arighi, Andrea; Fumagalli, Giorgio G.; Mandelli, Alessandra; Binetti, Giuliano; Cappa, Stefano; Bresolin, Nereo; Scarpini, Elio; and Galimberti, Daniela, "A novel MAPT mutation associated with the clinical phenotype of progressive nonfluent aphasia" (2011). Translational Neuroscience. 2318.
https://scholar.barrowneuro.org/neurobiology/2318