A Novel MAPT Mutation Associated with the Clinical Phenotype of Progressive Nonfluent Aphasia

Article type: Research Article

Authors: Villa, Chiara^a | Ghezzi, Laura^a | Pietroboni, Anna M.^a | Fenoglio, Chiara^a | Cortini, Francesca^a | Serpente, Maria^a | Cantoni, Claudia^a | Ridolfi, Elisa^a | Marcone, Alessandra^b | Benussi, Luisa^c | Ghidoni, Roberta^{c; d} | Jacini, Francesca^a | Arighi, Andrea^a | Fumagalli, Giorgio G.^a | Mandelli, Alessandra^a | Binetti, Giuliano^c | Cappa, Stefano^{b; e} | Bresolin, Nereo^a | Scarpini, Elio^a | Galimberti, Daniela^{a; *}

Affiliations: [a] Department of Neurological Sciences, University of Milan, IRCCS Fondazione Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy | [b] Division of Neurology, San Raffaele Turro Hospital, San Raffaele Scientific Institute, Milan, Italy | [c] NeuroBioGen-Lab-Memory Clinic, IRCCS Centro S. Giovanni di Dio-FBF, Brescia, Italy | [d] Proteomics Unit, IRCCS Centro S. Giovanni di Dio-FBF, Brescia, Italy | [e] Vita-Salute San Raffaele University, Milan, Italy

Correspondence: [*] Correspondence to: Daniela Galimberti, Tel.: + 39 2 55033847; Fax: + 39 2 50320430; E-mail: daniela.galimberti@unimi.it.

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.

Keywords: frontotemporal lobar degeneration (FTLD), MAPT, mutation, phenotype, progressive nonfluent aphasia (PNFA)

DOI: 10.3233/JAD-2011-102124

Journal: Journal of Alzheimer's Disease, vol. 26, no. 1, pp. 19-26, 2011