TY - JOUR
T1 - A novel MAPT mutation associated with the clinical phenotype of progressive nonfluent aphasia
AU - Villa, Chiara
AU - Ghezzi, Laura
AU - Pietroboni, Anna M.
AU - Fenoglio, Chiara
AU - Cortini, Francesca
AU - Serpente, Maria
AU - Cantoni, Claudia
AU - Ridolfi, Elisa
AU - Marcone, Alessandra
AU - Benussi, Luisa
AU - Ghidoni, Roberta
AU - Jacini, Francesca
AU - Arighi, Andrea
AU - Fumagalli, Giorgio G.
AU - Mandelli, Alessandra
AU - Binetti, Giuliano
AU - Cappa, Stefano
AU - Bresolin, Nereo
AU - Scarpini, Elio
AU - Galimberti, Daniela
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
KW - MAPT
KW - frontotemporal lobar degeneration (FTLD)
KW - mutation
KW - phenotype
KW - progressive nonfluent aphasia (PNFA)
UR - http://www.scopus.com/inward/record.url?scp=80052841914&partnerID=8YFLogxK
U2 - 10.3233/JAD-2011-102124
DO - 10.3233/JAD-2011-102124
M3 - Article
C2 - 21558644
AN - SCOPUS:80052841914
SN - 1387-2877
VL - 26
SP - 19
EP - 26
JO - Journal of Alzheimer's Disease
JF - Journal of Alzheimer's Disease
IS - 1
ER -