TY - JOUR
T1 - A novel Tau Mutation in exon 12, P. Q336H, causes hereditary pick disease
AU - Tacik, Pawel
AU - DeTure, Michael
AU - Hinkle, Kelly M.
AU - Lin, Wen Lang
AU - Sanchez-Contreras, Monica
AU - Carlomagno, Yari
AU - Pedraza, Otto
AU - Rademakers, Rosa
AU - Ross, Owen A.
AU - Wszolek, Zbigniew K.
AU - Dickson, Dennis W.
N1 - Publisher Copyright:
Copyright © 2015 by the American Association of Neuropathologists, Inc.
PY - 2015
Y1 - 2015
N2 - Pick disease (PiD) is a frontotemporal lobar degeneration with distinctive neuronal inclusions (Pick bodies) that are enriched in 3-repeat (3R) tau. Although mostly sporadic, mutations in the tau gene (MAPT) have been reported. We screened 24 cases of neuropathologically confirmed PiD for MAPT mutations and found a novel mutation (c. 1008G>C, p. Q336H) in 1 patient. Pathogenicity was confirmed on microtubule assembly and tau filament formation assays. The patient was compared with sporadic PiD and PiD associated with MAPT mutations from a review of the literature. The patient had behavioral changes at 55 years of age, followed by reduced verbal fluency, parkinsonism, and death at 63 years of age. His mother and maternal uncle had similar symptoms. Recombinant tau with p. Q336H mutation formed filaments faster than wild-type tau, especially with 3R tau. It also promoted more microtubule assembly than wild-type tau. We conclude that mutations in MAPT, including p. Q336H, can be associated with clinical, pathologic, and biochemical features that are similar to those in sporadic PiD. The pathomechanism of p. Q336H, and another previously reported variant at the same codon (p. Q336R), seems to be unique to MAPT mutations in that they not only predispose to abnormal tau filament formation but also facilitate microtubule assembly in a 3R tau-dependent manner.
AB - Pick disease (PiD) is a frontotemporal lobar degeneration with distinctive neuronal inclusions (Pick bodies) that are enriched in 3-repeat (3R) tau. Although mostly sporadic, mutations in the tau gene (MAPT) have been reported. We screened 24 cases of neuropathologically confirmed PiD for MAPT mutations and found a novel mutation (c. 1008G>C, p. Q336H) in 1 patient. Pathogenicity was confirmed on microtubule assembly and tau filament formation assays. The patient was compared with sporadic PiD and PiD associated with MAPT mutations from a review of the literature. The patient had behavioral changes at 55 years of age, followed by reduced verbal fluency, parkinsonism, and death at 63 years of age. His mother and maternal uncle had similar symptoms. Recombinant tau with p. Q336H mutation formed filaments faster than wild-type tau, especially with 3R tau. It also promoted more microtubule assembly than wild-type tau. We conclude that mutations in MAPT, including p. Q336H, can be associated with clinical, pathologic, and biochemical features that are similar to those in sporadic PiD. The pathomechanism of p. Q336H, and another previously reported variant at the same codon (p. Q336R), seems to be unique to MAPT mutations in that they not only predispose to abnormal tau filament formation but also facilitate microtubule assembly in a 3R tau-dependent manner.
KW - Dementia
KW - FTDP-17
KW - FTLD-tau
KW - Frontotemporal dementia
KW - Pick disease
KW - Tau gene
KW - Tau protein
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U2 - 10.1097/NEN.0000000000000248
DO - 10.1097/NEN.0000000000000248
M3 - Article
C2 - 26426266
AN - SCOPUS:84945194766
SN - 0022-3069
VL - 74
SP - 1042
EP - 1052
JO - Journal of Neuropathology and Experimental Neurology
JF - Journal of Neuropathology and Experimental Neurology
IS - 11
ER -