title: A Novel Tau Mutation in Exon 12, p.Q336H, Causes Hereditary Pick Disease.
abstract: 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.
authors.affiliation: From the Departments of Neurology (PT, ZKW), Neuroscience (MD, KMH, W-LL, MS-C, YC, RR, OAR, DWD), and Psychiatry and Psychology (OP), Mayo Clinic Florida, Jacksonville, Florida.
authors.forename: Pawel
authors.initials: P
authors.lastname: Tacik
authors.forename: Michael
authors.initials: M
authors.lastname: DeTure
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Hinkle
authors.forename: Wen-Lang
authors.initials: WL
authors.lastname: Lin
authors.forename: Monica
authors.initials: M
authors.lastname: Sanchez-Contreras
authors.forename: Yari
authors.initials: Y
authors.lastname: Carlomagno
authors.forename: Otto
authors.initials: O
authors.lastname: Pedraza
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
authors.forename: Owen A
authors.initials: OA
authors.lastname: Ross
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
mesh_terms: D001921:Brain / Q000378:metabolism / Q000473:pathology; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics*; D018698:Glutamic Acid / Q000235:genetics*; D006639:Histidine / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020774:Pick Disease of the Brain / Q000235:genetics* / Q000473:pathology; D025801:Ubiquitin / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics*
chemical_list: C054369:MAPT protein, human; D025801:Ubiquitin; D051844:alpha-Synuclein; D016875:tau Proteins; D018698:Glutamic Acid; D006639:Histidine