title: The MAPT p.A152T variant is a risk factor associated with tauopathies with atypical clinical and neuropathological features.
abstract: Microtubule-associated protein tau (MAPT) mutations have been shown to underlie frontotemporal dementia and a variety of additional sporadic tauopathies. We identified a rare p.A152T variant in MAPT exon 7 in two (of eight) patients with clinical presentation of parkinsonism and postmortem finding of neurofibrillary tangle pathology. Two siblings of one patient also carried the p.A152T variant, and both have progressive cognitive impairment. Further screening identified the variant in two other cases: one with pathologically confirmed corticobasal degeneration and another with the diagnosis of Parkinson's disease with dementia. The balance of evidence suggests this variant is associated with disease, but the very varied phenotype of the cases with the mutation is not consistent with it being a fully penetrant pathogenic mutation. Interestingly, this variation results in the creation of a new phosphorylation site that could cause reduced microtubule binding. We suggest that the A152T variant is a risk factor associated with the development of atypical neurodegenerative conditions with abnormal tau accumulation.
authors.affiliation: Reta Lila Weston Laboratories and Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK.
authors.forename: Eleanna
authors.initials: E
authors.lastname: Kara
authors.forename: Helen
authors.initials: H
authors.lastname: Ling
authors.forename: Alan M
authors.initials: AM
authors.lastname: Pittman
authors.forename: Karen
authors.initials: K
authors.lastname: Shaw
authors.forename: Rohan
authors.initials: R
authors.lastname: de Silva
authors.forename: Roberto
authors.initials: R
authors.lastname: Simone
authors.forename: Janice L
authors.initials: JL
authors.lastname: Holton
authors.forename: Jason D
authors.initials: JD
authors.lastname: Warren
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Rohrer
authors.forename: Georgia
authors.initials: G
authors.lastname: Xiromerisiou
authors.forename: Andrew
authors.initials: A
authors.lastname: Lees
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
authors.forename: Tamas
authors.initials: T
authors.lastname: Revesz
mesh_terms: D000369:Aged, 80 and over; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D006801:Humans; D008543:Melanins / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009422:Nervous System Diseases / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D016900:Neurofilament Proteins / Q000378:metabolism; D012307:Risk Factors; D024801:Tauopathies / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C054369:MAPT protein, human; D008543:Melanins; D016900:Neurofilament Proteins; C014121:neuromelanin; D016875:tau Proteins