Tau Gene Mutation G389R Causes a Tauopathy with Abundant Pick Body-like Inclusions and Axonal Deposits

• Published in: Journal of neuropathology and experimental neurology Vol. 58; no. 12; pp. 1207 - 1226
• Main Authors: Murrell, Jill R, Spillantini, Maria Grazia, Zolo, Paolo, Guazzelli, Mario, Smith, Michael J, Hasegawa, Masato, Redi, Francesco, Crowther, R Anthony, Pietrini, Pietro, Ghetti, Bernardino, Goedert, Michel
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Association of Neuropathologists, Inc 01.12.1999; Lippincott Williams & Wilkins; Oxford University Press
• Subjects: Adult; Axons - metabolism; Biological and medical sciences; Brain - metabolism; Brain - pathology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Frontotemporal dementia; Gene mutations; Genetic aspects; Humans; Immunohistochemistry; Inclusion Bodies - pathology; Magnetic Resonance Imaging; Male; Medical Records; Medical sciences; Microscopy, Electron; Microtubules - ultrastructure; Mutation - physiology; Neurodegenerative Diseases - diagnosis; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - metabolism; Neurodegenerative Diseases - pathology; Neurodegenerative Diseases - psychology; Neurology; Pedigree; tau Proteins - genetics; tau Proteins - metabolism; Human; Immunohistochemistry; Temporal lobe; Nervous system diseases; Frontal lobe; Family study; Nonsense mutation; Exploration; Cerebral disorder; Pick body; Pathology; Tau protein; Central nervous system disease; Degenerative disease; Dementia
• ISSN: 0022-3069; 1554-6578
• DOI: 10.1097/00005072-199912000-00002

Exonic and intronic mutations in Tou cause familial neurodegenerative syndromes characterized by frontotemporal dementia and dysfunction of multiple cortical and subcortical circuits. Here we describe a G389R mutation in exon 13 of Tau. When 38 years old, the proband presented with progressive aphasia and memory disturbance, followed by apathy, indifference, and hyperphagia. Repeated magnetic resonance imaging showed the dramatic progression of cerebral atrophy. Positron emission tomography revealed marked glucose hypometabolism that was most severe in left frontal, temporal, and parietal cortical regions. Rigidity, pyramidal signs and profound dementia progressed until death at 43 years of age. A paternal uncle, who had died at 43 years of age, had presented with similar symptoms. The probandʼs brain showed numerous tauimmunoreactive Pick body-like inclusions in the neocortex and the fascia dentata of the hippocampus. In addition, large numbers of tau-positive filamentous inclusions were present in axons in the frontal, temporal, and parietal lobes. Immunoblot analysis of sarkosyl-insoluble tau showed 2 major bands of 60 and 64 kDa. Upon dephosphorylation, these bands resolved into 4 bands consisting of three- and four-repeat tau isoforms. Most isolated tau filaments were straight and resembled filaments found in Alzheimer disease and some frontotemporal dementias with tau mutations. A smaller number of twisted filaments was also observed. Biochemically, recombinant tau proteins with the G389R mutation showed a reduced ability to promote microtubule assembly, suggesting that this may be the primary effect of the mutation. Taken together, the present findings indicate that the G389R mutation in Tou can cause a dementing condition that closely resembles Pickʼs disease.