title: A novel tau mutation, p.K317N, causes globular glial tauopathy.
abstract: Globular glial tauopathies (GGTs) are 4-repeat tauopathies neuropathologically characterized by tau-positive, globular glial inclusions, including both globular oligodendroglial inclusions and globular astrocytic inclusions. No mutations have been found in 25 of the 30 GGT cases reported in the literature who have been screened for mutations in microtubule associated protein tau (MAPT). In this report, six patients with GGT (four with subtype III and two with subtype I) were screened for MAPT mutations. They included 4 men and 2 women with a mean age at death of 73 years (55-83 years) and mean age at symptomatic onset of 66 years (50-77 years). Disease duration ranged from 5 to 14 years. All were homozygous for the MAPT H1 haplotype. Three patients had a positive family history of dementia, and a novel MAPT mutation (c.951G>C, p.K317N) was identified in one of them, a patient with subtype III. Recombinant tau protein bearing the lysine-to-asparagine substitution at amino acid residue 317 was used to assess functional significance of the variant on microtubule assembly and tau filament formation. Recombinant p.K317N tau had reduced ability to promote tubulin polymerization. Recombinant 3R and 4R tau bearing the p.K317N mutation showed decreased 3R tau and increased 4R tau filament assembly. These results strongly suggest that the p.K317N variant is pathogenic. Sequencing of MAPT should be considered in patients with GGT and a family history of dementia or movement disorder. Since several individuals in our series had a positive family history but no MAPT mutation, genetic factors other than MAPT may play a role in disease pathogenesis.
authors.affiliation: Department of Neurology, Mayo Clinic, Jacksonville, USA.
authors.forename: Pawel
authors.initials: P
authors.lastname: Tacik
authors.forename: Michael
authors.initials: M
authors.lastname: DeTure
authors.forename: Wen-Lang
authors.initials: WL
authors.lastname: Lin
authors.forename: Monica
authors.initials: M
authors.lastname: Sanchez Contreras
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Wojtas
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Hinkle
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Fujioka
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Baker
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Walton
authors.forename: Yari
authors.initials: Y
authors.lastname: Carlomagno
authors.forename: Patricia H
authors.initials: PH
authors.lastname: Brown
authors.forename: Audrey J
authors.initials: AJ
authors.lastname: Strongosky
authors.forename: Naomi
authors.initials: N
authors.lastname: Kouri
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Murray
authors.forename: Leonard
authors.initials: L
authors.lastname: Petrucelli
authors.forename: Keith A
authors.initials: KA
authors.lastname: Josephs
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: D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000378:metabolism / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D064347:Microscopy, Electrochemical, Scanning; D008870:Microtubules / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D058105:Polymerization; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D024801:Tauopathies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014404:Tubulin / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism
chemical_list: C054369:MAPT protein, human; D011994:Recombinant Proteins; D014404:Tubulin; D016875:tau Proteins