A novel tau mutation, p.K317N, causes globular glial tauopathy
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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.
KeywordsFTDP-17 Globular glial tauopathy (GGT) Hereditary tauopathies Tau biochemistry Tau gene (MAPT)
This study was supported by the NIH P50 NS072187 (DWD, ZKW, OAR, RR, AJS), the Max Kade Foundation (PT), NIH R01 NS078086 (OAR), NIH R01 NS080882 (RR), NIH R01 NS065782 (RR), NIH R01 AG026251 (RR), NIH P50 AG16574 (RR), the ALS Therapy Alliance (RR), the Consortium for Frontotemporal Degeneration Research (RR), the NIH R01 DC010367 (KAJ), the NIH R01 AG037491 (KAJ), the NIH R01 DC012519 (KAJ), and the Alzheimer’s Association (KAJ), the Mayo Clinic Foundation (LP), the NIH P50 AG016574 (LP), the NIH R01 NS089544-1 (LP), the BrightFocus Foundation (LP), the gift from Carl Edward Bolch, Jr., and Susan Bass Bolch Foundation (SF, ZKW). We are grateful to all patients, family members, and caregivers who agreed to brain donation; without their donation these studies would have been impossible. We also acknowledge expert technical assistance of Linda Rousseau and Virginia Phillips for histology and Monica Castanedes-Casey for immunohistochemistry.
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