A novel tau mutation, p.K317N, causes globular glial tauopathy

Pawel Tacik, Michael Deture, Wen Lang Lin, Monica Sanchez Contreras, Aleksandra Wojtas, Kelly M. Hinkle, Shinsuke Fujioka, Matthew C. Baker, Ronald L. Walton, Yari Carlomagno, Patricia H. Brown, Audrey J. Strongosky, Naomi Kouri, Melissa E Murray, Leonard Petrucelli, Keith Anthony Josephs, Rosa V Rademakers, Owen A Ross, Zbigniew K Wszolek, Dennis W Dickson

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)199-214
Number of pages16
JournalActa Neuropathologica
Volume130
Issue number2
DOIs
StatePublished - Apr 22 2015

Fingerprint

Tauopathies
Microtubule-Associated Proteins
Neuroglia
Mutation
Dementia
tau Proteins
Aptitude
Asparagine
Movement Disorders
Amino Acid Substitution
Tubulin
Age of Onset
Recombinant Proteins
Microtubules
Polymerization
Haplotypes
Lysine

Keywords

  • FTDP-17
  • Globular glial tauopathy (GGT)
  • Hereditary tauopathies
  • Tau biochemistry
  • Tau gene (MAPT)

ASJC Scopus subject areas

  • Clinical Neurology
  • Pathology and Forensic Medicine
  • Cellular and Molecular Neuroscience

Cite this

A novel tau mutation, p.K317N, causes globular glial tauopathy. / Tacik, Pawel; Deture, Michael; Lin, Wen Lang; Sanchez Contreras, Monica; Wojtas, Aleksandra; Hinkle, Kelly M.; Fujioka, Shinsuke; Baker, Matthew C.; Walton, Ronald L.; Carlomagno, Yari; Brown, Patricia H.; Strongosky, Audrey J.; Kouri, Naomi; Murray, Melissa E; Petrucelli, Leonard; Josephs, Keith Anthony; Rademakers, Rosa V; Ross, Owen A; Wszolek, Zbigniew K; Dickson, Dennis W.

In: Acta Neuropathologica, Vol. 130, No. 2, 22.04.2015, p. 199-214.

Research output: Contribution to journalArticle

Tacik, P, Deture, M, Lin, WL, Sanchez Contreras, M, Wojtas, A, Hinkle, KM, Fujioka, S, Baker, MC, Walton, RL, Carlomagno, Y, Brown, PH, Strongosky, AJ, Kouri, N, Murray, ME, Petrucelli, L, Josephs, KA, Rademakers, RV, Ross, OA, Wszolek, ZK & Dickson, DW 2015, 'A novel tau mutation, p.K317N, causes globular glial tauopathy', Acta Neuropathologica, vol. 130, no. 2, pp. 199-214. https://doi.org/10.1007/s00401-015-1425-0
Tacik P, Deture M, Lin WL, Sanchez Contreras M, Wojtas A, Hinkle KM et al. A novel tau mutation, p.K317N, causes globular glial tauopathy. Acta Neuropathologica. 2015 Apr 22;130(2):199-214. https://doi.org/10.1007/s00401-015-1425-0
Tacik, Pawel ; Deture, Michael ; Lin, Wen Lang ; Sanchez Contreras, Monica ; Wojtas, Aleksandra ; Hinkle, Kelly M. ; Fujioka, Shinsuke ; Baker, Matthew C. ; Walton, Ronald L. ; Carlomagno, Yari ; Brown, Patricia H. ; Strongosky, Audrey J. ; Kouri, Naomi ; Murray, Melissa E ; Petrucelli, Leonard ; Josephs, Keith Anthony ; Rademakers, Rosa V ; Ross, Owen A ; Wszolek, Zbigniew K ; Dickson, Dennis W. / A novel tau mutation, p.K317N, causes globular glial tauopathy. In: Acta Neuropathologica. 2015 ; Vol. 130, No. 2. pp. 199-214.
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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.",
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AU - Hinkle, Kelly M.

AU - Fujioka, Shinsuke

AU - Baker, Matthew C.

AU - Walton, Ronald L.

AU - Carlomagno, Yari

AU - Brown, Patricia H.

AU - Strongosky, Audrey J.

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AU - Murray, Melissa E

AU - Petrucelli, Leonard

AU - Josephs, Keith Anthony

AU - Rademakers, Rosa V

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