Acta Neuropathologica

, Volume 130, Issue 2, pp 199–214 | Cite as

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 A. Josephs
  • Rosa Rademakers
  • Owen A. Ross
  • Zbigniew K. Wszolek
  • Dennis W. Dickson
Original Paper

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.

Keywords

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

Supplementary material

401_2015_1425_MOESM1_ESM.tif (7.4 mb)
Supplementary material 1 (TIFF 7578 kb) Fig. 1 Pathologic characterization of 6 GGT cases with of phospho-tau (CP13) and 4R tau (RD4) tau immunohistochemistry as well as Gallyas sliver stain of the most severely affected areas of the white and gray matter, including motor cortex (case 1, subtype III; case 5, subtype III; case 6, subtype III), temporal lobe (case 2, subtype I; case 4, subtype I), and superior frontal gyrus (case 3, subtype III). Scale bar = 20 µm
401_2015_1425_MOESM2_ESM.tif (4.7 mb)
Supplementary material 2 (TIFF 4841 kb) Fig. 2 Chromatogram of novel MAPT p.K317N mutation. The arrow indicates the mutation site within exon 11 of MAPT
401_2015_1425_MOESM3_ESM.tif (465 kb)
Supplementary material 3 (TIFF 464 kb) Fig 3 (a) Effects of 4R0N p.K317N on aggregation. Tau aggregation induced by incubation of recombinant tau with dextran sulfate. Aggregation is 10% greater in 4R0N p.K317N (gray bars) than 4R0N (black bars) at 2 hours, but not different at 20 hours. (*p < 0.01); (b) Effects of 4R0N p.K317N on misfolding assessed by thioflavin S fluorescence. Tau misfolding is less in 4R0N p.K317N (gray bars), compared to 4R0N (black bars) at both 2 and 20 hours. (*p < 0.05)
401_2015_1425_MOESM4_ESM.tif (23.1 mb)
Supplementary material 4 (TIFF 23686 kb) Fig 4 Electron micrographs of recombinant 4R0N filaments (4R WT) and 4R0N p.K317N (4R K317N) at 1 hour. The scale bar = 200 nm

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Pawel Tacik
    • 1
  • Michael DeTure
    • 2
  • Wen-Lang Lin
    • 2
  • Monica Sanchez Contreras
    • 2
  • Aleksandra Wojtas
    • 2
  • Kelly M. Hinkle
    • 2
  • Shinsuke Fujioka
    • 1
    • 4
  • Matthew C. Baker
    • 2
  • Ronald L. Walton
    • 2
  • Yari Carlomagno
    • 2
  • Patricia H. Brown
    • 2
  • Audrey J. Strongosky
    • 1
  • Naomi Kouri
    • 2
  • Melissa E. Murray
    • 2
  • Leonard Petrucelli
    • 2
  • Keith A. Josephs
    • 3
  • Rosa Rademakers
    • 2
  • Owen A. Ross
    • 2
  • Zbigniew K. Wszolek
    • 1
  • Dennis W. Dickson
    • 2
  1. 1.Department of NeurologyMayo ClinicJacksonvilleUSA
  2. 2.Department of NeuroscienceMayo ClinicJacksonvilleUSA
  3. 3.Department of NeurologyMayo ClinicRochesterUSA
  4. 4.Department of NeurologyFukuoka UniversityFukuokaJapan

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