Tau pathology in a family with dementia and a P301L mutation in tau

Suzanne S. Mirra, Jill R. Murrell, Marla Gearing, Maria G. Spillantini, Michel Goedert, R. Anthony Crowther, Allan I. Levey, Randi Jones, Joanne Green, John M. Shoffner, Bruce H. Wainer, Marie L. Schmidt, John Q. Trojanowski, Bernardino Ghetti

Research output: Contribution to journalArticle

149 Citations (Scopus)

Abstract

Familial forms of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) have recently been associated with coding region and intronic mutations in the tau gene. Here we report our findings on 2 affected siblings from a family with early-onset dementia, characterized by extensive tau pathology and a Pro to Leu mutation at codon 301 of tau. The proband, a 55-year-old woman, and her 63-year-old brother died after a progressive dementing illness clinically diagnosed as Alzheimer disease. Their mother, 2 sisters, maternal aunt and uncle, and several cousins were also affected. Autopsy in both cases revealed frontotemporal atrophy and degeneration of basal ganglia and substantia nigra. Sequencing of exon 10 of the tau gene revealed a C to T transition at codon 301, resulting in a Pro to Leu substitution. Widespread neuronal and glial inclusions, neuropil threads, and astrocytic plaques similar to those seen in corticobasal degeneration were labeled with a battery of antibodies to phosphorylation-dependent and phosphorylation-independent epitopes spanning the entire tau sequence. Isolated tau filaments had the morphology of narrow twisted ribbons. Sarkosyl-insoluble tau exhibited 2 major bands of 64 and 68 kDa and a minor 72 kDa band, similar to the pattern seen in a familial tauopathy associated with an intronic tau mutation. These pathological tau bands predominantly contained the subset of tau isoforms with 4 microtubule-binding repeats selectively affected by the P301L missense mutation. Our findings emphasize the phenotypic and genetic heterogeneity of tauopathies and highlight intriguing links between FTDP-17 and other neurodegenerative diseases.

Original languageEnglish
Pages (from-to)335-345
Number of pages11
JournalJournal of Neuropathology and Experimental Neurology
Volume58
Issue number4
StatePublished - Apr 1999

Fingerprint

Tauopathies
Dementia
Siblings
Frontotemporal Dementia
Chromosomes, Human, Pair 17
Parkinsonian Disorders
Pathology
Codon
Mutation
Neuropil Threads
Phosphorylation
Mothers
Genetic Heterogeneity
Substantia Nigra
Missense Mutation
Basal Ganglia
Microtubules
Neuroglia
Neurodegenerative Diseases
Genes

Keywords

  • Corticobasal degeneration
  • Dementia
  • Frontotemporal dementia with parkinsonism
  • Mutation
  • Tau

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neuroscience(all)

Cite this

Mirra, S. S., Murrell, J. R., Gearing, M., Spillantini, M. G., Goedert, M., Crowther, R. A., ... Ghetti, B. (1999). Tau pathology in a family with dementia and a P301L mutation in tau. Journal of Neuropathology and Experimental Neurology, 58(4), 335-345.

Tau pathology in a family with dementia and a P301L mutation in tau. / Mirra, Suzanne S.; Murrell, Jill R.; Gearing, Marla; Spillantini, Maria G.; Goedert, Michel; Crowther, R. Anthony; Levey, Allan I.; Jones, Randi; Green, Joanne; Shoffner, John M.; Wainer, Bruce H.; Schmidt, Marie L.; Trojanowski, John Q.; Ghetti, Bernardino.

In: Journal of Neuropathology and Experimental Neurology, Vol. 58, No. 4, 04.1999, p. 335-345.

Research output: Contribution to journalArticle

Mirra, SS, Murrell, JR, Gearing, M, Spillantini, MG, Goedert, M, Crowther, RA, Levey, AI, Jones, R, Green, J, Shoffner, JM, Wainer, BH, Schmidt, ML, Trojanowski, JQ & Ghetti, B 1999, 'Tau pathology in a family with dementia and a P301L mutation in tau', Journal of Neuropathology and Experimental Neurology, vol. 58, no. 4, pp. 335-345.
Mirra SS, Murrell JR, Gearing M, Spillantini MG, Goedert M, Crowther RA et al. Tau pathology in a family with dementia and a P301L mutation in tau. Journal of Neuropathology and Experimental Neurology. 1999 Apr;58(4):335-345.
Mirra, Suzanne S. ; Murrell, Jill R. ; Gearing, Marla ; Spillantini, Maria G. ; Goedert, Michel ; Crowther, R. Anthony ; Levey, Allan I. ; Jones, Randi ; Green, Joanne ; Shoffner, John M. ; Wainer, Bruce H. ; Schmidt, Marie L. ; Trojanowski, John Q. ; Ghetti, Bernardino. / Tau pathology in a family with dementia and a P301L mutation in tau. In: Journal of Neuropathology and Experimental Neurology. 1999 ; Vol. 58, No. 4. pp. 335-345.
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