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Tau gene mutation in familial progressive subcortical gliosis

Nature Medicine volume 5, pages 454–457 (1999)Cite this article

Abstract

Familial forms of frontotemporal dementias are associated with mutations in the tau gene. A kindred affected by progressive subcortical gliosis (PSG), a rare form of presenile dementia, has genetic linkage to chromosome 17q21-22 (refs. 1,2, 3). This kindred (PSG-1) is included in the 'frontotemporal dementias and Parkinsonism linked to chromosome 17' group along with kindreds affected by apparently different forms of atypical dementias4. Some of these kindreds have mutations in the tau gene5,6,7,8,9,10. We report here that PSG-1 has a tau mutation at position +16 of the intron after exon 10. The mutation destabilizes a predicted stem–loop structure and leads to an over-representation of the soluble four-repeat tau isoforms, which assemble into wide, twisted, ribbon-like filaments and ultimately result in abundant neuronal and glial tau pathology. The mutations associated with PSG and other atypical dementias can be subdivided into three groups according to their tau gene locations and effects on tau. The existence of tau mutations with distinct pathogenetic mechanisms may explain the phenotypic heterogeneity of atypical dementias that previously led to their classification into separate disease entities.

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Figure 1: Tau immunostaining of neurons and glial cells.
Figure 2: Abnormal tau filaments.
Figure 3: Insoluble and soluble tau from control and familial subcortical gliosis (PSG) brains.

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Acknowledgements

The authors wish to thank R. Currier for providing the PSG 1 family and making autopsy tissue available, and D. Kofskey for technical assistance. Support for this work was provided by grants from the US National Institute of Health and by the Britton Fund as well as by the UK Medical Research Council (M.G., M.G.S. and R.A.C.), the Metropolitan Life Foundation (M.G.) and The Royal Society of London (M.G.S.).

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Authors and Affiliations

  1. Medical Research Council Laboratory of Molecular Biology , Hills Road, Cambridge, CB2 2QH, UK

    M. Goedert & R.A. Crowther

  2. Department of Neurology, Adrian Building, University of Cambridge, Cambridge, CB2 2PY, UK

    M.G. Spillantini

  3. Division of Neuropathology, Case Western Reserve University Cleveland, Ohio, 44106, USA

    S.G. Chen, P. Parchi, R.B. Petersen & P. Gambetti

  4. Institute of Neurology, University of Genova, Genova, 16132, Italy

    M. Tabaton

  5. Veterans Affairs Medical Center, Great Lakes Health Care System, Tomah, 54660, Wisconsin, USA

    D.J. Lanska

  6. Department of Neurology, University of Wisconsin, Madison, Wisconsin, 53792, USA

    D.J. Lanska

  7. Department of Neurology and Pathology, University of Kentucky, 101 Sanders Bldg., Lexington, 40536, Kentucky, USA

    W.R. Markesbery

  8. University of California, Gallo Center, San Francisco General Hospital, San Francisco, 94110, California, USA

    K.C. Wilhelmsen

  9. Neuropathology Laboratory, Mayo Clinic Jacksonville , Birdsall Research Bldg., Jacksonville, 32224, Florida, USA

    D.W. Dickson

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Goedert, M., Spillantini, M., Crowther, R. et al. Tau gene mutation in familial progressive subcortical gliosis . Nat Med 5, 454–457 (1999). https://doi.org/10.1038/7454

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