Nature Medicine
5, 454 - 457 (1999)
doi:10.1038/7454
Tau gene mutation in familial progressive subcortical gliosis
M. Goedert1, M.G. Spillantini2, R.A. Crowther1, S.G. Chen3, P. Parchi3, M. Tabaton4, D.J. Lanska5, W.R. Markesbery6, K.C. Wilhelmsen7, D.W. Dickson8, R.B. Petersen3
& P. Gambetti31
Medical Research Council Laboratory of Molecular Biology
, Hills Road, Cambridge CB2 2QH,
UK
2
Department of Neurology, Adrian Building, University
of Cambridge, Cambridge, CB2 2PY, UK
3
Division of Neuropathology, Case Western Reserve University,
Cleveland, Ohio, 44106, USA
4
Institute of Neurology, University of Genova,
Genova, 16132, Italy
5
Veterans Affairs Medical Center, Great Lakes Health
Care System, Tomah, Wisconsin, 54660,
USA and Department of Neurology, University of Wisconsin, Madison, Wisconsin,
53792, USA 6
Department of Neurology and Pathology, University of
Kentucky, 101 Sanders Bldg., Lexington,
Kentucky, 40536, USA
7
University of California, Gallo Center, San Francisco
General Hospital, San Francisco, California,
94110, USA
8
Neuropathology Laboratory, Mayo Clinic Jacksonville
, Birdsall Research Bldg., Jacksonville,
Florida, 32224, USA
Correspondence should be addressed to M. Goedert or P. Gambetti 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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