Nature Medicine Magazine

[Guest guest]

April 1999 Volume 5 Number 4 pp 454 - 457

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. sen3 & P. Gambetti3

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 gene5-10. 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.

1. Medical Research Council Laboratory of Molecular Biology, Hills Road,

Cambridge CB2 2QH,UK

2. Department of Neurology, 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

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 ville, Birdsall Research

Bldg., ville, Florida, 32224, USA

Correspondence should be addressed to M Goedert. and P Gambetti.