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Brain Advance Access originally published online on April 17, 2007
Brain 2007 130(5):1360-1374; doi:10.1093/brain/awm069
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© The Author (2007). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

A novel progranulin mutation associated with variable clinical presentation and tau, TDP43 and alpha-synuclein pathology

J. B. Leverenz1,3,5,7,*, C. E. Yu2,*, T. J. Montine6, E. Steinbart2,5, L. M. Bekris2, C. Zabetian2,5, L. K. Kwong9, V. M-Y. Lee9, G. D. Schellenberg1,2,4,5,8 and T. D. Bird2,4,5

1Mental Illness, 2Geriatric and 3Parkinson's Disease Research, Education, and Clinical Centers, Veteran Affairs Puget Sound Health Care System, Seattle, WA 98108, 4Departments of Medicine (Gerontology/Geriatrics and Medical Genetics), 5Neurology, 6Pathology (Neuropathology), 7Psychiatry and Behavioral Sciences and 8Pharmacology University of Washington School of Medicine, Seattle, WA 98195 and 9Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA

Correspondence to: Thomas D. Bird, MD, 1660 S Columbian Way S-182-GRECC, Seattle, WA 98108, USA E-mail: tomnroz{at}u.washington.edu

Mutations in the progranulin (GRN) gene have recently been reported as a cause of the frontotemporal dementia (FTD) syndrome. We performed a clinical, neuropathological and molecular genetic study of two families with FTD and the same novel mutation in GRN. Age of onset ranged from 35 to 75 years and all individuals progressed to a severe dementia syndrome with a mean disease duration of ~6–10 years. Variable clinical presentations included language impairment, behaviour change or parkinsonism. Seven total autopsies in the families (five in Family 1, two in Family 2) showed gross and microscopic evidence of neuronal loss in the neocortex, striatum, hippocampus and substantia nigra. All cases with material available for immunohistochemistry had cytoplasmic and intranuclear ubiquitin positive, tau negative inclusions that stained best with an antibody to the TDP43 protein. In addition, all but one had evidence of distinctive tau pathology. Two cases in Family 1 also had {alpha}-synuclein (SNCA) pathology, one with diffuse neocortical inclusions and neurites and unusual striatal cytoplasmic inclusions. Affected persons in both families had the same mutation in GRN (c.709-2A>G). A minigene construct showed that this mutation alters splicing of exon 7 and results in reduced mRNA message in brain.

A single GRN mutation in these two families was associated with variable clinical presentations consistent with the FTD syndrome. All cases had ubiquitin/TDP43 immuno-positive inclusions and most had additional tau pathology. Two cases had SNCA pathology. These findings suggest a link between mutations in GRN and aggregation of tau, TDP43 and SNCA.

Key Words: Frontotemporal dementia; progranulin; tau; alpha synuclein; Neurogenetics

Abbreviations: AD, Alzheimer's disease; FTD, frontotemporal dementia; SNCA, {alpha}-synuclein

.

Received November 22, 2006. Revised February 23, 2007. Accepted March 12, 2007.

*These authors contributed equally to this work.


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