Human Molecular Genetics Advance Access first published online on August 21, 2008
This version published online on August 22, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn257
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Common variation in the miR-659 binding-site of GRN is a major risk factor for TDP43-positive frontotemporal dementia
1 Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA 2 Department of Neurology, Mayo Clinic, Rochester, MN, USA 3 Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA 4 Department of Neurology, Mayo Clinic, Jacksonville, FL, USA 5a Division of Neurology, University of British Columbia, Vancouver, Canada 5b Department of Pathology, University of British Columbia, Vancouver, Canada
# Corresponding author: Rosa Rademakers, Ph.D., Assistant Professor and Associate Consultant, Mayo Clinic, Department of Neuroscience, 4500 San Pablo Road, Jacksonville, FL 32224, Phone (904) 953-6279; Fax (904) 953-7370 , E-mail: rademakers.rosa{at}mayo.edu
Received July 30, 2008; Revised July 30, 2008; Accepted August 20, 2008
Loss-of-function mutations in progranulin (GRN) cause ubiquitin- and TAR-DNA binding protein 43 (TDP-43)-positive frontotemporal dementia (FTLD-U), a progressive neurodegenerative disease affecting 
10% of early-onset dementia patients. Here we expand the role of GRN in FTLD-U and demonstrate that a common genetic variant (rs5848), located in the 3’untranslated region (UTR) of GRN in a binding-site for miR-659, is a major susceptibility factor for FTLD-U. In a series of pathologically confirmed FTLD-U patients without GRN mutations, we show that carriers homozygous for the T-allele of rs5848 have a 3.2-fold increased risk to develop FTLD-U compared to homozygous C-allele carriers (95% CI: 1.50-6.73). We further demonstrate that miR-659 can regulate GRN expression in vitro, with miR-659 binding more efficiently to the high risk T-allele of rs5848 resulting in augmented translational inhibition of GRN. A significant reduction in GRN protein was observed in homozygous T-allele carriers in vivo, through biochemical and immunohistochemical methods, mimicking the effect of heterozygous loss-of-function GRN mutations. In support of these findings, the neuropathology of homozygous rs5848 T-allele carriers frequently resembled the pathological FTLD-U subtype of GRN mutation carriers. We suggest that the expression of GRN is regulated by miRNAs and that common genetic variability in a miRNA binding-site can significantly increase the risk for FTLD-U. Translational regulation by miRNAs may represent a common mechanism underlying complex neurodegenerative disorders.
* Current address: Neuroscience Drug Discovery, Merck Research Laboratories, Boston, MA, USA
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