Common variation in the miR-659 binding-site of GRN is a major risk factor for TDP43-positive frontotemporal dementia

Rosa Rademakers, Jason L. Eriksen, Matt Baker, Todd Robinson, Zeshan Ahmed, Sarah J. Lincoln, Nicole Finch, Nicola J. Rutherford, Richard J. Crook, Keith A. Josephs, Bradley F. Boeve, David S. Knopman, Ronald C. Petersen, Joseph E. Parisi, Richard J. Caselli, Zbigniew K. Wszolek, Ryan J. Uitti, Howard Feldman, Michael L. Hutton, Ian R. MackenzieNeill R. Graff-Radford, Dennis W. Dickson

Research output: Contribution to journalArticlepeer-review

214 Scopus citations

Abstract

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 with 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.

Original languageEnglish (US)
Pages (from-to)3631-3642
Number of pages12
JournalHuman molecular genetics
Volume17
Issue number23
DOIs
StatePublished - 2008

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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