title: Common variation in the miR-659 binding-site of GRN is a major risk factor for TDP43-positive frontotemporal dementia.
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 approximately 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.
authors: Department of Neuroscience, Mayo Clinic, Jacksonville, FL FL 32224, USA. rademakers.rosa@mayo.edu
authors: Rosa
authors: R
authors: Rademakers
authors: Jason L
authors: JL
authors: Eriksen
authors: Matt
authors: M
authors: Baker
authors: Todd
authors: T
authors: Robinson
authors: Zeshan
authors: Z
authors: Ahmed
authors: Sarah J
authors: SJ
authors: Lincoln
authors: Nicole
authors: N
authors: Finch
authors: Nicola J
authors: NJ
authors: Rutherford
authors: Richard J
authors: RJ
authors: Crook
authors: Keith A
authors: KA
authors: Josephs
authors: Bradley F
authors: BF
authors: Boeve
authors: David S
authors: DS
authors: Knopman
authors: Ronald C
authors: RC
authors: Petersen
authors: Joseph E
authors: JE
authors: Parisi
authors: Richard J
authors: RJ
authors: Caselli
authors: Zbigniew K
authors: ZK
authors: Wszolek
authors: Ryan J
authors: RJ
authors: Uitti
authors: Howard
authors: H
authors: Feldman
authors: Michael L
authors: ML
authors: Hutton
authors: Ian R
authors: IR
authors: Mackenzie
authors: Neill R
authors: NR
authors: Graff-Radford
authors: Dennis W
authors: DW
authors: Dickson
mesh_terms: D000368:Aged; D001483:Base Sequence; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003704:Dementia / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D000077153:Progranulins; D014176:Protein Biosynthesis
chemical_list: D004268:DNA-Binding Proteins; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; C533992:MIRN659 microRNA, human; D035683:MicroRNAs; D000077153:Progranulins