Common variation in the miR-659 binding-site of GRN is a major risk factor for TDP43-positive frontotemporal dementia.
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.
Rademakers
Rosa
R
Department of Neuroscience, Mayo Clinic, Jacksonville, FL FL 32224, USA. rademakers.rosa@mayo.edu
Eriksen
Jason L
JL
Baker
Matt
M
Robinson
Todd
T
Ahmed
Zeshan
Z
Lincoln
Sarah J
SJ
Finch
Nicole
N
Rutherford
Nicola J
NJ
Crook
Richard J
RJ
Josephs
Keith A
KA
Boeve
Bradley F
BF
Knopman
David S
DS
Petersen
Ronald C
RC
Parisi
Joseph E
JE
Caselli
Richard J
RJ
Wszolek
Zbigniew K
ZK
Uitti
Ryan J
RJ
Feldman
Howard
H
Hutton
Michael L
ML
Mackenzie
Ian R
IR
Graff-Radford
Neill R
NR
Dickson
Dennis W
DW
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
D004268:DNA-Binding Proteins; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; C533992:MIRN659 microRNA, human; D035683:MicroRNAs; D000077153:Progranulins