@article{d70a4b36006e4029a797ffd8bea45a6a,
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 ∼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.",
author = "Rosa Rademakers and Eriksen, {Jason L.} and Matt Baker and Todd Robinson and Zeshan Ahmed and Lincoln, {Sarah J.} and Nicole Finch and Rutherford, {Nicola J.} and Crook, {Richard J.} and Josephs, {Keith A.} and Boeve, {Bradley F.} and Knopman, {David S.} and Petersen, {Ronald C.} and Parisi, {Joseph E.} and Caselli, {Richard J.} and Wszolek, {Zbigniew K.} and Uitti, {Ryan J.} and Howard Feldman and Hutton, {Michael L.} and Mackenzie, {Ian R.} and Graff-Radford, {Neill R.} and Dickson, {Dennis W.}",
note = "Funding Information: The work was supported by NIH grants P50-NS40256 (D.W.D., R.J.U. and Z.K.W.), P01-AG17216 (D.W.D. and Z.K.W.), P50-25711 (D.W.D.), P01-AG03949 (D.W.D.), P30-AG19610 (R.J.C.), R01-MH57899 (R.J.C.) and P50 AG16574 (B.F.B., D.S.K., D.W.D., J.E.P., M.L.H., N.R.G.-R. and R.R.). Additional support was obtained from Arizona Alzheimer{\textquoteright}s Research Consortium (R.J.C.), the Robert and Clarice Smith Fellowship in Neurodegenerative Disease (J.E.), the Pacific Alzheimer{\textquoteright}s Disease Research Foundation grant #C06-01 (D.W.D., H.F., I.R.M., R.J.U., R.R. and Z.K.W.) and the Canadian Institutes of Health Research Operating grant #74580 (I.R.M. and H.F.). Funding to pay the Open Access publication charges for this article was provided by The Mayo Foundation. Funding Information: FTLD-U case – control series. The MCJ brain bank comprises .2500 neurodegenerative brain samples primarily ascertained through The State of Florida Alzheimer{\textquoteright}s Disease Initiative funded through the Department of Elder Affairs, The Einstein Aging Study (P01-AG03949), The Udall Center for Excellence in Parkinson{\textquoteright}s Disease Research (P50-NS40256), CurePSP/The Society for Progressive Supranuclear Palsy, Mayo Clinic ADRC (P50-AG16574), the Alzheimer{\textquoteright}s Disease Patient Registry (ADPR) (P30-AG19610) and the Florida ADRC (P50-25711).",
year = "2008",
doi = "10.1093/hmg/ddn257",
language = "English (US)",
volume = "17",
pages = "3631--3642",
journal = "Human molecular genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "23",
}