GRN 3¢UTR+78 C>T is not associated with risk for ParkinsonÕs disease B. Jasinska-Myga a,b,c , C. Wider a,b , G. Opala c , A. Krygowska-Wajs d , M. Barcikowska e , K. Czyzewski f , M. Baker a , R. Rademakers a , R. J. Uitti b , M. J. Farrer a , O. A. Ross a and Z. K. Wszolek b a Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; b Department of Neurology, Mayo Clinic, Jacksonville, FL, USA; c Department of Neurology, Aging, Degenerative and Cerebrovascular Disorders, Medical University of Silesia, Katowice, Poland; d Department of Neurology, Collegium Medicum Jagiellonian University, Krakow, Poland; e Department of Neurodegenerative Disorders, Medical Research Center, Polish Academy of Sciences, Warsaw, Poland; and f Department of Neurology, MSWiA Hospital, Warsaw, Poland Keywords: genetics, GRN, miRNA, ParkinsonÕs disease, rs5848, SNP Received 10 January 2009 Accepted 18 February 2009 Background and purpose: A single nucleotide polymorphism in the 3¢-untranslated region of the progranulin gene (GRN;3¢UTR+78C>T; rs5848) was reported to alter the risk for frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). rs5848 is located within a micro-RNA binding site and affects the expression of GRN. Methods: As FTLD-U patients often present with parkinsonism, we investigated the association of GRN rs5848 and risk of ParkinsonÕs disease in two Caucasian patient– control series (n = 1413) from the US and Poland. Results: No association was observed between rs5848 and susceptibility to Parkin- sonÕs disease (individual series and combined analysis). Conclusions: This finding shows that GRN rs5848 does not affect the risk of ParkinsonÕs disease in the US and Polish populations. Introduction ParkinsonÕs disease (PD) is the most prevalent cause of parkinsonism, affecting 1% of the population at 65 years [1]. However, parkinsonism is also commonly observed in other disorders including frontotemporal lobar degeneration with tau (FTLD-tau) or ubiquitin- positive (FTLD-U) inclusions due to mutations in the microtubule-associated protein tau (MAPT, MIM#157140) and progranulin (GRN, MIM#138945) genes, respectively [2,3]. Furthermore, the manifesta- tion of parkinsonism suggests a clinical, pathological and molecular overlap between neurodegenerative disorders, including FTLD and PD. Common genetic variability in the MAPT gene is associated with risk of sporadic PD [4–6] and a small number of GRN mutation carriers have been clinically diagnosed with PD [3,7,8]. Their presentation was indistinguishable from idiopathic PD and was in accordance with existing clinical criteria. Recently, a single nucleotide polymorphism (SNP) (rs5848) in the 3¢-untranslated region (3¢UTR) of GRN was shown to alter the risk of FTLD-U. In an autopsy series, individuals homozygous for the rs5848 T allele were 3.2 times more likely to have FTLD-U than homozygous C-allele carriers [9]. rs5848 is located within a binding site for micro-RNA (miRNA) 659 (miR-659), which regulates GRN translation. By means of in silico analyses and in vitro studies, it was shown the rs5848 T allele increases binding of miR- 659 compared with the rs5848 C allele, thereby reducing levels of the progranulin protein. Moreover, reduced levels of the progranulin protein were identi- fied in vivo in homozygous rs5848 T-allele carriers, suggesting a mechanism similar to the loss-of-function induced by disease-causing GRN mutations [9]. Inter- estingly, loss-of-function mechanism, which is impli- cated in some forms of familial PD (parkin, DJ-1) and in FTLD-U (GRN) might be associated with different neuronal vulnerability. It is hypothesized that loss-of- function induced by GRN mutations leading to hap- loinsufficiency might be associated with neurodegen- eration of different neuronal populations with different clinical presentation, including not only FTLD but also PD [7,10]. Correspondence: Barbara Jasinska-Myga, Division of Neurogenetics, Morris K. Udall ParkinsonÕs Disease Research Center of Excellence, Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA (tel.: +904 953 0963; fax: +904 953 7370; e-mail: jasinskamyga.barbara@mayo.edu). Ó 2009 The Author(s) Journal compilation Ó 2009 EFNS 909 European Journal of Neurology 2009, 16: 909–911 doi:10.1111/j.1468-1331.2009.02621.x