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Progranulin variability has no major role in Parkinson disease genetic etiology

From the Neurodegenerative Brain Diseases Group (K.N., K.S., E.C., K.P., J.T., C.V.B., M.M.), Department of Molecular Genetics, VIB; Laboratory of Neurogenetics (K.N., K.S., E.C., K.P., M.M., J.T., C.V.B.), Laboratory of Neurobiology (P.P., P.C.), and Laboratory of Neurochemistry and Behaviour (S.E., P.P.D.D.), Institute Born-Bunge; University of Antwerp (K.N., K.S., S.E., E.C., K.P., M.M., P.P.D.D., J.T., C.V.B.), Antwerpen; Division of Neurology (P.P., P.C.), University Hospital Antwerp; and Memory Clinic and Department of Neurology (S.E., B.P., P.P.D.D.), ZNA Middelheim, Antwerpen, Belgium.

Address correspondence and reprint requests to Prof. Dr. Christine Van Broeckhoven, Neurodegenerative Brain Diseases Group, VIB-Department of Molecular Genetics, University of Antwerp-CDE, Universiteitsplein 1, B-2610 Antwerpen, Belgium christine.vanbroeckhoven{at}ua.ac.be

Background: Different loss-of-function mutations were identified underlying PGRN haploinsufficiency in patients with frontotemporal lobar degeneration. PGRN mutations were also identified in other neurodegenerative brain diseases such as amyotrophic lateral sclerosis and Alzheimer disease, though their biologic contribution to these diseases remains elusive. Because of its apparent role in neuronal survival, we argued that PGRN might also contribute to Parkinson disease (PD) pathogenesis.

Methods: We screened PGRN exons for mutations in 255 patients with PD and 459 control individuals by direct genomic sequencing. Genetic association of PGRN with risk for PD was assessed using single nucleotide polymorphisms (SNPs) across the gene.

Results: In patients we identified four missense mutations of which p.Asp33Glu and p.Arg514Met were absent in control individuals. Single SNP and haplotype analyses did not detect significant associations with PD.

Conclusions: Our results do not support a major role for PGRN in the genetic etiology of Parkinson disease (PD). At this stage and in the absence of functional data, it remains unclear whether p.Asp33Glu and p.Arg514Met are biologically relevant to PD pathogenesis in the mutation carriers.

Abbreviations: AD = Alzheimer disease; ALS = amyotrophic lateral sclerosis; DLBD = diffuse Lewy body disease; FTLDU-17 = frontotemporal lobar degeneration linked to chromosome 17q21; gDNA = genomic DNA; PD = Parkinson disease; PDD = PD dementia; SNP = single nucleotide polymorphisms; STR = simple tandem repeat.

This research was supported in part by the Special Research Fund of the University of Antwerp, the Institute for the Promotion of Innovation by Science and Technology-Flanders (IWT-F), the Fund for Scientific Research Flanders (FWO-F), de Stichting voor Alzheimer Onderzoek (SAO), and the Medical Foundation Queen Elisabeth (GSKE) to C.V.B.; the Medical Research Foundation Antwerp and Neurosearch Antwerp to P.P.D.D.; and the Interuniversity Attraction Poles program P6/43 of the Belgian Science Policy Office (to C.V.B. and P.P.D.D.), Belgium. The IWT-F provided a PhD fellowship to K.N.; J.T., K.S., and S.E. are holders of a postdoctoral fellowship of FWO-F, Belgium.

Disclosure: The authors report no disclosures.

Received April 27, 2008. Accepted in final form June 26, 2008.