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Published online before print June 18, 2008, doi:10.1212/01.wnl.0000319688.89790.7a)
© 2008 American Academy of Neurology Genetic variability in progranulin contributes to risk for clinically diagnosed Alzheimer diseaseFrom Neurodegenerative Brain Diseases Group (N.B., K.S., I.G., J.v.d.Z., M.V.d.B., M.M., K.P., M.C., C.V.B.), Department of Molecular Genetics and SWITCH Laboratory (S.M.-S., J.S., F.R.), VIB; Laboratory of Neurogenetics (N.B., K.S., I.G., J.v.d.Z., M.V.d.B., M.M., K.P., M.C., C.V.B.), Laboratory of Neurochemistry and Behaviour (S.E., P.P.D.D.), and Laboratory of Neuropathology (J.-J.M.), Institute Born-Bunge; University of Antwerp (N.B., K.S., S.E., I.G., J.v.d.Z., M.V.d.B., M.M., K.P., J.-J.M., M.C., P.P.D.D., C.V.B.), Antwerpen; University of Brussels (VUB) (S.M.-S., J.S., F.R.); and Memory Clinic and Department of Neurology (S.E., B.A.P., P.P.D.D.), Middelheim General Hospital, Antwerpen, Belgium. Address correspondence and reprint requests to Prof. Dr. Christine Van Broeckhoven, VIB-Department of Molecular Genetics, Neurodegenerative Brain Diseases Group, University of Antwerp–Campus CDE, Universiteitsplein 1, B-2610 Antwerpen, Belgium christine.vanbroeckhoven{at}ua.ac.be Objective: Loss-of-function mutations in the progranulin gene (PGRN) were identified in frontotemporal lobar degeneration (FTLD) with ubiquitin-immunoreactive neuronal inclusions (FTLD-U). We assessed whether PGRN also contributes to genetic risk for Alzheimer disease (AD) in an extended Belgian AD patient group (n = 779, onset age 74.7 ± 8.7 years). Methods: A mutation analysis of the PGRN coding region was performed. The effect of missense mutations was assessed using in silico predictions and protein modeling. Risk effects of common genetic variants were estimated by logistic regression analysis and gene-based haplotype association analysis. Results: We observed seven missense mutations in eight patients (1.3%). Convincing pathogenic evidence was obtained for two missense mutations, p.Cys139Arg and p.Pro451Leu, affecting PGRN protein folding and leading to loss of PGRN by degradation of the misfolded protein. In addition, we showed that PGRN haplotypes were associated with increased risk for AD. Conclusions: Our data support a role for PGRN in patients with clinically diagnosed Alzheimer disease (AD). Further, we hypothesize that at least some PGRN missense mutations might lead to loss of functional protein. Whether the underlying pathology in our cases proves to be AD, frontotemporal lobar degeneration, or a combination of the two must await further investigations.
Abbreviations: AD= Alzheimer disease; FTLD= frontotemporal lobar degeneration; FTLD-U= FTLD with ubiquitin-immunoreactive neuronal inclusions; MMSE= Mini-Mental State Examination; NINCDS-ADRDA= National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association; SNP= single nucleotide polymorphism; STR= short tandem repeat.
Received December 22, 2007. Accepted in final form April 28, 2008. e-Pub ahead of print on June 18, 2008, at www.neurology.org. Supported in part by the Fund for Scientific Research-Flanders (FWO-F); the Institute for Science and Technology–Flanders (IWT-F); the Special Research Fund of the University of Antwerp; the Stichting Alzheimer Onderzoek, the Interuniversity Attraction Poles (IUAP) program P6/43 of the Belgian Federal Science Policy Office, and the Medical Foundation Queen Elisabeth, Belgium; and a Zenith Award of the Alzheimer Association USA to C.V.B. In addition, P.P.D.D. was funded by the Medical Research Foundation and Neurosearch, Antwerp; K.S. and S.E. are postdoctoral fellows of the FWO-F. N.B. and I.G. are PhD fellows of the FWO-F. J.v.d.Z. is holder of a doctoral fellowship of IWT-F. S.M.S. is recipient of a Marie Curie Intra-European Fellowship. Disclosure: The authors report no disclosures. This article has been cited by other articles:
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