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This Article Figures Only Full Text Full Text (PDF) Take the CME quiz CME: Take the course for this article: Volume 71, Number 4, July 22, 2008 Data Supplement All Versions of this Article: 01.wnl.0000289191.54852.75v1 71/4/253    most recent Correspondence: Submit a response Alert me when this article is cited Alert me when Correspondence are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Sleegers, K. Articles by Broeckhoven, C. V. PubMed PubMed Citation Articles by Sleegers, K. Articles by Broeckhoven, C. V. Related Collections Amyotrophic lateral sclerosis All Genetics Association studies in genetics

Progranulin genetic variability contributes to amyotrophic lateral sclerosis

From the Neurodegenerative Brain Diseases Group (K.S., N.B., J.v.d.Z., S.S., T.D.P., M.V.d.B., M.C., C.V.B.) and Neurogenetics Group (P.D.J.), Department of Molecular Genetics, and SWITCH Laboratory (S.M.-S., J.S., F.R.) VIB, University of Antwerp (K.S., N.B., J.v.d.Z., S.S., T.D.P., M.V.d.B., M.C., P.D.J., C.V.B.), Antwerpen; University Brussels (VUB) (S.M.-S., J.S., F.R.); Department of Neurology (M.A.v.E., P.W.J.v.V., L.H.v.d.B.), Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, the Netherlands; Division of Neurology (P.V.D., W.R.), University Hospital Gasthuisberg, University of Leuven (KUL); and Division of Neurology (P.D.J.), University Hospital 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, Universiteitsplein 1, BE-2610 Antwerpen, Belgium christine.vanbroeckhoven{at}ua.ac.be

Objectives: Null mutations in progranulin (PGRN) cause ubiquitin-positive frontotemporal dementia (FTD) linked to chromosome 17q21 (FTDU-17). Here we examined PGRN genetic variability in amyotrophic lateral sclerosis (ALS), a neurodegenerative motor neuron disease that overlaps with FTD at a clinical, pathologic, and epidemiologic level.

Methods: We sequenced all exons, exon-intron boundaries, and 5' and 3' regulatory regions of PGRN in a Belgian sample of 230 patients with ALS. The frequency of observed genetic variants was determined in 436 healthy control individuals. The contribution of eight frequent polymorphisms to ALS risk, onset age, and survival was assessed in an association study in the Belgian sample and a replication series of 308 Dutch patients with ALS and 345 Dutch controls.

Results: In patients with ALS we identified 11 mutations, 5 of which were predicted to affect PGRN protein sequence or levels (four missense mutations and one 5' regulatory variant). Moreover, common variants (rs9897526, rs34424835, and rs850713) and haplotypes were significantly associated with a reduction in age at onset and a shorter survival after onset of ALS in both the Belgian and the Dutch studies.

Conclusion: PGRN acts as a modifier of the course of disease in patients with amyotrophic lateral sclerosis, through earlier onset and shorter survival.

Abbreviations: ALS = amyotrophic lateral sclerosis; FTD = frontotemporal dementia; FTDU = ubiquitin-positive subtype of frontotemporal dementia; HWE = Hardy-Weinberg equilibrium; SNP = single nucleotide polymorphism; Ub-ir = ubiquitin immunoreactive.

Supplemental data at www.neurology.org

e-Pub ahead of print on January 9, 2008, at www.neurology.org.

Supported by the Zenith Award of the Alzheimer Association USA, Stichting Alzheimer Onderzoek-Belgium, the EU contract LSHMCT-2003-503330 (APOPIS), the InterUniversity Attraction Poles (IAP) program P5/19 and P6/43 of the Belgian Federal Science Policy office (BELSPO), the Fund for Scientific Research-Flanders (FWO-F), and the Special Research Fund (BOF) of the University of Antwerp. K.S., P.V.D., and M.C. hold a postdoctoral fellowship and N.B. a doctoral fellowship of FWO-F, and J.v.d.Z. a doctoral fellowship of the Institute for Science and Technology-Flanders (IWT-F). S.M.-S. is recipient of a Marie Curie Intra-European Fellowship. L.H.v.d.B. is supported by a grant from the Netherlands Organization for Health Research and Development. W.R. is supported by the Research Council of the University of Leuven, and through the E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders.

Disclosure: The authors report no disclosures.

Received May 21, 2007. Accepted in final form August 13, 2007.

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