Genetic variability in progranulin contributes to risk for clinically diagnosed Alzheimer disease.
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.
VIB-Department of Molecular Genetics, Neurodegenerative Brain Diseases Group, University of Antwerp-Campus CDE, Universiteitsplein 1, B-2610 Antwerpen, Belgium. christine.vanbroeckhoven@ua.ac.be
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Brouwers
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Sleegers
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Engelborghs
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Maurer-Stroh
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Gijselinck
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van der Zee
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Pickut
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Van den Broeck
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Mattheijssens
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Peeters
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Schymkowitz
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Rousseau
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Martin
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Cruts
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De Deyn
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Van Broeckhoven
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D000595:Amino Acid Sequence / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D014644:Genetic Variation / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics; D000077153:Progranulins; D017510:Protein Folding
C492314:GRN protein, human; D005819:Genetic Markers; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins