Progranulin variability has no major role in Parkinson disease genetic etiology.
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.
Neurodegenerative Brain Diseases Group, VIB-Department of Molecular Genetics, University of Antwerp-CDE, Universiteitsplein 1, B-2610 Antwerpen, Belgium.
K
K
Nuytemans
P
P
Pals
K
K
Sleegers
S
S
Engelborghs
E
E
Corsmit
K
K
Peeters
B
B
Pickut
M
M
Mattheijssens
P
P
Cras
P P
PP
De Deyn
J
J
Theuns
C
C
Van Broeckhoven
D000368:Aged; D000595:Amino Acid Sequence; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D014644:Genetic Variation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010300:Parkinson Disease / Q000453:epidemiology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D000077153:Progranulins; D012189:Retrospective Studies; D012307:Risk Factors
C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins