Progranulin genetic variability contributes to amyotrophic lateral sclerosis.
OBJECTIVE
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.


CONCLUSIONS
PGRN acts as a modifier of the course of disease in patients with amyotrophic lateral sclerosis, through earlier onset and shorter survival.
Sleegers
K
K
Neurodegenerative Brain Diseases Group, VIB-Department of Molecular Genetics, University of Antwerp, Universiteitsplein 1, BE-2610 Antwerpen, Belgium.
Brouwers
N
N
Maurer-Stroh
S
S
van Es
M A
MA
Van Damme
P
P
van Vught
P W J
PW
van der Zee
J
J
Serneels
S
S
De Pooter
T
T
Van den Broeck
M
M
Cruts
M
M
Schymkowitz
J
J
De Jonghe
P
P
Rousseau
F
F
van den Berg
L H
LH
Robberecht
W
W
Van Broeckhoven
C
C
D000328:Adult; D017668:Age of Onset; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D001530:Belgium; D004252:DNA Mutational Analysis; D003704:Dementia / Q000235:genetics; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D020125:Mutation, Missense / Q000235:genetics; D009426:Netherlands; D011110:Polymorphism, Genetic / Q000235:genetics; D000077153:Progranulins; D015996:Survival Rate
C492314:GRN protein, human; D005819:Genetic Markers; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins