Serum biomarker for progranulin-associated frontotemporal lobar degeneration.
OBJECTIVE
Mutations that lead to a loss of progranulin (PGRN) explain a considerable portion of the occurrence of frontotemporal lobar degeneration. We tested a biomarker allowing rapid detection of a loss of PGRN.


METHODS
We used an enzyme-linked immunosorbent assay to measure in serum the PGRN protein levels of six affected and eight unaffected carriers from within an extended Belgian founder family segregating the null mutation IVS1+5G>C. Further, we measured serum PGRN levels in 2 patients with another null mutation (a Met1 and a frameshift mutation), in 4 patients carrying a predicted pathogenic missense mutation and in 5 patients carrying a benign missense polymorphism, in 9 unaffected noncarrier relatives, and in 22 community controls.


RESULTS
Serum PGRN levels were reduced in both affected and unaffected null mutation carriers compared with noncarrier relatives (p(exact) < 0.0001), and allowed perfect discrimination between carriers and noncarriers (sensitivity: 1.0; 1 - specificity: 0.0). Serum PGRN levels in Cys139Arg and Arg564Cys mutation carriers were significantly lower than in controls, but greater than in null mutation carriers, fitting the hypothesis of partial loss of function caused by these missense mutations. As expected, levels for carriers of benign missense polymorphisms were not significantly different from controls.


CONCLUSIONS
Our results indicate that the serum PGRN level is a reliable biomarker for diagnosing and early detection of frontotemporal lobar degeneration caused by PGRN null mutations, and provided the first in vivo evidence that at least some missense mutations in PGRN may lead to a (partial) loss of PGRN.
Sleegers
Kristel
K
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB (Flanders Institute for Biotechnology), University of Antwerp, Universiteitsplein 1, Antwerp, Belgium.
Brouwers
Nathalie
N
Van Damme
Philip
P
Engelborghs
Sebastiaan
S
Gijselinck
Ilse
I
van der Zee
Julie
J
Peeters
Karin
K
Mattheijssens
Maria
M
Cruts
Marc
M
Vandenberghe
Rik
R
De Deyn
Peter P
PP
Robberecht
Wim
W
Van Broeckhoven
Christine
C
D000368:Aged; D000369:Aged, 80 and over; D001120:Arginine / Q000235:genetics; D015415:Biomarkers / Q000097:blood*; D003545:Cysteine / Q000235:genetics; D003704:Dementia / Q000097:blood* / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics; D000077153:Progranulins
D015415:Biomarkers; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D001120:Arginine; D003545:Cysteine