Mutations other than null mutations producing a pathogenic loss of progranulin in frontotemporal dementia.
Null mutations in the progranulin gene (GRN, PGRN) were recently identified as the causal mechanism underlying frontotemporal dementia (FTD) with ubiquitin-positive brain pathology linked to chromosome 17 (FTDU-17). In a Belgian and French FTD series comprising 332 patients, we reported 13 PGRN null mutations which were mainly nonsense and frameshift mutations resulting in premature stop codons. Here we report in the same patient series three missense mutations of which two (c.743C>T, p.Pro248Leu and c.1294C>T, p.Arg432Cys) were predicted in silico to severely affect protein folding and/or processing leading to PGRN protein haploinsufficiency. In addition, we observed three sequence variations in the 5' regulatory region that might potentially affect PGRN transcription activity. Our findings extend the mutation spectrum in PGRN leading to loss of functional PGRN as the basis for FTD.
van der Zee
Julie
J
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium.
Le Ber
Isabelle
I
Maurer-Stroh
Sebastian
S
Engelborghs
Sebastiaan
S
Gijselinck
Ilse
I
Camuzat
Agnès
A
Brouwers
Nathalie
N
Vandenberghe
Rik
R
Sleegers
Kristel
K
Hannequin
Didier
D
Dermaut
Bart
B
Schymkowitz
Joost
J
Campion
Dominique
D
Santens
Patrick
P
Martin
Jean-Jacques
JJ
Lacomblez
Lucette
L
De Pooter
Tim
T
Peeters
Karin
K
Mattheijssens
Maria
M
Vercelletto
Martine
M
Van den Broeck
Marleen
M
Cruts
Marc
M
De Deyn
Peter P
PP
Rousseau
Frederic
F
Brice
Alexis
A
Van Broeckhoven
Christine
C
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D016022:Case-Control Studies; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D003704:Dementia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D000077153:Progranulins; D011487:Protein Conformation; D017510:Protein Folding; D017434:Protein Structure, Tertiary
C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins