Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21.
Frontotemporal dementia (FTD) with ubiquitin-immunoreactive neuronal inclusions (both cytoplasmic and nuclear) of unknown nature has been linked to a chromosome 17q21 region (FTDU-17) containing MAPT (microtubule-associated protein tau). FTDU-17 patients have consistently been shown to lack a tau-immunoreactive pathology, a feature characteristic of FTD with parkinsonism linked to mutations in MAPT (FTDP-17). Furthermore, in FTDU-17 patients, mutations in MAPT and genomic rearrangements in the MAPT region have been excluded by both genomic sequencing and fluorescence in situ hybridization on mechanically stretched chromosomes. Here we demonstrate that FTDU-17 is caused by mutations in the gene coding for progranulin (PGRN), a growth factor involved in multiple physiological and pathological processes including tumorigenesis. Besides the production of truncated PGRN proteins due to premature stop codons, we identified a mutation within the splice donor site of intron 0 (IVS0 + 5G > C), indicating loss of the mutant transcript by nuclear degradation. The finding was made within an extensively documented Belgian FTDU-17 founder family. Transcript and protein analyses confirmed the absence of the mutant allele and a reduction in the expression of PGRN. We also identified a mutation (c.3G > A) in the Met1 translation initiation codon, indicating loss of PGRN due to lack of translation of the mutant allele. Our data provide evidence that PGRN haploinsufficiency leads to neurodegeneration because of reduced PGRN-mediated neuronal survival. Furthermore, in a Belgian series of familial FTD patients, PGRN mutations were 3.5 times more frequent than mutations in MAPT, underscoring a principal involvement of PGRN in FTD pathogenesis.
Cruts
Marc
M
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, Universiteitsplein 1, BE-2610 Antwerpen, Belgium.
Gijselinck
Ilse
I
van der Zee
Julie
J
Engelborghs
Sebastiaan
S
Wils
Hans
H
Pirici
Daniel
D
Rademakers
Rosa
R
Vandenberghe
Rik
R
Dermaut
Bart
B
Martin
Jean-Jacques
JJ
van Duijn
Cornelia
C
Peeters
Karin
K
Sciot
Raf
R
Santens
Patrick
P
De Pooter
Tim
T
Mattheijssens
Maria
M
Van den Broeck
Marleen
M
Cuijt
Ivy
I
Vennekens
Krist'l
K
De Deyn
Peter P
PP
Kumar-Singh
Samir
S
Van Broeckhoven
Christine
C
D001530:Belgium; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D004252:DNA Mutational Analysis; D003704:Dementia / Q000235:genetics* / Q000503:physiopathology; D005625:Frontal Lobe / Q000378:metabolism / Q000503:physiopathology*; D008040:Genetic Linkage / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D020161:Physical Chromosome Mapping; D000077153:Progranulins; D022821:RNA Splice Sites / Q000235:genetics; D013702:Temporal Lobe / Q000378:metabolism / Q000503:physiopathology*; D025801:Ubiquitin / Q000378:metabolism*
D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D022821:RNA Splice Sites; D025801:Ubiquitin