TY - JOUR
T1 - Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21
AU - Cruts, Marc
AU - Gijselinck, Ilse
AU - Van Der Zee, Julie
AU - Engelborghs, Sebastiaan
AU - Wils, Hans
AU - Pirici, Daniel
AU - Rademakers, Rosa
AU - Vandenberghe, Rik
AU - Dermaut, Bart
AU - Martin, Jean Jacques
AU - Van Duijn, Cornelia
AU - Peeters, Karin
AU - Sciot, Raf
AU - Santens, Patrick
AU - De Pooter, Tim
AU - Mattheijssens, Maria
AU - Van Den Broeck, Marleen
AU - Cuijt, Ivy
AU - Vennekens, Krist'l
AU - De Deyn, Peter P.
AU - Kumar-Singh, Samir
AU - Van Broeckhoven, Christine
N1 - Funding Information:
Acknowledgements The authors are grateful to the patients and family members for their kind cooperation in this study, and to the personnel of the VIB Genetic Service Facility (http://www.vibgeneticservicefacility.be) and IBB Biobank. We thank S. Serneels for help with genetic analyses, and E. De Leenheir and B. Van Everbroeck for support with the neuropathology studies. The research described in this paper was supported by the Special Research Fund of the University of Antwerp, the Fund for Scientific Research Flanders (FWO-F), the Interuniversity Attraction Poles program P5/19 of the Belgian Science Policy Office, the International Alzheimer Research Foundation, an EU contract (APOPIS), and a Zenith award of the Alzheimer’s Association USA. The FWO-F provided postdoctoral fellowships to M.C., S.E. and R.R., a PhD fellowship to I.G., and clinical investigator award to R.V. J.v.d.Z. is holder of a PhD fellowship of the Institute for Science and Technology Flanders (IWT-F), Belgium.
PY - 2006/8/24
Y1 - 2006/8/24
N2 - 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.
AB - 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.
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U2 - 10.1038/nature05017
DO - 10.1038/nature05017
M3 - Article
C2 - 16862115
AN - SCOPUS:33746910649
SN - 0028-0836
VL - 442
SP - 920
EP - 924
JO - Nature
JF - Nature
IS - 7105
ER -