Isabelle Le Ber and Julie van der Zee contributed equally to this work.
Article first published online: 13 APR 2007
© 2007 Wiley-Liss, Inc.
Volume 28, Issue 9, pages 846–855, September 2007
How to Cite
Le Ber, I., van der Zee, J., Hannequin, D., Gijselinck, I., Campion, D., Puel, M., Laquerrière, A., De Pooter, T., Camuzat, A., Van den Broeck, M., Dubois, B., Sellal, F., Lacomblez, L., Vercelletto, M., Thomas-Antérion, C., Michel, B.-F., Golfier, V., Didic, M., Salachas, F., Duyckaerts, C., Cruts, M., Verpillat, P., Van Broeckhoven, C. and Brice, A. (2007), Progranulin null mutations in both sporadic and familial frontotemporal dementia. Hum. Mutat., 28: 846–855. doi: 10.1002/humu.20520
Communicated by Jean-Louis Mandel
The members of the French Research Network on FTD/FTD-MND are listed in Appendix A.
- Issue published online: 26 JUL 2007
- Article first published online: 13 APR 2007
- Manuscript Accepted: 9 FEB 2007
- Manuscript Received: 12 OCT 2006
- Agence Nationale pour la Recherche
- France-Alzheimer Association
- University of Antwerp
- Interuniversity Attraction Poles Program P5/19 of the Belgian Science Policy Office
- International Alzheimer Research Foundation, Belgium
- Zenith Award of the Alzheimer's Association, USA
- Institute for Science and Technology Flanders (IWT-F), Belgium
- CRIC AP-HP. Grant Number: 01107
- EU. Grant Number: LSHMCT-2003-503330 (APOPIS)
- GIS-Institut des Maladies Rares. Grant Numbers: A03081DS, APS03002DSA
- frontotemporal dementia;
- ubiquitin-immunoreactive inclusions;
- TAR DNA-binding protein
Frontotemporal dementia (FTD) is the second most frequent type of neurodegenerative dementias. Mutations in the progranulin gene (GRN, PGRN) were recently identified in FTDU-17, an FTD subtype characterized by ubiquitin-immunoreactive inclusions and linkage to chromosome 17q21. We looked for PGRN mutations in a large series of 210 FTD patients (52 familial, 158 sporadic) to accurately evaluate the frequency of PGRN mutations in both sporadic and familial FTD, and FTD with associated motoneuron disease (FTD-MND), as well as to study the clinical phenotype of patients with a PGRN mutation. We identified nine novel PGRN null mutations in 10 index patients. The relative frequency of PGRN null mutations in FTD was 4.8% (10/210) and 12.8% (5/39) in pure familial forms. Interestingly, 5/158 (3.2%) apparently sporadic FTD patients carried a PGRN mutation, suggesting the possibility of de novo mutations or incomplete penetrance. In contrast, none of the 43 patients with FTD-MND had PGRN mutations, supporting that FTDU-17 and FTD-MND are genetically distinct. The clinical phenotype of PGRN mutation carriers was particular because of the wide range in onset age and the frequent occurrence of early apraxia (50%), visual hallucinations (30%), and parkinsonism (30%) during the course of the disease. This study supports that PGRN null mutations represent a more frequent cause of FTD than MAPT mutations (4.8% vs. 2.9%) but are not responsible for FTD-MND. It also demonstrates that half of the patients with a PGRN mutation in our series had no apparent family history of dementia. Taking this into account, genetic testing should be now considered more systematically, even in patients without obvious familial history of FTD. Hum Mutat 28(9), 846–855, 2007. © 2007 Wiley-Liss, Inc.