Mutations other than null mutations producing a pathogenic loss of progranulin in frontotemporal dementia
Year: 2007
Type: article
Study design: Observational Study
Abstract: 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.
Source: Human Mutation
DOI: 10.1002/humu.9484
Authors: Julie van der Zee, Isabelle Le Ber, Sebastian Maurer-Stroh, Sebastiaan Engelborghs, Ilse Gijselinck, Agnès Camuzat, Nathalie Brouwers, Rik Vandenberghe, Kristel Sleegers, Didier Hannequin, Bart Dermaut, Joost Schymkowitz, Dominique Campion, Patrick Santens, Jean-Jacques Martin, Lucette Lacomblez, Tim De Pooter, Karin Peeters, Maria Mattheijssens, Martine Vercelletto, Marleen Van den Broeck, Marc Cruts, Peter P. De Deyn, Frederic Rousseau, Alexis Brice, Christine Van Broeckhoven
Institutions: University of Antwerp, VIB-UAntwerp Center for Molecular Neurology, Inserm, Assistance Publique – Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Vrije Universiteit Brussel, ZNA Middelheim Hospital, KU Leuven, Centre Hospitalier Universitaire de Rouen, Ghent University Hospital, Institute Born-Bunge, Université Pierre-et-Marie-Curie, Centre Hospitalier Universitaire de Nantes
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: Neurosearch Antwerp, Institut National de la Santé et de la Recherche Médicale, Belgian Federal Science Policy Office, Fonds Wetenschappelijk Onderzoek, GIS-Institut des Maladies Rares, Universiteit Antwerpen, Internationale Stichting Alzheimer Onderzoek, Vlaamse regering, Instituut Born-Bunge, Fondation pour la Recherche sur Alzheimer, Bijzonder Onderzoeksfonds UGent
OpenAlex ID: W2021985297