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Mutations other than null mutations producing a pathogenic loss of progranulin in frontotemporal dementia

2007; Wiley; Volume: 28; Issue: 4 Linguagem: Inglês

10.1002/humu.9484

1098-1004

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 Paul De Deyn, Frédéric Rousseau, Alexis Brice, Christine Van Broeckhoven,

Parkinson's Disease Mechanisms and Treatments

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. © 2007 Wiley-Liss, Inc.