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Progranulin null mutations in both sporadic and familial frontotemporal dementia
Author(s) -
Le Ber Isabelle,
van der Zee Julie,
Hannequin Didier,
Gijselinck Ilse,
Campion Dominique,
Puel Michèle,
Laquerrière Annie,
De Pooter Tim,
Camuzat Agnès,
Van den Broeck Marleen,
Dubois Bruno,
Sellal François,
Lacomblez Lucette,
Vercelletto Martine,
ThomasAntérion Catherine,
Michel BernardFrançois,
Golfier Véronique,
Didic Mira,
Salachas François,
Duyckaerts Charles,
Cruts Marc,
Verpillat Patrice,
Van Broeckhoven Christine,
Brice Alexis
Publication year - 2007
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.20520
Subject(s) - frontotemporal dementia , biology , parkinsonism , mutation , genetics , dementia , penetrance , frontotemporal lobar degeneration , null allele , phenotype , disease , pathology , gene , medicine
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.