Progranulin null mutations in both sporadic and familial frontotemporal dementia.
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.
Le Ber
Isabelle
I
INSERM, UMR679, Paris, France.
van der Zee
Julie
J
Hannequin
Didier
D
Gijselinck
Ilse
I
Campion
Dominique
D
Puel
Michèle
M
Laquerrière
Annie
A
De Pooter
Tim
T
Camuzat
Agnès
A
Van den Broeck
Marleen
M
Dubois
Bruno
B
Sellal
François
F
Lacomblez
Lucette
L
Vercelletto
Martine
M
Thomas-Antérion
Catherine
C
Michel
Bernard-François
BF
Golfier
Véronique
V
Didic
Mira
M
Salachas
François
F
Duyckaerts
Charles
C
Cruts
Marc
M
Verpillat
Patrice
P
Van Broeckhoven
Christine
C
Brice
Alexis
A
D000368:Aged; D000369:Aged, 80 and over; D018389:Codon, Nonsense / Q000032:analysis; D003704:Dementia / Q000235:genetics* / Q000473:pathology; D005260:Female; D005820:Genetic Testing; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D000077153:Progranulins; D016875:tau Proteins / Q000235:genetics
D018389:Codon, Nonsense; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; C054369:MAPT protein, human; D000077153:Progranulins; D016875:tau Proteins