GRN deletion in familial frontotemporal dementia showing association with clinical variability in 3 familial cases.
Progranulin (GRN) gene mutations have been genetically associated with frontotemporal dementia (FTD) and are present in about 23% of patients with familial FTD. However, the neurobiology of this secreted glycoprotein remains unclear. Here, we report the identification of 3 pedigrees of Southern Italian extraction in whom FTD segregates with autosomal dominant inheritance patterns. We present evidence that all the available patients in these 3 familial cases are carrying the rare GRN gene exon 6 deletion g10325_10331delCTGCTGT (relative to nt 1 inNG_007886.1), alias Cys157LysfsX97. This mutation was previously described in 2 sporadic cases but was never associated with familial cases. Our patients demonstrate heterogeneous clinical phenotypes, such as the behavioral variant (bvFTD) in the affected men and the nonfluent/agrammatic variant of primary progressive aphasia (nfvPPA) in the affected woman. Haploinsufficiency was revealed by both quantitative real-time PCR of the gene and protein analyses. These findings provide further support for a previously proposed role for the GRN gene in the genetic etiology of FTD and its phenotypic variability.
Geriatric Clinic "Frullone" ASL Napoli 1, Naples, Italy.
Graziella
G
Milan
Institute of Protein Biochemistry (IBP), CNR, Naples, Italy.
Sabrina
S
Napoletano
Institute of Bioimaging and Biostructures, CNR, Naples, Italy.
Sabina
S
Pappatà
Department of Environmental, Biological, Pharmaceutical Science and Technology, Second University of Naples, Caserta, Italy.
Maria Teresa
MT
Gentile
Department of Environmental, Biological, Pharmaceutical Science and Technology, Second University of Naples, Caserta, Italy.
Luca
L
Colucci-D'Amato
Villa Camaldoli Foundation Clinic, Naples, Italy.
Gennaro
G
Della Rocca
IRCCS Multimedica, Milano, Italy.
Anna
A
Maciag
Department of Clinical Medicine & Surgery, University of Naples "Federico II", Naples, Italy.
Carmen Palermo
CP
Rossetti
Department of Biology, University of Naples Federico II, Naples, Italy.
Laura
L
Fucci
IRCCS Multimedica, Milano, Italy; Department of Medicine, University of Salerno, Salerno, Italy.
Annibale
A
Puca
Villa Camaldoli Foundation Clinic, Naples, Italy; Department of Psychology, Second University of Naples, Caserta, Italy.
Dario
D
Grossi
Department of Clinical Medicine & Surgery, University of Naples "Federico II", Naples, Italy.
Alfredo
A
Postiglione
Institute of Protein Biochemistry (IBP), CNR, Naples, Italy. Electronic address: emilia.vitale@cnr.it.
Emilia
E
Vitale
D000368:Aged; D000369:Aged, 80 and over; D005091:Exons / Q000235:genetics; D005260:Female; D057180:Frontotemporal Dementia / Q000235:genetics*; D017353:Gene Deletion; D005799:Genes, Dominant / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D057895:Haploinsufficiency / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D007558:Italy; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D000077153:Progranulins; D060888:Real-Time Polymerase Chain Reaction
C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins
Frontotemporal dementia; Phenotype; Progranulin