title: Mutations other than null mutations producing a pathogenic loss of progranulin in frontotemporal dementia.
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.
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: van der Zee
authors.forename: Isabelle
authors.initials: I
authors.lastname: Le Ber
authors.forename: Sebastian
authors.initials: S
authors.lastname: Maurer-Stroh
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Engelborghs
authors.forename: Ilse
authors.initials: I
authors.lastname: Gijselinck
authors.forename: Agnès
authors.initials: A
authors.lastname: Camuzat
authors.forename: Nathalie
authors.initials: N
authors.lastname: Brouwers
authors.forename: Rik
authors.initials: R
authors.lastname: Vandenberghe
authors.forename: Kristel
authors.initials: K
authors.lastname: Sleegers
authors.forename: Didier
authors.initials: D
authors.lastname: Hannequin
authors.forename: Bart
authors.initials: B
authors.lastname: Dermaut
authors.forename: Joost
authors.initials: J
authors.lastname: Schymkowitz
authors.forename: Dominique
authors.initials: D
authors.lastname: Campion
authors.forename: Patrick
authors.initials: P
authors.lastname: Santens
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Martin
authors.forename: Lucette
authors.initials: L
authors.lastname: Lacomblez
authors.forename: Tim
authors.initials: T
authors.lastname: De Pooter
authors.forename: Karin
authors.initials: K
authors.lastname: Peeters
authors.forename: Maria
authors.initials: M
authors.lastname: Mattheijssens
authors.forename: Martine
authors.initials: M
authors.lastname: Vercelletto
authors.forename: Marleen
authors.initials: M
authors.lastname: Van den Broeck
authors.forename: Marc
authors.initials: M
authors.lastname: Cruts
authors.forename: Peter P
authors.initials: PP
authors.lastname: De Deyn
authors.forename: Frederic
authors.initials: F
authors.lastname: Rousseau
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D016022:Case-Control Studies; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D003704:Dementia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D000077153:Progranulins; D011487:Protein Conformation; D017510:Protein Folding; D017434:Protein Structure, Tertiary
chemical_list: C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins