title: Molecular characterization of novel progranulin (GRN) mutations in frontotemporal dementia.
abstract: Frontotemporal dementia (FTD) is a clinical term encompassing dementia characterized by the presence of two major phenotypes: 1) behavioral and personality disorder, and 2) language disorder, which includes primary progressive aphasia and semantic dementia. Recently, the gene for familial frontotemporal lobar degeneration (FTLD) with ubiquitin-positive, tau-negative inclusions (FTLD-U) linked to chromosome 17 was cloned. In the present study, 62 unrelated patients from the Washington University Alzheimer's Disease Research Center and the Midwest Consortium for FTD with clinically diagnosed FTD and/or neuropathologically characterized cases of FTLD-U with or without motor neuron disease (MND) were screened for mutations in the progranulin gene (GRN; also PGRN). We discovered two pathogenic mutations in four families: 1) a single-base substitution within the 3' splice acceptor site of intron 6/exon 7 (g.5913A>G [IVS6-2A>G]) causing skipping of exon 7 and premature termination of the coding sequence (PTC); and 2) a missense mutation in exon 1 (g.4068C>A) introducing a charged amino acid in the hydrophobic core of the signal peptide at residue 9 (p.A9D). Functional analysis in mutation carriers for the splice acceptor site mutation revealed a 50% decrease in GRN mRNA and protein levels, supporting haploinsufficiency. In contrast, there was no significant difference in the total GRN mRNA between cases and controls carrying the p.A9D mutation. Further, subcellular fractionation and confocal microscopy indicate that although the mutant protein is expressed, it is not secreted, and appears to be trapped within an intracellular compartment, possibly resulting in a functional haploinsufficiency.
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Odity
authors.initials: O
authors.lastname: Mukherjee
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Michael
authors.initials: M
authors.lastname: Gitcho
authors.forename: Sumi
authors.initials: S
authors.lastname: Chakraverty
authors.forename: Lisa
authors.initials: L
authors.lastname: Taylor-Reinwald
authors.forename: Shantia
authors.initials: S
authors.lastname: Shears
authors.forename: John S K
authors.initials: JS
authors.lastname: Kauwe
authors.forename: Joanne
authors.initials: J
authors.lastname: Norton
authors.forename: Denise
authors.initials: D
authors.lastname: Levitch
authors.forename: Eileen H
authors.initials: EH
authors.lastname: Bigio
authors.forename: Kimmo J
authors.initials: KJ
authors.lastname: Hatanpaa
authors.forename: Charles L
authors.initials: CL
authors.lastname: White
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Cairns
authors.forename: Alison
authors.initials: A
authors.lastname: Goate
mesh_terms: D017668:Age of Onset; D000368:Aged; D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D016022:Case-Control Studies; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D003704:Dementia / Q000134:cerebrospinal fluid / Q000235:genetics* / Q000378:metabolism; D005260:Female; D018703:Founder Effect; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000134:cerebrospinal fluid / Q000235:genetics* / Q000378:metabolism; D007438:Introns; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D000077153:Progranulins; D022821:RNA Splice Sites; D012326:RNA Splicing / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D014162:Transfection
chemical_list: D017931:DNA Primers; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D022821:RNA Splice Sites; D012333:RNA, Messenger