title: Plasma progranulin levels predict progranulin mutation status in frontotemporal dementia patients and asymptomatic family members.
abstract: Mutations in the progranulin gene (GRN) are an important cause of frontotemporal lobar degeneration (FTLD) with ubiquitin and TAR DNA-binding protein 43 (TDP43)-positive pathology. The clinical presentation associated with GRN mutations is heterogeneous and may include clinical probable Alzheimer's disease. All GRN mutations identified thus far cause disease through a uniform disease mechanism, i.e. the loss of functional GRN or haploinsufficiency. To determine if expression of GRN in plasma could predict GRN mutation status and could be used as a biological marker, we optimized a GRN ELISA and studied plasma samples of a consecutive clinical FTLD series of 219 patients, 70 control individuals, 72 early-onset probable Alzheimer's disease patients and nine symptomatic and 18 asymptomatic relatives of GRN mutation families. All FTLD patients with GRN loss-of-function mutations showed significantly reduced levels of GRN in plasma to about one third of the levels observed in non-GRN carriers and control individuals (P < 0.001). No overlap in distributions of GRN levels was observed between the eight GRN loss-of-function mutation carriers (range: 53-94 ng/ml) and 191 non-GRN mutation carriers (range: 115-386 ng/ml). Similar low levels of GRN were identified in asymptomatic GRN mutation carriers. Importantly, ELISA analyses also identified one probable Alzheimer's disease patient (1.4%) carrying a loss-of-function mutation in GRN. Biochemical analyses further showed that the GRN ELISA only detects full-length GRN, no intermediate granulin fragments. This study demonstrates that using a GRN ELISA in plasma, pathogenic GRN mutations can be accurately detected in symptomatic and asymptomatic carriers. The approximately 75% reduction in full-length GRN, suggests an unbalanced GRN metabolism in loss-of-function mutation carriers whereby more GRN is processed into granulins. We propose that plasma GRN levels could be used as a reliable and inexpensive tool to identify all GRN mutation carriers in early-onset dementia populations and asymptomatic at-risk individuals.
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: NiCole
authors.initials: N
authors.lastname: Finch
authors.forename: Matt
authors.initials: M
authors.lastname: Baker
authors.forename: Richard
authors.initials: R
authors.lastname: Crook
authors.forename: Katie
authors.initials: K
authors.lastname: Swanson
authors.forename: Karen
authors.initials: K
authors.lastname: Kuntz
authors.forename: Rebecca
authors.initials: R
authors.lastname: Surtees
authors.forename: Gina
authors.initials: G
authors.lastname: Bisceglio
authors.forename: Anne
authors.initials: A
authors.lastname: Rovelet-Lecrux
authors.forename: Bradley
authors.initials: B
authors.lastname: Boeve
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.forename: Steven G
authors.initials: SG
authors.lastname: Younkin
authors.forename: Vincent
authors.initials: V
authors.lastname: Deramecourt
authors.forename: Julia
authors.initials: J
authors.lastname: Crook
authors.forename: Neill R
authors.initials: NR
authors.lastname: Graff-Radford
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
mesh_terms: D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000097:blood / Q000175:diagnosis / Q000235:genetics; D015415:Biomarkers / Q000097:blood; D015331:Cohort Studies; D003704:Dementia / Q000097:blood / Q000175:diagnosis* / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005192:Family Health; D005260:Female; D006579:Heterozygote; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000077153:Progranulins; D012680:Sensitivity and Specificity
chemical_list: D015415:Biomarkers; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins