title: Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration.
abstract: Null mutations in the progranulin gene (PGRN) were recently reported to cause tau-negative frontotemporal dementia linked to chromosome 17. We assessed the genetic contribution of PGRN mutations in an extended population of patients with frontotemporal lobar degeneration (FTLD) (N=378). Mutations were identified in 10% of the total FTLD population and 23% of patients with a positive family history. This mutation frequency dropped to 5% when analysis was restricted to an unbiased FTLD subpopulation (N=167) derived from patients referred to Alzheimer's Disease Research Centers (ADRC). Among the ADRC patients, PGRN mutations were equally frequent as mutations in the tau gene (MAPT). We identified 23 different pathogenic PGRN mutations, including a total of 21 nonsense, frameshift and splice-site mutations that cause premature termination of the coding sequence and degradation of the mutant RNA by nonsense-mediated decay. We also observed an unusual splice-site mutation in the exon 1 5' splice site, which leads to loss of the Kozac sequence, and a missense mutation in the hydrophobic core of the PGRN signal peptide. Both mutations revealed novel mechanisms that result in loss of functional PGRN. One mutation, c.1477C>T (p.Arg493X), was detected in eight independently ascertained familial FTLD patients who were shown to share a common extended haplotype over the PGRN genomic region. Clinical examination of patients with PGRN mutations revealed highly variable onset ages with language dysfunction as a common presenting symptom. Neuropathological examination showed FTLD with ubiquitin-positive cytoplasmic and intranuclear inclusions in all PGRN mutation carriers.
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gass
authors.forename: Ashley
authors.initials: A
authors.lastname: Cannon
authors.forename: Ian R
authors.initials: IR
authors.lastname: Mackenzie
authors.forename: Bradley
authors.initials: B
authors.lastname: Boeve
authors.forename: Matt
authors.initials: M
authors.lastname: Baker
authors.forename: Jennifer
authors.initials: J
authors.lastname: Adamson
authors.forename: Richard
authors.initials: R
authors.lastname: Crook
authors.forename: Stacey
authors.initials: S
authors.lastname: Melquist
authors.forename: Karen
authors.initials: K
authors.lastname: Kuntz
authors.forename: Ron
authors.initials: R
authors.lastname: Petersen
authors.forename: Keith
authors.initials: K
authors.lastname: Josephs
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Pickering-Brown
authors.forename: Neill
authors.initials: N
authors.lastname: Graff-Radford
authors.forename: Ryan
authors.initials: R
authors.lastname: Uitti
authors.forename: Dennis
authors.initials: D
authors.lastname: Dickson
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Wszolek
authors.forename: John
authors.initials: J
authors.lastname: Gonzalez
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Beach
authors.forename: Eileen
authors.initials: E
authors.lastname: Bigio
authors.forename: Nancy
authors.initials: N
authors.lastname: Johnson
authors.forename: Sandra
authors.initials: S
authors.lastname: Weintraub
authors.forename: Marsel
authors.initials: M
authors.lastname: Mesulam
authors.forename: Charles L
authors.initials: CL
authors.lastname: White
authors.forename: Bryan
authors.initials: B
authors.lastname: Woodruff
authors.forename: Richard
authors.initials: R
authors.lastname: Caselli
authors.forename: Ging-Yuek
authors.initials: GY
authors.lastname: Hsiung
authors.forename: Howard
authors.initials: H
authors.lastname: Feldman
authors.forename: Dave
authors.initials: D
authors.lastname: Knopman
authors.forename: Mike
authors.initials: M
authors.lastname: Hutton
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis; D001923:Brain Chemistry; D003704:Dementia / Q000235:genetics* / Q000378:metabolism; D018703:Founder Effect; D018628:Gene Dosage; D005838:Genotype; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D000077153:Progranulins; D025801:Ubiquitin / Q000235:genetics*
chemical_list: C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D025801:Ubiquitin