Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration.
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.
Gass
Jennifer
J
Department of Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
Cannon
Ashley
A
Mackenzie
Ian R
IR
Boeve
Bradley
B
Baker
Matt
M
Adamson
Jennifer
J
Crook
Richard
R
Melquist
Stacey
S
Kuntz
Karen
K
Petersen
Ron
R
Josephs
Keith
K
Pickering-Brown
Stuart M
SM
Graff-Radford
Neill
N
Uitti
Ryan
R
Dickson
Dennis
D
Wszolek
Zbigniew
Z
Gonzalez
John
J
Beach
Thomas G
TG
Bigio
Eileen
E
Johnson
Nancy
N
Weintraub
Sandra
S
Mesulam
Marsel
M
White
Charles L
CL
Woodruff
Bryan
B
Caselli
Richard
R
Hsiung
Ging-Yuek
GY
Feldman
Howard
H
Knopman
Dave
D
Hutton
Mike
M
Rademakers
Rosa
R
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*
C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D025801:Ubiquitin