title: Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17.
abstract: Frontotemporal dementia (FTD) is the second most common cause of dementia in people under the age of 65 years. A large proportion of FTD patients (35-50%) have a family history of dementia, consistent with a strong genetic component to the disease. In 1998, mutations in the gene encoding the microtubule-associated protein tau (MAPT) were shown to cause familial FTD with parkinsonism linked to chromosome 17q21 (FTDP-17). The neuropathology of patients with defined MAPT mutations is characterized by cytoplasmic neurofibrillary inclusions composed of hyperphosphorylated tau. However, in multiple FTD families with significant evidence for linkage to the same region on chromosome 17q21 (D17S1787-D17S806), mutations in MAPT have not been found and the patients consistently lack tau-immunoreactive inclusion pathology. In contrast, these patients have ubiquitin (ub)-immunoreactive neuronal cytoplasmic inclusions and characteristic lentiform ub-immunoreactive neuronal intranuclear inclusions. Here we demonstrate that in these families, FTD is caused by mutations in progranulin (PGRN) that are likely to create null alleles. PGRN is located 1.7 Mb centromeric of MAPT on chromosome 17q21.31 and encodes a 68.5-kDa secreted growth factor involved in the regulation of multiple processes including development, wound repair and inflammation. PGRN has also been strongly linked to tumorigenesis. Moreover, PGRN expression is increased in activated microglia in many neurodegenerative diseases including Creutzfeldt-Jakob disease, motor neuron disease and Alzheimer's disease. Our results identify mutations in PGRN as a cause of neurodegenerative disease and indicate the importance of PGRN function for neuronal survival.
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, Florida 32224, USA.
authors.forename: Matt
authors.initials: M
authors.lastname: Baker
authors.forename: Ian R
authors.initials: IR
authors.lastname: Mackenzie
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Pickering-Brown
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gass
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
authors.forename: Caroline
authors.initials: C
authors.lastname: Lindholm
authors.forename: Julie
authors.initials: J
authors.lastname: Snowden
authors.forename: Jennifer
authors.initials: J
authors.lastname: Adamson
authors.forename: A Dessa
authors.initials: AD
authors.lastname: Sadovnick
authors.forename: Sara
authors.initials: S
authors.lastname: Rollinson
authors.forename: Ashley
authors.initials: A
authors.lastname: Cannon
authors.forename: Emily
authors.initials: E
authors.lastname: Dwosh
authors.forename: David
authors.initials: D
authors.lastname: Neary
authors.forename: Stacey
authors.initials: S
authors.lastname: Melquist
authors.forename: Anna
authors.initials: A
authors.lastname: Richardson
authors.forename: Dennis
authors.initials: D
authors.lastname: Dickson
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Berger
authors.forename: Jason
authors.initials: J
authors.lastname: Eriksen
authors.forename: Todd
authors.initials: T
authors.lastname: Robinson
authors.forename: Cynthia
authors.initials: C
authors.lastname: Zehr
authors.forename: Chad A
authors.initials: CA
authors.lastname: Dickey
authors.forename: Richard
authors.initials: R
authors.lastname: Crook
authors.forename: Eileen
authors.initials: E
authors.lastname: McGowan
authors.forename: David
authors.initials: D
authors.lastname: Mann
authors.forename: Bradley
authors.initials: B
authors.lastname: Boeve
authors.forename: Howard
authors.initials: H
authors.lastname: Feldman
authors.forename: Mike
authors.initials: M
authors.lastname: Hutton
mesh_terms: D002470:Cell Survival; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D018388:Codon, Terminator / Q000235:genetics; D003704:Dementia / Q000235:genetics* / Q000503:physiopathology; D005625:Frontal Lobe / Q000378:metabolism / Q000503:physiopathology*; D008040:Genetic Linkage / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D020161:Physical Chromosome Mapping; D000077153:Progranulins; D011498:Protein Precursors / Q000235:genetics* / Q000378:metabolism; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013702:Temporal Lobe / Q000378:metabolism / Q000503:physiopathology*; D016875:tau Proteins / Q000172:deficiency / Q000235:genetics
chemical_list: D018388:Codon, Terminator; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D011498:Protein Precursors; D012333:RNA, Messenger; D016875:tau Proteins