title: Novel progranulin variants do not disrupt progranulin secretion and cleavage.
abstract: A subset of frontotemporal dementia cases are neuropathologically defined by tau-negative, TAR DNA-binding protein-43, and ubiquitin-positive inclusions in the brain and are associated with mutations in the progranulin gene (GRN). Deep sequencing of families exhibiting late-onset dementia revealed several novel variants in GRN. Because of the small size of these families and limited availability of samples, it was not possible to determine whether the variants segregated with the disease. Furthermore, none of these families had autopsy confirmation of diagnosis. We sought to determine if these novel GRN variants alter progranulin (PGRN) protein stability, PGRN secretion, and PGRN cleavage in cultured cells. All the novel GRN variants behave like PGRN wild-type protein, suggesting that these variants represent rare polymorphisms. However, it remains possible that these variants affect other aspects of PGRN function or represent risk factors for dementia when combined with other modifying genes.
authors.affiliation: Department of Psychiatry and Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Celeste M
authors.initials: CM
authors.lastname: Karch
authors.forename: Amanda T
authors.initials: AT
authors.lastname: Jeng
authors.forename: Tara
authors.initials: T
authors.lastname: Skorupa
authors.forename: Carlos
authors.initials: C
authors.lastname: Cruchaga
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
mesh_terms: D002461:Cell Line, Transformed; D005786:Gene Expression Regulation / Q000235:genetics; D005838:Genotype; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics*; D000077153:Progranulins; D014162:Transfection
chemical_list: C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins
keywords: Frontotemporal dementia; Granulin; Late-onset Alzheimer's disease; Progranulin