title: Reduced secretion and altered proteolytic processing caused by missense mutations in progranulin.
abstract: Progranulin (GRN) is a secreted growth factor involved in various cellular functions, and loss-of-function mutations are a major cause of frontotemporal lobar degeneration (FTLD) with TDP-43 positive pathology. Most FTLD-related GRN mutations are nonsense mutations resulting in reduced GRN expression. Nonsynonymous GRN missense mutations have been described as risk factor for neurodegenerative brain diseases, but their pathogenic nature remains largely elusive. We identified a double missense mutation in GRN leading to amino acid changes p.D33E and p.G35R in an FTLD patient from Turkish origin. Biochemical and cell biological analysis of the double-mutation together with 2 so-far uncharacterized GRN missense mutations (p.C105R and p.V514M) revealed a reduced secretion efficiency of the GRN p.D33E/p.G35R and p.C105R proteins. Furthermore, loss of the conserved cysteine residue affects protein folding and altered proteolytic processing by neutrophil elastase and proteinase 3. Our data indicate that the described variants may cause a loss-of-function, albeit to a lesser extent than GRN null mutations, and hence could be considered as low-penetrant risk factors for neurodegenerative diseases.
authors.affiliation: Biochemistry, Biomedical Center (BMC), Ludwig-Maximilians University, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; Department of Molecular Genetics, Neurodegenerative Brain Diseases Group, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. Electronic address: gernot.kleinberger@mail03.med.uni-muenchen.de.
authors.forename: Gernot
authors.initials: G
authors.lastname: Kleinberger
authors.affiliation: Biochemistry, Biomedical Center (BMC), Ludwig-Maximilians University, Munich, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Capell
authors.affiliation: Department of Molecular Genetics, Neurodegenerative Brain Diseases Group, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Brouwers
authors.affiliation: Biochemistry, Biomedical Center (BMC), Ludwig-Maximilians University, Munich, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Fellerer
authors.affiliation: Department of Molecular Genetics, Neurodegenerative Brain Diseases Group, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Kristel
authors.initials: K
authors.lastname: Sleegers
authors.affiliation: Department of Molecular Genetics, Neurodegenerative Brain Diseases Group, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: Cruts
authors.affiliation: Department of Molecular Genetics, Neurodegenerative Brain Diseases Group, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
authors.affiliation: Biochemistry, Biomedical Center (BMC), Ludwig-Maximilians University, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; German Center for Neurodegenerative Diseases, DZNE, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Haass
mesh_terms: D003545:Cysteine; D004268:DNA-Binding Proteins / Q000378:metabolism; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D019272:Leukocyte Elastase / Q000502:physiology; D020125:Mutation, Missense; D053146:Myeloblastin / Q000502:physiology; D000077153:Progranulins; D017510:Protein Folding; D059748:Proteolysis; D012307:Risk Factors
chemical_list: D004268:DNA-Binding Proteins; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; C000598624:TARDBP protein, human; D019272:Leukocyte Elastase; D053146:Myeloblastin; D003545:Cysteine
keywords: Frontotemporal dementia; Granulin; Missense mutation; Progranulin; Protein processing