title: Missense mutations in progranulin gene associated with frontotemporal lobar degeneration: study of pathogenetic features.
abstract: GRN, the gene coding for the progranulin (PGRN) protein, was recognized as a gene linked to frontotemporal lobar degeneration (FTLD). The first mutations identified were null mutations giving rise to haploinsufficiency. Missense mutations were subsequently detected, but only a small subset has been functionally investigated. We identified missense mutations (C105Y, A199V, and R298H) in FTLD cases with family history and/or with low plasma PGRN levels. The aim of this study was to determine their pathogenicity. We performed functional studies, analyzing PGRN expression, secretion, and cleavage by elastase. GRN C105Y affected both secretion and elastase cleavage, likely representing a pathogenic mutation. GRN A199V did not alter the physiological properties of PGRN and GRN R298H produced only moderate effects on PGRN secretion, indicating that their pathogenicity is uncertain. In the absence of strong segregation data and neuropathological examinations, genetic, biomarker, and functional studies can be applied to an algorithm to assess the likelihood of pathogenicity for a mutation. This information can improve our understanding of the complex mechanisms by which GRN mutations lead to FTLD.
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA; Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: Celeste M
authors.initials: CM
authors.lastname: Karch
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: Lubov
authors.initials: L
authors.lastname: Ezerskiy
authors.affiliation: Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Redaelli
authors.affiliation: Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
authors.forename: Anna Rita
authors.initials: AR
authors.lastname: Giovagnoli
authors.affiliation: Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Tiraboschi
authors.affiliation: Division of Neurology, Geriatric Hospital, INRCA-IRCCS, Ancona, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pelliccioni
authors.affiliation: Division of Neurology, Geriatric Hospital, INRCA-IRCCS, Ancona, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Pelliccioni
authors.affiliation: Bioinformatics Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
authors.forename: Dimos
authors.initials: D
authors.lastname: Kapetis
authors.affiliation: Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: D'Amato
authors.affiliation: Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Piccoli
authors.affiliation: Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
authors.forename: Maria Giulia
authors.initials: MG
authors.lastname: Ferretti
authors.affiliation: Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Tagliavini
authors.affiliation: Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy. Electronic address: grossi@istituto-besta.it.
authors.forename: Giacomina
authors.initials: G
authors.lastname: Rossi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002475:Cellobiose / Q000031:analogs & derivatives; D015331:Cohort Studies; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics* / Q000473:pathology; D018628:Gene Dosage; D056726:Genetic Association Studies; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis / Q000235:genetics*; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D000077153:Progranulins
chemical_list: C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D002475:Cellobiose; C048667:cellobial
keywords: Frontotemporal lobar degeneration; Functional analysis; GRN; Mutation; Pathogenetic; Progranulin