title: Missense mutation in GRN gene affecting RNA splicing and plasma progranulin level in a family affected by frontotemporal lobar degeneration.
abstract: Gene coding for progranulin, GRN, is a major gene linked to frontotemporal lobar degeneration. While most of pathogenic GRN mutations are null mutations leading to haploinsufficiency, GRN missense mutations do not have an obvious pathogenicity, and only a few have been revealed to act through different pathogenetic mechanisms, such as cytoplasmic missorting, protein degradation, and abnormal cleavage by elastase. The aim of this study was to disclose the pathogenetic mechanisms of the GRN A199V missense mutation, which was previously reported not to alter physiological progranulin features but was associated with a reduced plasma progranulin level. After investigating the family pedigree, we performed genetic and biochemical analysis on its members and performed RNA expression studies. We found that the mutation segregates with the disease and discovered that its pathogenic feature is the alteration of GRN mRNA splicing, actually leading to haploinsufficiency. Thus, when facing with a missense GRN mutation, its pathogenetic effects should be investigated, especially if associated with low plasma progranulin levels, to determine its nature of either benign polymorphism or pathogenic mutation.
authors.affiliation: Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Luzzi
authors.affiliation: Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
authors.forename: Lara
authors.initials: L
authors.lastname: Colleoni
authors.affiliation: Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Corbetta
authors.affiliation: Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Baldinelli
authors.affiliation: Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Fiori
authors.affiliation: Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Girelli
authors.affiliation: Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Silvestrini
authors.affiliation: Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Caroppo
authors.affiliation: Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Giaccone
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: giacomina.rossi@istituto-besta.it.
authors.forename: Giacomina
authors.initials: G
authors.lastname: Rossi
mesh_terms: D000368:Aged; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000097:blood* / Q000235:genetics*; D056726:Genetic Association Studies; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D000077153:Progranulins; D012326:RNA Splicing / Q000235:genetics*
chemical_list: C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins
keywords: Frontotemporal lobar degeneration; GRN; Mutation; Progranulin; RNA; Splicing