title: A mutation in the 5'-UTR of GRN gene associated with frontotemporal lobar degeneration: phenotypic variability and possible pathogenetic mechanisms.
abstract: Frontotemporal lobar degeneration (FTLD) is a very heterogeneous disorder. It is genetically linked to three major genes: microtubule-associated protein tau (MAPT), progranulin (GRN), and C9ORF72. In particular, mutations in GRN account for 5-10% of all cases and give rise to a wide spectrum of clinical phenotypes, ranging from behavioral frontotemporal dementia (bvFTD) to primary progressive aphasia, including progressive non-fluent aphasia (PNFA) and semantic dementia, and corticobasal syndrome (CBS). We studied a family affected by FTLD whose members showed three different phenotypes: bvFTD, PNFA, and CBS. We performed plasma progranulin measurement before any genetic analyses and, due to the low level detected, we sequenced GRN and found the new mutation EX0-5' splice site A > G in the 5'-UTR region, where no pathogenic mutations had been previously demonstrated. Genetic analyses of MAPT and C9ORF72 were normal. GRN mRNA expression showed about 50% reduction caused by this mutation, and similar results were found for progranulin level. Testing of nonsense mediated RNA decay gave negative results, suggesting a different mechanism of mRNA degradation. In summary, the EX0-5' splice site A > G mutation widens the GRN regions affected by null mutations, including the 5'-UTR, and confirms once more the large phenotypic variability linked to GRN mutations.
authors.affiliation: Division of Neurology, Department of Clinical and Experimental Medicine, Second University of Naples, Italy.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Puoti
authors.affiliation: Division of Neurology, Department of Clinical and Experimental Medicine, Second University of Naples, Italy.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Lerza
authors.affiliation: Division of Neurology V - 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 - Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
authors.forename: Orso
authors.initials: O
authors.lastname: Bugiani
authors.affiliation: Division of Neurology V - Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Tagliavini
authors.affiliation: Division of Neurology V - Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
authors.forename: Giacomina
authors.initials: G
authors.lastname: Rossi
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics*; D000368:Aged; D000073885:C9orf72 Protein; D002461:Cell Line, Transformed; D004252:DNA Mutational Analysis; D004797:Enzyme-Linked Immunosorbent Assay; D005192:Family Health; D005260:Female; D019788:Fluorodeoxyglucose F18; D057174:Frontotemporal Lobar Degeneration / Q000097:blood / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D005838:Genotype; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood / Q000235:genetics*; D007558:Italy; D008214:Lymphocytes / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D049268:Positron-Emission Tomography; D000077153:Progranulins; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D020121:5' Untranslated Regions; D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D011506:Proteins; D012333:RNA, Messenger; D019788:Fluorodeoxyglucose F18
keywords: Frontotemporal lobar degeneration; GRN; haploinsufficiency; mutation; phenotype; progranulin