title: Understanding phenotype variability in frontotemporal lobar degeneration due to granulin mutation.
abstract: Phenotype in patients with granulin (GRN) mutations is unpredictable, ranging from behavioral variant frontotemporal dementia (bvFTD) to agrammatic variant of primary progressive aphasia (avPPA). To date the wide clinical variability of FTLD-GRN remains unexplained. The aim of the study was to identify genetic pathways differentiating phenotypic expression in patients carrying GRN mutations. Patients carrying the same GRNT272SfsX10 mutation were enrolled, a careful clinical assessment was carried out, and the diagnosis of either bvFTD (n = 10, age = 63.9 ± 9.4) or avPPA (n = 6, age = 58.8 ± 4.7) was done. Microarray gene expression analysis on leukocytes was performed. Genes differentially expressed between the groups were validated by real time polymerase chain reaction considering an age-matched healthy controls group (n = 16, age = 58.4 ± 10.7). We further considered a group of FTD with no GRN mutations (GRN-) (n = 21, 13 bvFTD, and 8 avPPA) for comparisons. Real-time polymerase chain reaction (PCR) confirmed a significant decrease in leukocytes mRNA messenger RNA (mRNA) levels of RAP1GAP in bvFTD patients as compared with avPPA (p = 0.049). This finding was specific for patients with GRN mutations, as we did not observe this pattern in FTD GRN-patients (p = 0.99). The alteration of RAP1GAP mRNA levels may explain the clinical variability of GRN-FTLD patients. This is the first report linking a molecular pathway to specific phenotype expression in FTLD-GRN. To understand the clinical relevance of our early results it will be mandatory to extend the observation to other clinical and neuropathological series.
authors.affiliation: Genetic Unit, IRCCS S.Giovanni di Dio, Fatebenefratelli, Brescia, Italy.
authors.forename: Cristian
authors.initials: C
authors.lastname: Bonvicini
authors.affiliation: Genetic Unit, IRCCS S.Giovanni di Dio, Fatebenefratelli, Brescia, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Milanesi
authors.affiliation: Centre for Neurodegenerative Disorders, Neurology Unit, University of Brescia, Brescia, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pilotto
authors.affiliation: Departement of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Cattane
authors.affiliation: Centre for Neurodegenerative Disorders, Neurology Unit, University of Brescia, Brescia, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Premi
authors.affiliation: Department of Laboratories, III Laboratory of Analysis, Brescia Hospital, Brescia, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Archetti
authors.affiliation: Centre for Neurodegenerative Disorders, Neurology Unit, University of Brescia, Brescia, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Padovani
authors.affiliation: Genetic Unit, IRCCS S.Giovanni di Dio, Fatebenefratelli, Brescia, Italy; Departement of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Gennarelli
authors.affiliation: Centre for Neurodegenerative Disorders, Neurology Unit, University of Brescia, Brescia, Italy. Electronic address: bborroni@inwind.it.
authors.forename: Barbara
authors.initials: B
authors.lastname: Borroni
mesh_terms: D000368:Aged; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics*; D020690:GTPase-Activating Proteins / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D007962:Leukocytes; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D016133:Polymerase Chain Reaction; D000077153:Progranulins; D012333:RNA, Messenger
chemical_list: D020690:GTPase-Activating Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; C484658:RAP1GAP protein, human; D012333:RNA, Messenger
keywords: Frontotemporal dementia; GRN mutations; Genetic modulation; Phenotype variability; avPPA; bvFTD