title: Rs5848 variant influences GRN mRNA levels in brain and peripheral mononuclear cells in patients with Alzheimer's disease.
abstract: Mutations in the progranulin gene (GRN), causative for Frontotemporal Lobar Degeneration with ubiquitin-immunoreactive neuronal inclusions (FTLD-U), could also be associated with Alzheimer's disease (AD). The influence of GRN genetic variability on susceptibility to AD and on expression levels in a series of neuropathologically-confirmed AD patients as well as in peripheral mononuclear cells (PBMC) and in cells isolated from cerebrospinal fluid (CSF) was investigated. An association study of rs9897526 and rs5848 was carried out in an Italian population and in a replication population of European American patients and controls. None of the variants tested act as unequivocal susceptibility factor in both populations although rs9897526 anticipated the onset of the disease in the Italian population. GRN expression in the parietal lobe of AD cases showed a 0.76-fold decrease compared with controls (1.31 +/- 0.07 versus 1.73 +/- 0.12, P = 0.0025). Patients carrying the rs5848 TT genotype had the lowest GRN expression levels (0.96 +/- 0.12, P = 0.014). Despite no significant differences were found in the relative PBMC and CSF GRN expression in patients compared to controls, stratifying patients according to the presence of rs5848 T allele, a 0.57-fold decrease in GRN mRNA levels over C carriers was found in PBMC (1.22 +/- 0.23 versus 0.70 +/- 0.12, P = 0.04). Similarly to data obtained in brain samples, patients carrying the TT genotype showed the lowest GRN mRNA levels (TT = 0.46 +/- 0.14, CC = 1.22 +/- 0.23; P = 0.013). These data argue against a direct role of GRN as a susceptibility factor for sporadic AD but support a role of GRN as a disease-modifying gene, possibly contributing to the failure of neuronal survival.
authors.affiliation: Department of Neurological Sciences, Dino Ferrari Center, University of Milan, IRCCS Fondazione Ospedale Maggiore Policlinico, Milan, Italy. chiara.fenoglio@unimi.it
authors.forename: Chiara
authors.initials: C
authors.lastname: Fenoglio
authors.forename: Daniela
authors.initials: D
authors.lastname: Galimberti
authors.forename: Francesca
authors.initials: F
authors.lastname: Cortini
authors.forename: John S K
authors.initials: JS
authors.lastname: Kauwe
authors.forename: Carlos
authors.initials: C
authors.lastname: Cruchaga
authors.forename: Eliana
authors.initials: E
authors.lastname: Venturelli
authors.forename: Chiara
authors.initials: C
authors.lastname: Villa
authors.forename: Maria
authors.initials: M
authors.lastname: Serpente
authors.forename: Diego
authors.initials: D
authors.lastname: Scalabrini
authors.forename: Kevin
authors.initials: K
authors.lastname: Mayo
authors.forename: Laura M
authors.initials: LM
authors.lastname: Piccio
authors.forename: Francesca
authors.initials: F
authors.lastname: Clerici
authors.forename: Diego
authors.initials: D
authors.lastname: Albani
authors.forename: Claudio
authors.initials: C
authors.lastname: Mariani
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Forloni
authors.forename: Nereo
authors.initials: N
authors.lastname: Bresolin
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
authors.forename: Elio
authors.initials: E
authors.lastname: Scarpini
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D007558:Italy / Q000453:epidemiology; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs; D017354:Point Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D000077153:Progranulins
chemical_list: C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D035683:MicroRNAs; D000077153:Progranulins