title: Molecular signature of disease onset in granulin mutation carriers: a gene expression analysis study.
abstract: Mutations within Granulin (GRN) gene are causative of autosomal dominant frontotemporal lobar degeneration (FTLD). Though GRN mutations are inherited at birth, the disease onset usually occurs in the sixth decade of life. The objective of this study was to identify new genetic pathways linked to inherited GRN disease and involved in the shift from asymptomatic to symptomatic stages. Microarray gene expression analysis on leukocytes was carried out on 15 patients carrying GRN T272SfsX10 mutation, and their asymptomatic siblings with (n = 14) or without (n = 11) GRN mutation. The results were then validated by real-time polymerase chain reaction, and compared with those obtained in a cohort of FTLD without GRN mutation (n = 16). The association between candidate genes and damage of specific brain areas was investigated by voxel-based morphometry on magnetic resonance imaging scans (family-wise error-corrected). Leukocytes mRNA levels of TMEM40 and LY6G6F and other genes mainly involved in inflammation were significantly higher in patients carrying GRN mutations compared with asymptomatic carriers and other FTLD. The higher the levels of TMEM40 the greater is the damage of parietal lobule; the higher the LY6G6F gene expression the greater is the atrophy in superior frontal gyrus. Enhanced inflammation associated with the onset of GRN disease might be either related to disease pathogenetic mechanism leading to neurodegeneration or to a compensatory pathway that counteracts disease progression. The identification of specific molecular targets of GRN-FTLD disease is essential when considering future disease-modifying therapies.
authors: Department of Biomedical Sciences and Biotechnology, School of Medicine, University of Brescia, Brescia, Italy.
authors: Elena
authors: E
authors: Milanesi
authors: Cristian
authors: C
authors: Bonvicini
authors: Antonella
authors: A
authors: Alberici
authors: Andrea
authors: A
authors: Pilotto
authors: Nadia
authors: N
authors: Cattane
authors: Enrico
authors: E
authors: Premi
authors: Stefano
authors: S
authors: Gazzina
authors: Silvana
authors: S
authors: Archetti
authors: Roberto
authors: R
authors: Gasparotti
authors: Vanessa
authors: V
authors: Cancelli
authors: Massimo
authors: M
authors: Gennarelli
authors: Alessandro
authors: A
authors: Padovani
authors: Barbara
authors: B
authors: Borroni
mesh_terms: D000328:Adult; D000368:Aged; D015331:Cohort Studies; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006579:Heterozygote; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics*; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000077153:Progranulins; D040081:Protein Array Analysis / Q000379:methods
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins