TY - JOUR
T1 - Molecular signature of disease onset in Granulin mutation carriers
T2 - A gene expression analysis study
AU - Milanesi, Elena
AU - Bonvicini, Cristian
AU - Alberici, Antonella
AU - Pilotto, Andrea
AU - Cattane, Nadia
AU - Premi, Enrico
AU - Gazzina, Stefano
AU - Archetti, Silvana
AU - Gasparotti, Roberto
AU - Cancelli, Vanessa
AU - Gennarelli, Massimo
AU - Padovani, Alessandro
AU - Borroni, Barbara
PY - 2013/7
Y1 - 2013/7
N2 - 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.
AB - 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.
KW - Frontotemporal dementia
KW - Frontotemporal lobar degeneration
KW - Gene expression
KW - Granulin
KW - Inflammation
KW - Mutations
KW - Progranulin
UR - http://www.scopus.com/inward/record.url?scp=84875822759&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84875822759&partnerID=8YFLogxK
U2 - 10.1016/j.neurobiolaging.2012.11.016
DO - 10.1016/j.neurobiolaging.2012.11.016
M3 - Article
C2 - 23419701
AN - SCOPUS:84875822759
VL - 34
SP - 1837
EP - 1845
JO - Neurobiology of Aging
JF - Neurobiology of Aging
SN - 0197-4580
IS - 7
ER -