Rs5848 Variant Influences GRN mRNA Levels in Brain and Peripheral Mononuclear Cells in Patients with Alzheimer's Disease

University of Milan, Milano, Lombardy, Italy
Journal of Alzheimer's disease: JAD (Impact Factor: 4.15). 08/2009; 18(3):603-12. DOI: 10.3233/JAD-2009-1170
Source: PubMed


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.

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Available from: Diego Albani
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    • "However, not much is known about the possible roles of PGRN in GRN mutation non-carriers subjects. Recently, some common variants of GRN were found to be associated with AD, probably due to their influence on GRN mRNA expression levels [13]. In particular, the rs5848 polymorphism was found to influence serum PGRN levels, with TT carriers having a lower level of serum PGRN than CT and CC carriers [14]. "
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    ABSTRACT: Plasma progranulin (PGRN) levels constitute a potentially invaluable biomarker for neurodegenerative diseases including frontotemporal lobar dementia (FTLD) and, perhaps, Alzheimer's disease (AD). We assessed plasma PGRN levels in 107 AD patients, 36 FTLD patients, and 107 controls. We found that, in female AD patients, there is a positive correlation between PGRN levels and age. Although no significant differences were found between patients and controls, we observed higher levels in females compared to males; in AD patients, a positive correlation between PGRN levels and age was observed in females. In conclusion, our data suggest that PGRN may not be a good biomarker for AD; moreover, gender may influence the plasma PGRN levels of AD patients.
    Full-text · Article · Feb 2013 · Journal of Alzheimer's disease: JAD
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    • "Some of this clinical variability could be explained by specific variants of a modifying gene. Common variations in the GRN gene (rs9897526, rs5848) (Fenoglio et al., 2009) and the Transmembrane Protein 106B gene (TMEM106B) (rs1990622, rs1020004) (Finch et al., 2011) were reported to influence age of onset. Since 1990 we have been studying a large FTD family encompassing 37 affected subjects over 4 generations segregating the c.1145insA mutation of the GRN gene (Bruni et al., 2007). "
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    ABSTRACT: The objectives of this study were to estimate frontotemporal dementia (FTD) prevalence, identify FTD-related mutations, and correlate FTD phenotype with mutations in a Southern Italian population. The study population consisted of subjects ≥ 50 years of age residing in the Community of Biv. on January 1, 2004, and a door-to-door 2-phase design was used. Genetic and biochemical analyses were done on samples collected from 32 patients. Prevalence rates were 0.6 for Alzheimer's disease, 0.4 for vascular dementia (VD), 3.5 for FTD, 0.2 for Parkinson dementia, and 1.2 for unspecified dementia. Three GRN (1 known and 2 novel) mutations with reduced plasma protein levels were found associated to 3 distinct phenotypes (behavioral, affective, and delirious type). We report an unusually high FTD prevalence in the investigated population, but a low prevalence of Alzheimer's disease. We confirm the heterogeneity of FTD phenotype associated with different GRN mutations.
    Full-text · Article · Jul 2012 · Neurobiology of aging
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    ABSTRACT: To assess the influence of rs5848 polymorphism in serum progranulin (PGRN) level in a cohort of subjects with Alzheimer and related dementias from a tertiary referral clinic. Mutations in the GRN gene cause autosomal dominant frontotemporal dementia (FTD) with TDP-43 pathology (FTLD-TDP) through haploinsufficiency. It has recently been shown that homozygous carriers of the T allele of rs5848 have an elevated risk of developing FTD, and this polymorphism may play a role in the pathogenesis of other dementia by modifying progranulin level. We hypothesize that genotype of rs5848 may influence serum PGRN level in AD, FTD, and other dementias. Blood samples were obtained from patients with cognitive impairment and dementia referred to a tertiary dementia clinic, as well as samples from a cohort of healthy controls. Serum PGRN level was measured using an ELISA assay, and rs5848 genotype was determined by a TaqMan assay. We found that rs5848 SNP significantly influenced serum PGRN level, with TT genotype having the lowest levels, and CC as the highest. This relationship is observed in each of the subgroups. We also confirmed that GRN mutation carriers had significantly lower serum PGRN levels than all other groups. The rs5848 polymorphism significantly influences serum PGRN with TT carriers having a lower level of serum PGRN then CT and CC carriers. This is consistent with the finding that miR-659 binding to the high risk T allele of rs5848 may augment translational inhibition of GRN and alter risk of FTD and possibly other dementias.
    Full-text · Article · Nov 2010 · Journal of the neurological sciences
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