Association of the variant Cys139Arg at GRN gene to the clinical spectrum of frontotemporal lobar degeneration.

BACKGROUND: Progranulin protein (PGRN) is a cysteine-rich growth factor encoded by the progranulin gene (GRN). PGRN mutations were identified in patients with frontotemporal lobar degeneration (FTLD) and recently its role as risk factor has been described in patients with probable Alzheimer's disease (AD). To date, more than 100 genetic variants in GRN gene have been described and the pathogenic nature is still unclear for almost 36% of them. OBJECTIVE: Here, we describe three clinical cases carrying the PGRN variation Cys139Arg in order to increase the knowledge on the association of this variant to the clinical spectrum of FTLD. METHODS: The genetic analysis was performed using high resolution melting analysis. The Human Progranulin ELISA Kit was used in order to determine PGRN expression levels in the plasma samples. RESULTS: The three patients carrying the genetic variation showed three final different clinical diagnosis, respectively behavioral frontotemporal dementia, semantic dementia, and corticobasal syndrome, thus underlining the clinical heterogeneity typically associated with GRN mutations. All cases shared similar plasma PGRN levels that resulted intermediate between those measured in controls and in GRN null mutation carriers, showing a partial reduction of the protein in plasma. Moreover, according to the bioinformatics software, the Cys139Arg variation causes a decreased stability of the structure of the protein. CONCLUSION: We describe three new patients affected by neurological syndromes included in the clinical spectrum of FTLD carrying the Cys139Arg genetic variant, thus suggesting a possible implication in the pathogenesis of FTLD.

Ataxia-telangiectasia mutated (ATM) genetic variant in Italian centenarians.

Lifespan is attributable to genetic factors and some studies have attempted to identify putative genes implicated in human longevity. Several genetic loci have been associated with longevity, but some of these are not replicable, probably due to the vast differences among ethnicities. We analyzed in 128 Italian long-lived individuals and 150 unrelated healthy subjects, the recently reported association between rs189037 in the ataxia-telangiectasia mutated gene promoter and longevity in Chinese nonagenarians/centenarians. Our study confirms the association between the rs189037 C/T genotype and longevity in Italian centenarians, with an odds ratio of 1.85 (95 % CI 0.99-3.45). To understand the genetic basis for longevity is an extraordinarily difficult task, and therefore it is important to replicate any positive findings, especially if detected in other ethnic groups, in order to reach reliable conclusions on the real effect that candidate genes have on longevity.

Fibroblasts from PS1 mutated pre-symptomatic subjects and Alzheimer's disease patients share a unique protein levels profile.

In Alzheimer's disease (AD), a major goal is to improve early detection, as the diagnosis cannot be made until patients exhibit a noticeable decline in cognition and the brain is irreversibly damaged. With this aim in mind, we performed proteome analysis of familial AD fibroblasts from both demented and pre-symptomatic subjects, using a 2D-PAGE based approach and then identifying proteins by mass spectrometry. We compared primary fibroblast cultures from skin biopsy of presenilin 1 (PS1) mutated patients, pre-symptomatic subjects carrying mutations in the PS1 gene but healthy at the time of skin biopsy, and age-matched individuals as control. 15 differentially expressed proteins were identified in PS1 mutated fibroblasts, related to cell adhesion and cytoskeleton, energy and glucose metabolism, stress response and ubiquitin-proteasome system, and signal transduction. Interestingly, many of these proteins have been previously associated with AD and neurodegeneration. Overall results indicated that a unique protein profile can be identified by peripheral cell analysis of PS1 mutated individuals, and showed that fibroblasts are a useful cell model for pathological investigations as well as identification of potential biomarkers for AD diagnosis at early stages.

Lack of association between TNF-alpha polymorphisms and Alzheimer's disease in an Italian cohort.

Tumor necrosis factor-alpha (TNF-alpha) is a pro-inflammatory cytokine that plays an important role in the inflammatory process that can be observed in Alzheimer's disease (AD) brain. Different functional promoter polymorphisms within genes modulating inflammation have been demonstrated to elevate the AD risk; thus, we studied five common variations within the promoter region of the TNF-alpha gene in 609 subjects (253 AD patients and 356 controls). No positive associations were found, confirming the greater part of previous studies. Moreover, we also investigated the combined haplotypes of the five different polymorphisms without finding a positive association. Thus, the present investigation does not support the proposal that common nucleotide variations in the TNF-alpha gene can influence the development of AD at least in Italian population.

SNPs in neurotrophin system genes and Alzheimer's disease in an Italian population.

Increasing evidence suggests a role for nerve growth factor (NGFB), brain-derived neurotrophic factor (BDNF), and their receptors, nerve growth factor receptor (NGFR), and neurotrophin tyrosine kinase receptors 1 and 2 (NTRK1 and NTRK2), in Alzheimer's disease (AD). However, genetic association between the neurotrophin system genes and AD has been poorly investigated. We genotyped 21 single nucleotide polymorphisms (SNPs) within these genes in a population of Italian AD patients and healthy controls. We found an allele-wise association of rs2072446 on NGFR with familial AD (fAD, p = 0.047), and a genotype-wise association of rs2289656 on NTRK2 with sporadic AD (sAD, p = 0.0036). rs6336 on NTRK1 resulted associated to early-onset sAD in both allele-wise (p = 0.028) and genotype-wise (p = 0.014) analysis, while rs1048218 on BDNF showed allele-wise association with late-onset sAD (p = 0.047). A trend to association with sAD and/or fAD was observed for other SNPs. Our results suggest that genetic variants of neurotrophin system genes might confer susceptibility to AD.

Cystatin C and apoe polymorphisms in Italian Alzheimer's disease.

Recent studies have reported a genetic association between the 73 G/A polymorphism within exon 1 of the cystatin C gene and Alzheimer's disease (AD) with conflicting results. To further investigate the proposed association and to clarify the role of CST3 as risk factor for AD, we analyzed the genotype and allele frequency distribution of CST3 G73A and apolipoprotein (ApoE) gene polymorphisms in 243 Italian patients with AD and 186 controls. Patients with AD were consecutively collected among the outpatients from the Neurology Department at the University of Florence. All 429 subjects were genotyped for CST3 and ApoE polymorphisms. After stratification according to age, the GG frequency resulted slightly higher in younger (<65 years) cases, but far from statistically significant. There was also no evidence of a statistical interaction between CST3 and ApoE polymorphisms. In conclusion, our data suggest that the CST3 genetic variant is not a susceptibility factor in AD, nor mitigate the effect of the ApoE varepsilon4 allele in the risk of developing AD.