Compound heterozygosity in DJ-1 gene non-coding portion related to parkinsonism.
ABSTRACT In this study we analysed the DJ-1 gene in 40 sporadic patients with early onset Parkinson's disease and 100 appropriate controls, originated from southern Italy. We identified a single patient with age at onset of 38 years carrying two previously undescribed heterozygous mutations, both located in non-coding regions. The first mutation was a nucleotide change in the promoter region of the gene (g.159C>G) and the second one was an insertion in the intron 4 splice site (IVS4+3insA). In the same patient, genomic rearrangements were excluded. No DJ-1 mutations were found in the remaining parkinsonian patients. Our results support the growing importance of mutations in non-coding portion of human genome, and confirm that alterations in DJ-1 are a cause, even if rare, of early-onset Parkinson's disease.
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ABSTRACT: Intensive research over the last 15 years has led to the identification of several autosomal recessive and dominant genes that cause familial Parkinson's disease (PD). Importantly, the functional characterization of these genes has shed considerable insights into the molecular mechanisms underlying the etiology and pathogenesis of PD. Collectively; these studies implicate aberrant protein and mitochondrial homeostasis as key contributors to the development of PD, with oxidative stress likely acting as an important nexus between the two pathogenic events. Interestingly, recent genome-wide association studies (GWAS) have revealed variations in at least two of the identified familial PD genes (i.e. α-synuclein and LRRK2) as significant risk factors for the development of sporadic PD. At the same time, the studies also uncovered variability in novel alleles that is associated with increased risk for the disease. Additionally, in-silico meta-analyses of GWAS data have allowed major steps into the investigation of the roles of gene-gene and gene-environment interactions in sporadic PD. The emergent picture from the progress made thus far is that the etiology of sporadic PD is multi-factorial and presumably involves a complex interplay between a multitude of gene networks and the environment. Nonetheless, the biochemical pathways underlying familial and sporadic forms of PD are likely to be shared.Current Genomics 12/2013; 14(8):486-501. · 2.87 Impact Factor
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ABSTRACT: The pathogenesis of many neurodegenerative disorders arises in association with the misfolding and accumulation of a wide variety of proteins. Much emphasis has been placed on understanding the nature of these protein accumulations, including their composition, the process by which they are formed and the physiological impact they impose at cellular and, ultimately, organismal levels. Alpha-synuclein (ASYN) is the major component of protein inclusions known as Lewy bodies and Lewy neurites, which are the typical pathological hallmarks in disorders referred to as synucleinopathies. In addition, mutations or multiplications in the gene encoding for ASYN have also been shown to cause familial cases of PD, the most common synucleinopathy. Although the precise function of ASYN remains unclear, it appears to be involved in a vast array of cellular processes. Here, we review, in depth, a spectrum of cellular and molecular mechanisms that have been implicated in synucleinopathies. Importantly, detailed understanding of the biology/pathobiology of ASYN may enable the development of novel avenues for diagnosis and/or therapeutic intervention in synucleinopathies.Journal of Parkinson's disease. 11/2013;
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ABSTRACT: We analysed the DJ1 gene in a large consecutive series (N=163) of Italian unrelated Early Onset Parkinson Disease (EOPD: onset ≤40 years of age) patients and 100 healthy controls (mean age 64±7ys). No homozygous or compound heterozygous mutations with an obvious pathogenic effect were found. Several variants were identified, some of which were novels. All variants had similar frequency in patients and in controls. Our data suggest that DJ1 mutations are very rare in Italian EOPD. Other genes and risk factors for PD are still to be identified.Neuroscience Letters 10/2013; · 2.06 Impact Factor