Compound heterozygosity in DJ-1 gene non-coding portion related to parkinsonism
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.
[Show abstract] [Hide abstract] ABSTRACT: Alternative splicing is a crucial mechanism of gene expression regulation that enormously increases the coding potential of our genome and represents an intermediate step between messenger RNA (mRNA) transcription and protein posttranslational modifications. Alternative splicing occupies a central position in the development and functions of the nervous system. Therefore, its deregulation frequently leads to several neurological human disorders. In the present review, we provide an updated overview on the impact of alternative splicing in Parkinson's disease (PD), the second most common neurodegenerative disorder worldwide. We will describe the alternative splicing of major PD-linked genes by collecting the current evidences about this intricate and not carefully explored aspect. Assessing the role of this mechanism on PD pathobiology may represent a central step toward an improved understanding of this complex disease.0Comments 5Citations
- "A large homozygous deletion and a missense mutation (L166P) in DJ-1 gene were first identified in both Italian and Dutch consanguineous families [89, 90]. Additional mutations have been collected in other PD families and include missense mutations in coding and promoter regions, frame shifts, copy number variations [91, 88], and splice site alterations [92, 93]. DJ-1 gene maps to chromosome 1 (1p36.23) "
[Show abstract] [Hide abstract] 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.0Comments 3Citations
- "Klein and colleagues did not find any DJ1 mutation in 65 PD patients with onset before 50 years of age . Tarantino and colleagues tested 40 PD patients with onset before 45 years of age and found a single patient carrying two de novo heterozygous nucleotidic substitutions, both located in noncoding regions . We found the same variants in one PD patients as well as in healthy controls (seeTable 1 ). "
[Show abstract] [Hide abstract] ABSTRACT: Alterations occur within distal neuronal compartments, including axons and synapses, during the course of neurodegenerative diseases such as Parkinson's disease (PD). These changes could hold important implications for the functioning of neural networks, especially since research studies have shown a loss of dendritic spines locating to medium spiny projection neurons and impaired axonal transport in PD-affected brains. However, despite ever-increasing awareness of the vulnerability of synapses and axons, inadequate understanding of the independent mechanisms regulating non-somatic neurodegeneration prevails. This has resulted in limited therapeutic strategies capable of targeting these distinct cellular compartments. Deregulated protein synthesis, folding and degrading proteins, and protein quality-control systems have repeatedly been linked with morphological and functional alterations of synapses in the PD-affected brains. Here, we review current understanding concerning the proteins involved in structural and functional changes that affect synaptic contact-points in PD. The collection of studies discussed emphasizes the need for developing therapeutics aimed at deregulated protein synthesis and degradation pathways operating at axonal and dendritic synapses for preserving "normal" circuitry and function, for as long as possible.0Comments 12Citations
- "In particular, affected members of the Dutch family carried a homozygous deletion of PARK7 exons 1–5, whilst Italian patients were homozygous carriers of a missense mutation (L166P). Since then, various DJ-1 missense mutations in coding and promoter regions, frameshift and splice site mutations, as well as exonic deletions, have also been reported to be present in some PD patients141142143144145146. However, other studies have been less optimistic and have detected no or extremely low occurrence of DJ-1 mutations in the PD populations screened for147148149150151152153. "