DJ-1 (PARK7) mutations are less frequent than Parkin (PARK2) mutations in early-onset Parkinson disease

Sapienza University of Rome, Roma, Latium, Italy
Neurology (Impact Factor: 8.29). 03/2004; 62(3):389-94. DOI: 10.1212/01.WNL.0000113022.51739.88
Source: PubMed


Mutations in the Parkin gene (PARK2) are the most commonly identified cause of recessively inherited early-onset Parkinson disease (EOPD) but account for only a portion of cases. DJ-1 (PARK7) was recently reported as a second gene associated with recessively inherited PD with a homozygous exon deletion and a homozygous point mutation in two families.
To investigate the frequency of DJ-1 mutations, the authors performed mutational analysis of all six coding exons of DJ-1 in 100 EOPD patients. For the detection of exon rearrangements, the authors developed a quantitative duplex PCR assay. Denaturing high performance liquid chromatography analysis was used to screen for point mutations and small deletions. Further, Parkin analysis was performed as previously described.
The authors identified two carriers of single heterozygous loss-of-function DJ-1 mutations, including a heterozygous deletion of exons 5 to 7 and an 11-base pair deletion, removing the invariant donor splice site in intron 5. Interestingly, both DJ-1 mutations identified in this study were found in the heterozygous state only. The authors also detected a polymorphism (R98Q) in 1.5% of the chromosomes in both the patient and control group. In the same patient sample, 17 cases were detected with mutations in the Parkin gene.
Mutations in DJ-1 are less frequent than mutations in Parkin in EOPD patients but should be considered as a possible cause of EOPD. The effect of single heterozygous mutations in DJ-1 on the nigrostriatal system, as described for heterozygous changes in Parkin and PARK6, remains to be elucidated.

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    • "For example, DJ-1 (PARK7) deletion and point mutations have been found to cause autosomal recessive PD (Bonifati et al., 2003). DJ-1 mutations are the second most frequent identifiable genetic cause of PD after parkin (Abou-Sleiman et al., 2003; Hedrich et al., 2004). "
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    ABSTRACT: The molecular mechanisms leading to neurodegeneration in Parkinson's disease remain elusive. Deletion and mutations of DJ-1 (PARK7) have been reported to cause autosomal recessive familial Parkinson's disease. Wildtype DJ-1 scavenges H(2)O(2) by cysteine oxidation in response to oxidative stress, and thus confers neuroprotection. Activation of the transcription factor NF-E2-related factor-2 (Nrf2) has also been shown to be important for protection against oxidative stress in many models of neurodegenerative diseases. Previous data indicate that DJ-1 affects the transcriptional functions and stability of Nrf2. However, this observation has not been confirmed. In the current study, the role of DJ-1 in the regulation of Nrf2 is examined in primary cultured neurons, astrocytes and in vivo. The prototypical Nrf2 activator tBHQ protected primary cortical neurons derived from DJ-1-knockout (KO) as well as DJ-1 wildtype mice by activation of Nrf2-ARE pathway. Nrf2 nuclear translocation, robust increases in canonical Nrf2-driven genes and proteins, and dramatic activation of the ARE reporter gene, hPAP, were observed after tBHQ treatment. These results were further confirmed by siRNA-mediated DJ-1 knockdown in primary cortical astrocytes from ARE-hPAP mice and tBHQ administration into the striatum of mouse brain. In addition, overexpression of Nrf2 with adenovirus preferentially in astrocytes from DJ-1-KO mice enhanced survival of neurons under oxidative insults. These findings indicate that activation of the Nrf2-ARE pathway is independent of DJ-1, and Nrf2 activation is a potential therapeutic target to prevent neurodegeneration in sporadic and DJ-1 familial Parkinson's disease.
    Full-text · Article · Mar 2010 · European Journal of Neuroscience
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    • "1 was identified as the causative gene of PARK7 - linked familial EOPD ( Bonifati et al . 2003 ) , however , several cohort studies reported that DJ - 1 mutations were quite rare and the frequency was estimated to be only 1 – 2% of early - onset cases ( Abou - Sleiman et al . 2003 ; Hague et al . 2003 ; Clark et al . 2004 ; Djarmati et al . 2004 ; Hedrich et al . 2004 , 2006 ; Hering et al . 2004 ) . Furthermore , no DJ - 1 mutations have been identified so far in Japanese population ( Tomiy - ama et al . 2009 ) . The DJ - 1 contains 8 exons and encodes a 189 a . a . protein that forms a dimer and belongs to the THiJ / Pfp1 / DJ - 1 family . Several pathogenic mutations have been identified in the DJ"
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    ABSTRACT: Parkinson's disease (PD) is one of the most common movement disorders caused by the loss of dopaminergic neuronal cells. The molecular mechanisms underlying neuronal degeneration in PD remain unknown; however, it is now clear that genetic factors contribute to the pathogenesis of this disease. Approximately, 5% of patients with clinical features of PD have clear familial etiology, which show a classical recessive or dominant Mendelian mode of inheritance. Over the decade, more than 15 loci and 11 causative genes have been identified so far and many studies shed light on their implication in not only monogenic but also sporadic form of PD. Recent studies revealed that PD-associated genes play important roles in cellular functions, such as mitochondrial functions, ubiquitin-proteasomal system, autophagy-lysosomal pathway and membrane trafficking. Furthermore, the proteins encoded by PD-associated genes can interact with each other and such gene products may share a common pathway that leads to nigral degeneration. However, their precise roles in the disease and their normal functions remain poorly understood. In this study, we review recent progress in knowledge about the genes associated with familial PD.
    Full-text · Article · Sep 2009 · Journal of Neurochemistry
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    • "Considerably fewer mutations (NE20) were reported for PARK7, accounting for o1% of early-onset PD etiology [Abou-Sleiman et al., 2003; Bonifati et al., 2003; Clark et al., 2004; Hague et al., 2003; Hedrich et al., 2004; Hering et al., 2004; Lockhart et al., 2004]. Among these, two multiple-exon deletions have been observed; a 14-kb deletion of exons 1 to 5 [Bonifati et al., 2003] and a smaller deletion of exons 5 to 7 [Hedrich et al., 2004], identified in one family each. Analysis of LRRK2 identified numerous simple mutations, accounting for $5% of patients with familial [Di Fonzo et al., 2005; Farrer et al., 2005; Goldwurm et al., 2005; Kachergus et al., 2005; Mata et al., 2005b; Nichols et al., 2005; Zabetian et al., 2005] and 2% of patients with sporadic PD [Gilks et al., 2005]. "
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    ABSTRACT: The relative contribution of simple mutations and copy number variations (CNVs) in SNCA, PARK2, PINK1, PARK7, and LRRK2 to the genetic etiology of Parkinson disease (PD) is still unclear because most studies did not completely analyze each gene. In a large group of Belgian PD patients (N = 310) and control individuals (N = 270), we determined the mutation frequency of both simple mutations and CNVs in these five PD genes, using direct sequencing, multiplex amplicon quantification (MAQ), and real-time PCR assays. Overall, we identified 14 novel heterozygous variants, of which 11 were absent in control individuals. We observed eight PARK2 (multiple) exon multiplications in PD patients and one exon deletion in a control individual. Furthermore, we identified one SNCA whole-gene duplication. The PARK2 and LRRK2 mutation frequencies in Belgian PD patients were similar to those reported in other studies. However, at this stage the true pathogenic nature of some heterozygous mutations in recessive genes remains elusive. Furthermore, though mutations is SNCA, PINK1, and PARK7 are rare, our identification of a SNCA duplication confirmed that screening of these genes remains meaningful.
    Full-text · Article · Jul 2009 · Human Mutation
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