Novel PINK1 mutations in early-onset Parkinsonism

Juntendo University, Edo, Tōkyō, Japan
Annals of Neurology (Impact Factor: 9.98). 09/2004; 56(3):424-7. DOI: 10.1002/ana.20251
Source: PubMed


PINK1 was recently found to be associated with PARK6 as the causative gene. We performed mutation analysis in eight inbred families whose haplotypes link to the PARK6 region. We identified six pathogenic mutations (R246X, H271Q, E417G, L347P, and Q239X/R492X) in six unrelated families. All sites of mutations were novel, suggesting that PINK1 may be the second most common causative gene next to parkin in parkinsonism with the recessive mode of inheritance.

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    • "The PINK [Rogaeva et al., 2004; Brooks et al., 2009] and DJ-1 [Bonifati et al., 2003] genes were sequenced with published primers. PARK2, PINK1, and DJ-1 exon dosage were analyzed by MLPA 1 and confirmed by real-time PCR [Bonifati et al., 2003; Hatano et al., 2004; Mellick et al., 2009]. The possible consequences of the novel PINK1 point mutations and all CNVs identified were predicted at the protein level by using Translate tool from ExPASy portal [Artimo et al., 2012]. "
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    ABSTRACT: Mutations in PARK2, PINK1, and DJ-1 have been associated with autosomal recessive early-onset Parkinson's disease. Here, we report the prevalence of sequence and structural mutations in these three main recessive genes in Mexican Mestizo patients. The complete sequences of these three genes were analyzed by homo/heteroduplex DNA formation and direct sequencing; exon dosage was determined by multiplex ligation-dependent probe amplification and real-time PCR in 127 patients belonging to 122 families and 120 healthy Mexican Mestizo controls. All individuals had been previously screened for the three most common LRRK2 mutations. The presence of two mutations in compound heterozygous or homozygous genotypes was found in 16 unrelated patients, 10 had mutations in PARK2, six in PINK1, and none in DJ-1. Two PARK2-PINK1 and one PARK2-LRRK2 digenic cases were observed. Novel mutations were identified in PARK2 and PINK1 genes, including PINK1 duplication for the first time. Exon dosage deletions were the most frequent mutations in PARK2 (mainly in exons 9 and 12), followed by those in PINK1. The high prevalence of heterozygous mutations in PARK2 (12.3%) and the novel heterozygous and homozygous point mutations in PINK1 observed in familial and sporadic cases from various states of Mexico support the concept that single heterozygous mutations in recessive Parkinson's disease genes play a pathogenic role. These data have important implications for genetic counseling of Mexican Mestizo patients with early-onset Parkinson's disease. The presence of digenic inheritance underscores the importance of studying several genes in this disease. A step-ordered strategy for molecular diagnosis is proposed. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 04/2014; 165(3). DOI:10.1002/ajmg.b.32228 · 3.42 Impact Factor
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    • "Mutations in the mitochondrial serine/threonine kinase PTEN-induced putative kinase 1 (PINK1) correlate with disease incidence (Valente et al., 2004a). Many of these mutations cluster in the kinase domain of PINK1 and result in a non-functional protein (Hatano et al., 2004; Rohe et al., 2004; Valente et al., 2004a,b; Sha et al., 2010). Deficiencies of pink1 in Drosophila lead to changes in mitochondrial morphology, increased sensitivity to oxidative stress and reduced viability (Clark et al., 2006). "
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    ABSTRACT: Protein-folding occurs in several intracellular locations including the endoplasmic reticulum and mitochondria. In normal conditions there is a balance between the levels of unfolded proteins and protein folding machinery. Disruption of homeostasis and an accumulation of unfolded proteins trigger stress responses, or unfolded protein responses (UPR), in these organelles. These pathways signal to increase the folding capacity, inhibit protein import or expression, increase protein degradation, and potentially trigger cell death. Many aging-related neurodegenerative diseases involve the accumulation of misfolded proteins in both the endoplasmic reticulum and mitochondria. The exact participation of the UPRs in the onset of neurodegeneration is unclear, but there is significant evidence for the alteration of these pathways in the endoplasmic reticulum and mitochondria. Here we will discuss the involvement of endoplasmic reticulum and mitochondrial stress and the possible contributions of the UPR in these organelles to the development of two neurodegenerative diseases, Parkinson's disease (PD) and Alzheimer's disease (AD).
    Frontiers in Aging Neuroscience 04/2012; 4(article 5):5. DOI:10.3389/fnagi.2012.00005 · 4.00 Impact Factor
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    • "The target for ubiquitination and the implications of this process are not understood, but mitochondria marked in this way are subsequently degraded by mitophagy. Importantly, the PINK1-Parkin system is strongly linked to Parkinson's disease: a loss-of-function mutation in PARKIN is the most common mutation associated with the early onset form of the disease [103]. The second form of mitophagy encountered in mammalian cells, NIX-dependent mitophagy, is associated with reticulocyte maturation [104]. "
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    ABSTRACT: Research into the selective autophagic degradation of mitochondria-mitophagy-has intensified in recent years, yielding significant insights into the function, mechanism, and regulation of this process in the eukaryotic cell. However, while some molecular players in budding yeast, such as Atg32p, Uth1p, and Aup1p, have been identified, studies further interrogating the mechanistic and regulatory features of mitophagy have yielded inconsistent and sometimes conflicting results. In this review, we focus on the current understanding of mitophagy mechanism, induction, and regulation in yeast, and suggest that differences in experimental conditions used in the various studies of mitophagy may contribute to the observed discrepancies. Consideration and understanding of these differences may help place the mechanism and regulation of mitophagy in context, and further indicate the intricate role that this essential process plays in the life and death of eukaryotic cells.
    International Journal of Cell Biology 04/2012; 2012:431684. DOI:10.1155/2012/431684
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