PINK1, Parkin, and DJ-1 mutations in Italian patients with early-onset Parkinsonism

Department of Neurology, University of Lübeck, Lübeck, Germany.
European Journal of HumanGenetics (Impact Factor: 4.35). 10/2005; 13(9):1086-93. DOI: 10.1038/sj.ejhg.5201455
Source: PubMed


Recessively inherited early-onset parkinsonism (EOP) has been associated with mutations in the Parkin, DJ-1, and PINK1 genes. We studied the prevalence of mutations in all three genes in 65 Italian patients (mean age of onset: 43.2+/-5.4 years, 62 sporadic, three familial), selected by age at onset equal or younger than 51 years. Clinical features were compatible with idiopathic Parkinson's disease in all cases. To detect small sequence alterations in Parkin, DJ-1, and PINK1, we performed a conventional mutational analysis (SSCP/dHPLC/sequencing) of all coding exons of these genes. To test for the presence of exon rearrangements in PINK1, we established a new quantitative duplex PCR assay. Gene dosage alterations in Parkin and DJ-1 were excluded using previously reported protocols. Five patients (8%; one woman/four men; mean age at onset: 38.2+/-9.7 (range 25-49) years) carried mutations in one of the genes studied: three cases had novel PINK1 mutations, one of which occurred twice (homozygous c.1602_1603insCAA; heterozygous c.1602_1603insCAA; heterozygous c.836G>A), and two patients had known Parkin mutations (heterozygous c.734A>T and c.924C>T; heterozygous c.924C>T). Family history was negative for all mutation carriers, but one with a history of tremor. Additionally, we detected one novel polymorphism (c.344A>T) and four novel PINK1 changes of unknown pathogenic significance (-21G/A; IVS1+97A/G; IVS3+38_40delTTT; c.852C>T), but no exon rearrangements. No mutations were found in the DJ-1 gene. The number of mutation carriers in both the Parkin and the PINK1 gene in our cohort is low but comparable, suggesting that PINK1 has to be considered in EOP.


Available from: Birgitt Schuele, Aug 12, 2014
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    • "Mutations in the PINK1 gene on chromosome 1p36 have been reported in ~5% of patients with autosomal recessive PD (13). PINK1 mutations have been reported in patients with autosomal recessive early-onset PD (AREP) in Italy (14,15). The frequency of PINK1 mutations in patients with AREP is between 2.9 and 29%, with the mutation frequency varying greatly depending on ethnicity (16–20). "
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    ABSTRACT: The present study aimed to investigate the association between T313M polymorphism at exon 4 of the PTEN-induced putative kinase 1 (PINK1) gene and Parkinson's disease (PD) in the Uygur and Han populations of Xinjiang, China. Genetic DNA was extracted from 364 patients with PD from the Uygur and Han populations, as well as 346 normal control patients. Four exons of the PINK1 gene were amplified using quantitative polymerase chain reaction. The exons were then digested for restriction fragment length polymorphism analysis. Gene types and allele frequencies were identified using agarose gel electrophoresis followed by DNA sequencing to analyze the T313M polymorphisms. In the Han population, T313M polymorphism allele frequency was observed to be significantly different between the PD group and the control group (χ(2)=6.247; P<0.05). Significant differences were observed in in the T313M allele and genotype frequencies between the Uygur and Han populations (χ(2)=5.475 and χ(2)=10.950, respectively; P<0.05). Polymorphisms in the PINK1 T313M mutation may be associated with genetic susceptibility to PD.
    Experimental and therapeutic medicine 07/2014; 8(1):286-290. DOI:10.3892/etm.2014.1702 · 1.27 Impact Factor
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    • "The absence of pathogenic mutations in PINK1 gene in our population is consistent with other studies [19, 23, 27], supporting the hypothesis that mutations in PINK1 may not be a relevant cause of EOPD among Brazilian sporadic and familial patients. Our results of PARK2 gene are in agreement with studies worldwide that have found similar frequencies of PARK2 point mutations in different populations [18–20, 23, 24] (Table 3), although they differ from the frequency identified by other Brazilian groups (5.5% and 11.1%) [21, 22]. One possible explanation for these different results would be the reduced sample sizes tested by them (72 and 45 patients, resp.) "
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    ABSTRACT: Parkinson's disease is the second most frequent neurodegenerative disorder in the world, affecting 1-2% of individuals over the age of 65. The etiology of Parkinson's disease is complex, with the involvement of gene-environment interactions. Although it is considered a disease of late manifestation, early-onset forms of parkinsonism contribute to 5-10% of all cases. In the present study, we screened mutations in coding regions of PARK2 and PINK1 genes in 136 unrelated Brazilian patients with early-onset Parkinson's disease through automatic sequencing. We identified six missense variants in PARK2 gene: one known pathogenic mutation, two variants of uncertain role, and three nonpathogenic changes. No pathogenic mutation was identified in PINK1 gene, only benign polymorphisms. All putative pathogenic variants found in this study were in heterozygous state. Our data show that PARK2 point mutations are more common in Brazilian early-onset Parkinson's disease patients (2.9%) than PINK1 missense variants (0%), corroborating other studies worldwide.
    Disease markers 08/2013; 35(3):181-5. DOI:10.1155/2013/597158 · 1.56 Impact Factor
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    • "After the identification of the PARK6 locus in 2001, two point mutations have been reported in the PINK1 gene: G309D in a Spanish family and W437X in two Italian families (Valente et al., 2001, 2004a). Several studies have then described various point mutations and more rarely exon deletions (Hatano et al., 2004; Healy et al., 2004; Rogaeva et al., 2004; Valente et al., 2004b; Bonifati et al., 2005; Klein et al., 2005; Li et al., 2005; Ibanez et al., 2006). PINK1 has an intermediate frequency between Parkin and DJ1, estimated as 1%–9% with a great variability being present among different ethnicities (Thomas and Beal, 2007). "
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    ABSTRACT: Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. A progressive movement disorder typified by the production of bradykinesia, tremor, rigidity, and impairment of postural reflexes, PD is characterized by a depletion of dopamine in the striatum. For the last decade, several Mendelian forms of PD have been identified. Mutations in these genes potentially lead to autosomal dominant (alpha-synuclein and LRRK2), or autosomal recessive PD (Parkin, PINK1, DJ1, and ATP13A2). This article will spotlight these six distinct genes unambiguously associated with Mendelian PD and the function of their encoded proteins.
    The Anatomical Record Advances in Integrative Anatomy and Evolutionary Biology 11/2009; 292(12):1893-901. DOI:10.1002/ar.20968 · 1.54 Impact Factor
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