Deletions in the Parkin gene and genetic heterogeneity in a Greek family with early onset Parkinson's disease
ABSTRACT Parkinson's disease is the second most common neurodegenerative disease after Alzheimer's disease and is manifested as a movement disorder. A positive family history is the second most important risk factor for developing the illness, after age. Both autosomal dominant and recessive forms of the illness have been described. Recently deletions in a novel gene, parkin, have been associated with the autosomal recessive form of the illness in Japanese families. In this study, we demonstrate that deletions of exons 5, 6 and 7 of the parkin gene are present in two affected individuals of a Greek pedigree with early onset Parkinson's disease. However, no deletions were identified in a different branch of the same pedigree with three affected individuals. These results suggest that deletions in the parkin gene will be found in other families besides those of Japanese origin and that there must be at least one additional locus responsible for early onset autosomal recessive Parkinson's disease.
- SourceAvailable from: Pedro J García-Ruiz
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- "The Park-2 gene encodes the ubiquitin protein ligase parkin that is implicated in proteasome-dependent protein degradation . Loss-of-function mutations in the Park-2 gene cause autosomal-recessive juvenile parkinsonism (AR- JP), one of the most common forms of familial parkinsonism        that is characterized by a selective loss of dopaminergic neurons in the substantia nigra without the appearance of Lewy bodies    . Single parkin mutations have been detected in patients with Parkinson's disease (PD) , while mutations in the Park-2 gene have also been found in patients with certain tauopathies  . "
ABSTRACT: While mutations in the Park-2 gene are the most frequent cause of autosomal-recessive juvenile parkinsonism (AR-JP), they are also present in several forms of tauopathies. Conversely, in some forms of parkinsonism, mutations in the tau gene have also been observed. Deletion of the Park-2 gene and over-expression of mutant tau independently produce mild brain alterations in mice. However, the presence of both mutations simultaneously causes a tau neuropathology, involving reactive astrocytosis, neuron loss in the cortex and hippocampus, and lesions in nigrostriatal and motor neurons. Furthermore, mutant tau over-expression in mice produces important memory impairment. When "parkin" function was abolished in young tau transgenic mice, the memory alterations were exaggerated. Moreover, additional exploratory and motor deficits were observed in older mice, causing the memory alterations to be underestimated. Thus, while memory deficits are more severe in young mice they were somehow attenuated by exploratory impairments in ageing mutants. This double mutant animal will serve as a useful experimental tool to investigate the abnormal processing of hyperphosphorylated tau and its relationship to the development of the cognitive deficits associated with certain neurodegenerative diseases.Behavioural Brain Research 07/2008; 189(2):350-6. DOI:10.1016/j.bbr.2008.01.017 · 3.39 Impact Factor
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- "The linkage of parkin to PD was originally described in families with inherited AR-JP (Kitada et al., 1998). Although the vast majority of parkinrelated PD cases are inherited recessively, an increasing number of reports identify a proportion of PD patients in which only a single copy is mutated (Leroy et al., 1998; Maruyama et al., 2000; Farrer et al., 2001; Lucking et al., 2001; West et al., 2002; Foroud et al., 2003; Tan et al., 2003; Mata et al., 2004). Given the complexity of analyzing the 1.3 Mb parkin genomic locus, it is possible that a proportion of these apparent dominant cases represent a failure to ascertain a second site mutation. "
ABSTRACT: Mutations in human parkin have been identified in familial Parkinson's disease and in some sporadic cases. Here, we report that expression of mutant but not wild-type human parkin in Drosophila causes age-dependent, selective degeneration of dopaminergic (DA) neurons accompanied by a progressive motor impairment. Overexpression or knockdown of the Drosophila vesicular monoamine transporter, which regulates cytosolic DA homeostasis, partially rescues or exacerbates, respectively, the degenerative phenotypes caused by mutant human parkin. These results support a model in which the vulnerability of DA neurons to parkin-induced neurotoxicity results from the interaction of mutant parkin with cytoplasmic dopamine.The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 02/2007; 27(5):981-92. DOI:10.1523/JNEUROSCI.4810-06.2007 · 6.75 Impact Factor
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- "Parkinson disease (PD [MIM 168600]) is the second most common neurodegenerative disorder and is characterized clinically by rigidity, bradykinesia, and resting tremor. PD has been shown to have a genetic component contributing to the disorder, including mutations in several genes (e.g., a-synuclein, Parkin, UCHL1, LRRK2, and PINK1) that lead to rare Mendelian forms of the disease (Polymeropoulos et al. 1997; Kitada et al. 1998; Leroy et al. 1998; Paisan-Ruiz et al. 2004; Valente et al. 2004). The age at which an individual first manifests symptoms of the disease (i.e., age at onset [AAO]) also appears to be genetically controlled (Destefano et al. 2002; Li et al. 2002), but only a few genes (e.g., APOE, GSTO1/2, and IDE) that affect AAO have been identified (Karamohamed et al. 2003; Li et al. 2003, 2004; Blomqvist et al. 2004). "
ABSTRACT: We previously reported a linkage region on chromosome 1p (LOD = 3.41) for genes controlling age at onset (AAO) in Parkinson disease (PD). This region overlaps with the previously reported PARK10 locus. To identify the gene(s) associated with AAO and risk of PD in this region, we first applied a genomic convergence approach that combined gene expression and linkage data. No significant results were found. Second, we performed association mapping across a 19.2-Mb region centered under the AAO linkage peak. An iterative association mapping approach was done by initially genotyping single-nucleotide polymorphisms at an average distance of 100 kb apart and then by increasing the density of markers as needed. Using the overall data set of 267 multiplex families, we identified six associated genes in the region, but further screening of a subset of 83 families linked to the chromosome 1 locus identified only two genes significantly associated with AAO in PD: the gamma subunit of the translation initiation factor EIF2B gene (EIF2B3), which was more significant in the linked subset and the ubiquitin-specific protease 24 gene (USP24). Unexpectedly, the human immunodeficiency virus enhancer-binding protein 3 gene (HIVEP3) was found to be associated with risk for susceptibility to PD. We used several criteria to define significant results in the presence of multiple testing, including criteria derived from a novel cluster approach. The known or putative functions of these genes fit well with the current suspected pathogenic mechanisms of PD and thus show great potential as candidates for the PARK10 locus.The American Journal of Human Genetics 09/2005; 77(2):252-64. DOI:10.1086/432588 · 10.99 Impact Factor