Mutations in the PTEN-induced putative kinase 1 (PINK1) gene at 1p36 have been involved in autosomal recessive early-onset parkinsonism.
To describe the clinical and genetic features of the largest kindred reported to date with early-onset parkinsonism associated with the PINK1 gene.
Clinical and genetic study.
Collaborative study. Patients Eight patients from Sudan with particularly early onset (ages 9-17 years) and phenotypes varying from dopa-responsive dystonia-like to typical early-onset parkinsonism.
The PINK1 genotype and Parkinson disease status of all available family members.
The disease was caused by a novel mutation, p.A217D, located in the highly conserved adenosine triphosphate orientation site of the PINK1 kinase domain.
This study extends the phenotypic and molecular spectrum of the PINK1 gene and the geographic origin of patients with PINK1 gene mutations.
"A key issue with this is whether administration of PINK1 inhibitors to human cancer patients could have the potential to induce Parkinson's disease. In the literature, the youngest age of the onset of Parkinson's disease in patients harbouring homozygous PINK1 mutations is approximately 10 (A217D mutation) , suggesting that at least a decade of PINK1 inhibition is required before Parkinson's disease symptoms develop. It is thus likely that short periods of exposure to compounds that inhibit PINK1 for cancer treatments would carry a reduced risk of Parkinson's disease compared with chronic long-term treatment. "
[Show abstract][Hide abstract] ABSTRACT: Missense mutations of the phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1) gene cause autosomal-recessive Parkinson's disease. To date, little is known about the intrinsic catalytic properties of PINK1 since the human enzyme displays such low kinase activity in vitro. We have discovered that, in contrast to mammalian PINK1, insect orthologues of PINK1 we have investigated-namely Drosophila melanogaster (dPINK1), Tribolium castaneum (TcPINK1) and Pediculus humanus corporis (PhcPINK1)-are active as judged by their ability to phosphorylate the generic substrate myelin basic protein. We have exploited the most active orthologue, TcPINK1, to assess its substrate specificity and elaborated a peptide substrate (PINKtide, KKWIpYRRSPRRR) that can be employed to quantify PINK1 kinase activity. Analysis of PINKtide variants reveal that PINK1 phosphorylates serine or threonine, but not tyrosine, and we show that PINK1 exhibits a preference for a proline at the +1 position relative to the phosphorylation site. We have also, for the first time, been able to investigate the effect of Parkinson's disease-associated PINK1 missense mutations, and found that nearly all those located within the kinase domain, as well as the C-terminal non-catalytic region, markedly suppress kinase activity. This emphasizes the crucial importance of PINK1 kinase activity in preventing the development of Parkinson's disease. Our findings will aid future studies aimed at understanding how the activity of PINK1 is regulated and the identification of physiological substrates.
Open Biology 11/2011; 1(3):110012. DOI:10.1098/rsob.110012 · 5.78 Impact Factor
"Some patients show additional psychiatric disturbances, particularly anxiety and depression, which is only relatively rarely observed in Parkin-related cases.92 Occasionally, PINK1 mutations are found in late-onset Parkinson’s disease, restless legs syndrome with parkinsonism, and dopa-responsive dystonia.87–89 Pathological changes in a single reported case were those of typical Lewy body disease.93 "
[Show abstract][Hide abstract] ABSTRACT: Parkinson's disease can be caused by rare familial genetic mutations, but in most cases it is likely to result from an interaction between multiple genetic and environmental risk factors. Over recent years, many variants in a growing number of genes involved in the pathogenesis of Parkinson's disease have been identified. Mutations in several genes have been shown to cause familial parkinsonism. In this review, we discuss 12 of them (SNCA, LRRK2, Parkin, PINK1, DJ1, ATP13A2, PLA2G6, FBXO7, UCHL1, GIGYF2, HTRA2, and EIF4G1). Additionally, six genes have been shown conclusively to be risk factors for sporadic Parkinson's disease, and are also discussed (GBA, MAPT, BST1, PARK16, GAK, and HLA). Many more genes and genetic loci have been suggested, but need confirmation. There is evidence that pathways involved in the rare familial forms also play a role in the sporadic form, and that the respective genes might also be risk factors for sporadic Parkinson's disease. The identification of genes involved in the development of Parkinson's disease will improve our understanding of the underlying molecular mechanisms, and will hopefully lead to new drug targets and treatment strategies.
The Application of Clinical Genetics 06/2011; 4(67–80):67-80. DOI:10.2147/TACG.S11639
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