Phenotypic spectrum of PINK1‐associated parkinsonism in 15 mutation carriers from 1 family

Hiller, Anja; Hagenah, Johann; Djarmati, Ana; Hedrich, Katja; Reetz, Kathrin; Schneider‐Gold, Christiane; Kress, W.; Münchau, Alexander; Klein, Christine

doi:10.1002/mds.21059

Cited by 20 publications

(16 citation statements)

References 6 publications

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“…Several lines of evidence suggest that heterozygous Parkin and PINK1 mutations are indeed a susceptibility factor, however, this topic is highly debated. Important insights into the role of heterozygous mutations come from the detailed neurological assessment of heterozygous relatives of index patients that are known to carry two mutations (Khan et al 2005;Criscuolo et al 2006;Hedrich et al 2006;Hiller et al 2007;Eggers et al 2010). Notably, the identification of affected individuals in successive generations makes it unlikely that a second mutation in the respective gene had been missed, as may be the case in case-only and case-control studies.…”

Section: Genetic Principles and Exceptions Thereof In Familial Pdmentioning

confidence: 99%

Genetics of Parkinson's Disease

Klein

Westenberger

2012

Cold Spring Harbor Perspectives in Medicine

1,062

780

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Fifteen years of genetic research in Parkinson's disease (PD) have led to the identification of several monogenic forms of the disorder and of numerous genetic risk factors increasing the risk to develop PD. Monogenic forms, caused by a single mutation in a dominantly or recessively inherited gene, are well-established, albeit relatively rare types of PD. They collectively account for about 30% of the familial and 3%-5% of the sporadic cases. In this article, we will summarize the current knowledge and understanding of the molecular genetics of PD. In brief, we will review familial forms of PD, basic genetic principles of inheritance (and their exceptions in PD), followed by current methods for the identification of PD genes and risk factors, and implications for genetic testing.

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Section: Genetic Principles and Exceptions Thereof In Familial Pdmentioning

confidence: 99%

Genetics of Parkinson's Disease

Klein

Westenberger

2012

Cold Spring Harbor Perspectives in Medicine

1,062

780

View full text Add to dashboard Cite

show abstract

“…14 Three of the Parkin 13,15 and five of the PINK1 14,16 mutation carriers had minor motor signs upon careful clinical examination, but were not aware of the motor signs and motor signs did not interfere with their daily activities. None of these subjects had a Unified Parkinson's Disease Rating Scale score of more than 4 or met the international accepted diagnostic criteria of probable PD.…”

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confidence: 99%

Heterozygous carriers of a Parkin or PINK1 mutation share a common functional endophenotype

Nuenen¹,

Weiss²,

Bloem³

et al. 2009

Neurology

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Objective: To use a combined neurogenetic-neuroimaging approach to examine the functional consequences of preclinical dopaminergic nigrostriatal dysfunction in the human motor system. Specifically, we examined how a single heterozygous mutation in different genes associated with recessively inherited Parkinson disease alters the cortical control of sequential finger movements. Methods:Nonmanifesting individuals carrying a single heterozygous Parkin (n ϭ 13) or PINK1 (n ϭ 9) mutation and 23 healthy controls without these mutations were studied with functional MRI (fMRI). During fMRI, participants performed simple sequences of three thumb-to-finger opposition movements with their right dominant hand. Since heterozygous Parkin and PINK1 mutations cause a latent dopaminergic nigrostriatal dysfunction, we predicted a compensatory recruitment of those rostral premotor areas that are normally implicated in the control of complex motor sequences. We expected this overactivity to be independent of the underlying genotype.Results: Task performance was comparable for all groups. The performance of a simple motor sequence task consistently activated the rostral supplementary motor area and right rostral dorsal premotor cortex in mutation carriers but not in controls. Task-related activation of these premotor areas was similar in carriers of a Parkin or PINK1 mutation. Conclusion: Mutations in different genes linked to recessively inherited Parkinson disease areassociated with an additional recruitment of rostral supplementary motor area and rostral dorsal premotor cortex during a simple motor sequence task. These premotor areas were recruited independently of the underlying genotype. The observed activation most likely reflects a "generic" compensatory mechanism to maintain motor function in the context of a mild dopaminergic deficit. Neurology ® 2009;72:1041-1047 GLOSSARY BOLD ϭ blood oxygen level-dependent; CMA ϭ cingulate motor area; FDR ϭ false discovery rate; fMRI ϭ functional MRI; HRF ϭ hemodynamic response function; IPS ϭ intraparietal sulcus; M1 HAND ϭ primary motor hand area; PD ϭ Parkinson disease; PMd ϭ dorsal premotor cortex; SMA ϭ supplementary motor area; SPM ϭ statistical parametric mapping; SVC ϭ small volume correction; TE ϭ echo time; TMS ϭ transcranial magnetic stimulation; TR ϭ repetition time; VOI ϭ volumes of interest.Several genes have been identified that can lead to Parkinson disease (PD), including four recessively inherited forms caused by mutations in the Parkin (PARK2), DJ-1 (PARK7), PINK1 (PARK6), and ATP13A2 (PARK9) genes.1-3 These familial forms of PD show a substantial clinical overlap with sporadic PD. Nonmanifesting individuals who carry a single heterozygous mutation in the Parkin and PINK1 gene associated with recessively inherited PD

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“…For example, Abou-Sleiman et al (2006b) reported a higher incidence of heterozygous PINK1 mutations in sporadic PD patients. In addition, Hiller et al (2007) found that six heterozygous carriers of a PD-associated nonsense PINK1 mutation (c. 1366 C > T; p.Q456X) display 'subtle but unequivocal signs of motor impairment.' However, several pieces of evidence against this notion were also presented (see Klein et al 2007 for review).…”

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confidence: 99%

Biochemical aspects of the neuroprotective mechanism of PTEN‐induced kinase‐1 (PINK1)

Mills

Sim

Mok

et al. 2008

Journal of Neurochemistry

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Parkinson's disease (PD) is a common neurodegenerative disorder characterized by selective loss of dopaminergic neurons in the substantia nigra and formation of intracellular inclusions known as Lewy bodies in remaining cells. Despite recent development in PD research, rigorous biomarkers for pre-symptomatic diagnosis of PD are not available. Elucidation of the molecular basis of PD pathogenesis will facilitate the search of these biomarkers to allow early treatment. In addition to common sporadic PD, there exist rare familial forms of Parkinsonism, usually characterized by earlier age of onset and, in some cases, absence of typical Lewy body Abbreviations used: HtrA2, high temperature requirement serine protease 2; IKK, IjBa kinase; JNK, c-Jun NH 2 -terminal kinase; NF-jB, nuclear factor-jB; PanK2, pantothenate kinase 2; PD, Parkinson's disease; PI3-kinase, phosphatidylinositol-3 kinase; PINK1, PTEN-induced kinase 1; PTEN, phosphatase and tensin homologue deleted on chromosone 10; PTP, mitochondrial permeability transition pore; ROS, reactive oxygen species; siRNA, small interfering RNA; TIM, translocase of the inner membrane; TRAF, tumor necrosis factor receptor-associated factor; TRAP, tumor necrosis factor receptor-associated protein. AbstractMutations in PTEN-induced kinase 1 (PINK1) gene cause PARK6 familial Parkinsonism. To decipher the role of PINK1 in pathogenesis of Parkinson's disease (PD), researchers need to identify protein substrates of PINK1 kinase activity that govern neuronal survival, and establish whether aberrant regulation and inactivation of PINK1 contribute to both familial Parkinsonism and idiopathic PD. These studies should take into account the several unique structural and functional features of PINK1. First PINK1 is a rare example of a protein kinase with a predicted mitochondrial-targeting sequence and a possible resident mitochondrial function. Second, bioinformatic analysis reveals unique insert regions within the kinase domain that are potentially involved in regulation of kinase activity, substrate selectivity and stability of PINK1. Third, the C-terminal region contains functional motifs governing kinase activity and substrate selectivity. Fourth, accumulating evidence suggests that PINK1 interacts with other signaling proteins implicated in PD pathogenesis and mitochondrial dysfunction. The most prominent examples are the E3 ubiquitin ligase Parkin, the mitochondrial protease high temperature requirement serine protease 2 and the mitochondrial chaperone tumor necrosis factor receptor-associated protein 1. How PINK1 may regulate these proteins to maintain neuronal survival is unclear. This review describes the unique structural features of PINK1 and their possible roles in governing mitochondrial import, processing, kinase activity, substrate selectivity and stability of PINK1. Based upon the findings of previous studies of PINK1 function in cell lines and animal models, we propose a model on the neuroprotective mechanism of PINK1. This model may serve as a conceptual framework...

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Phenotypic spectrum of PINK1‐associated parkinsonism in 15 mutation carriers from 1 family

Cited by 20 publications

References 6 publications

Genetics of Parkinson's Disease

Genetics of Parkinson's Disease

Heterozygous carriers of a Parkin or PINK1 mutation share a common functional endophenotype

Biochemical aspects of the neuroprotective mechanism of PTEN‐induced kinase‐1 (PINK1)

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