PINK1 homozygous W437X mutation in a patient with apparent dominant transmission of parkinsonism

Criscuolo, Chiara; Volpe, Giovanni; Rosa, Anna De; Varrone, Andrea; Marongiu, Roberta; Mancini, P; Salvatore, Elena; Dallapiccola, Bruno; Filla, Alessandro; Valente, Enza Maria; Michele, Giuseppe De

doi:10.1002/mds.20933

Cited by 49 publications

(51 citation statements)

References 16 publications

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“…In published families, the vast majority of heterozygotes are healthy, often including subjects old enough to have manifested the disease (Wu et al, 2002;Munhoz et al, 2004;Valente et al, 2004a;Marongiu et al, 2007). Yet, few Parkin and PINK1 pedigrees have been described in which some heterozygous relatives received a diagnosis of possible, probable or even definite PD Criscuolo et al, 2006;Hedrich et al, 2006). In these rare cases, however, other "private" genetic and/or environmental factors might concur to influence the disease risk.…”

Section: Discussionmentioning

confidence: 99%

PINK1heterozygous rare variants: prevalence, significance and phenotypic spectrum

et al. 2008

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Heterozygous rare variants in the PINK1 gene, as well as in other genes causing autosomal recessive parkinsonism, have been reported both in patients and healthy controls. Their pathogenic significance is uncertain, but they have been suggested to represent risk factors to develop Parkinson disease (PD). The few large studies that assessed the frequency of PINK1 heterozygotes in cases and controls yielded controversial results, and the phenotypic spectrum is largely unknown. We retrospectively analyzed the occurrence of PINK1 heterozygous rare variants in over 1100 sporadic and familial patients of all onset ages and in 400 controls. Twenty patients and 6 controls were heterozygous, with frequencies (1.8% vs. 1.5%) not significantly different in the two groups. Clinical features of heterozygotes were indistinguishable to those of wild-type patients, with mean disease onset 10 years later than in carriers of two mutations but worse disease progression. A meta-analysis indicated that, in PINK1 heterozygotes, the PD risk is only slightly increased with a non significant odds ratio of 1.62. These findings suggest that PINK1 heterozygous rare variants play only a minor susceptibility significance should be kept distinct from that of homozygous/compound heterozygous mutations, that cause parkinsonism inherited in a mendelian fashion.

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Section: Discussionmentioning

confidence: 99%

PINK1heterozygous rare variants: prevalence, significance and phenotypic spectrum

et al. 2008

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“…Plasmid and Adenovirus Constructs-Plasmid vectors expressing PINK1 wild-type, G309D variant (22), C-terminal truncated variant W437X (23), and kinase-dead triple mutant (K219A/D362A/D384A (20)) were constructed as HA-tagged forms at the C-terminal end using the pDNR-CMV vector (Clontech). The vectors were converted into adenovirus constructs using an Adeno-X Expression System 2 (Clontech).…”

Section: Methodsmentioning

confidence: 99%

“…1A). Two PD-linked PINK1 variants, G309D and W437X (22,23), showed lower levels of protective function, although the control vector carrying LacZ showed no effect. Caspase-3/7 activation induced by rotenone was also suppressed by wild-type PINK1 (Fig.…”

Section: Mtorc2 a New Target Of Pink1mentioning

confidence: 95%

A New Cytosolic Pathway from a Parkinson Disease-associated Kinase, BRPK/PINK1

Murata

Sakaguchi

et al. 2011

Journal of Biological Chemistry

112

115

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Accumulating evidence indicates that dysfunction of mitochondria is a common feature of Parkinson disease. Functional loss of a familial Parkinson disease-linked gene, BRPK/PINK1 (PINK1), results in deterioration of mitochondrial functions and eventual neuronal cell death. A mitochondrial chaperone protein has been shown to be a substrate of PINK1 kinase activity. In this study, we demonstrated that PINK1 has another action point in the cytoplasm. Phosphorylation of Akt at Ser-473 was enhanced by overexpression of PINK1, and the Akt activation was crucial for protection of SH-SY5Y cells from various cytotoxic agents, including oxidative stress. Enhanced Akt phosphorylation was not due to activation of phosphatidylinositol 3-kinase but due to activation of mammalian target of rapamycin complex 2 (mTORC2) by PINK1. Rictor, a specific component of mTORC2, was phosphorylated by overexpression of PINK1. Furthermore, overexpression of PINK1 enhanced cell motility. These results indicate that PINK1 exerts its cytoprotective function not only in mitochondria but also in the cytoplasm through activation of mTORC2. Parkinson disease (PD)2 is a neurodegenerative disorder with progressive loss of dopaminergic neurons, affecting more than 1% of the population older than 65 years. The molecular pathogenesis of PD is not well understood, but identification of genes causatively linked to familial PD has provided insights into the mechanisms. This is rationalized by the fact that symptoms observed in familial PD patients with different genetic abnormalities are very similar to those of sporadic idiopathic PD

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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

1,115

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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PINK1 homozygous W437X mutation in a patient with apparent dominant transmission of parkinsonism

Cited by 49 publications

References 16 publications

PINK1heterozygous rare variants: prevalence, significance and phenotypic spectrum

PINK1heterozygous rare variants: prevalence, significance and phenotypic spectrum

A New Cytosolic Pathway from a Parkinson Disease-associated Kinase, BRPK/PINK1

Genetics of Parkinson's Disease

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