Hereditary Early-Onset Parkinson's Disease Caused by Mutations in
            <i>PINK1</i>

Valente, Enza Maria; Abou‐Sleiman, Patrick M.; Caputo, Viviana; Muqit, Miratul M. K.; Harvey, Kirsten; Gispert, Suzana; Ali, Zeeshan; Turco, Domenico Del; Bentivoglio, Anna Rita; Healy, Daniel G.; Albanese, Alberto; Nussbaum, Robert L.; Gonzalez-Maldonado, R; Deller, Thomas; Salvi, Sergio; Cortelli, Pietro; Gilks, William P.; Latchman, David S.; Harvey, Roberk J.; Dallapiccola, Bruno; Auburger, Georg; Wood, Nicholas W.

doi:10.1126/science.1096284

Cited by 3,144 publications

(2,366 citation statements)

References 16 publications

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“…Direct sequencing of the complete coding region and the exon/intron boundaries of the candidate genes POLG, 3 POLG2, 4 C10orf2 (Twinkle),5 SLC25A4 (ANT1),7 OPA1, 17 PINK1, 29 and PARK2 30 were carried out as previously described. Large gene deletions or duplications in PARK2 and PINK1 genes were tested by using the MLPA assay for Parkinson disease (SALSA MLPA Kit P051/P052 Parkinson; MRC‐Holland, Amsterdam, the Netherlands).…”

Section: Methodsmentioning

confidence: 99%

Syndromic parkinsonism and dementia associated with OPA1 missense mutations

Carelli

Musumeci

Caporali

et al. 2015

Annals of Neurology

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160

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ObjectiveMounting evidence links neurodegenerative disorders such as Parkinson disease and Alzheimer disease with mitochondrial dysfunction, and recent emphasis has focused on mitochondrial dynamics and quality control. Mitochondrial dynamics and mtDNA maintenance is another link recently emerged, implicating mutations in the mitochondrial fusion genes OPA1 and MFN2 in the pathogenesis of multisystem syndromes characterized by neurodegeneration and accumulation of mtDNA multiple deletions in postmitotic tissues. Here, we report 2 Italian families affected by dominant chronic progressive external ophthalmoplegia (CPEO) complicated by parkinsonism and dementia.MethodsPatients were extensively studied by optical coherence tomography (OCT) to assess retinal nerve fibers, and underwent muscle and brain magnetic resonance spectroscopy (MRS), and muscle biopsy and fibroblasts were analyzed. Candidate genes were sequenced, and mtDNA was analyzed for rearrangements.ResultsAffected individuals displayed a slowly progressive syndrome characterized by CPEO, mitochondrial myopathy, sensorineural deafness, peripheral neuropathy, parkinsonism, and/or cognitive impairment, in most cases without visual complains, but with subclinical loss of retinal nerve fibers at OCT. Muscle biopsies showed cytochrome c oxidase‐negative fibers and mtDNA multiple deletions, and MRS displayed defective oxidative metabolism in muscle and brain. We found 2 heterozygous OPA1 missense mutations affecting highly conserved amino acid positions (p.G488R, p.A495V) in the guanosine triphosphatase domain, each segregating with affected individuals. Fibroblast studies showed a reduced amount of OPA1 protein with normal mRNA expression, fragmented mitochondria, impaired bioenergetics, increased autophagy and mitophagy.InterpretationThe association of CPEO and parkinsonism/dementia with subclinical optic neuropathy widens the phenotypic spectrum of OPA1 mutations, highlighting the association of defective mitochondrial dynamics, mtDNA multiple deletions, and altered mitophagy with parkinsonism. Ann Neurol 2015;78:21–38

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Section: Methodsmentioning

confidence: 99%

Syndromic parkinsonism and dementia associated with OPA1 missense mutations

Carelli

Musumeci

Caporali

et al. 2015

Annals of Neurology

Self Cite

160

106

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“…To date (2010), 11 genes and an additional 3 genetic loci have been associated with PD [168][169][170][171][172][173][174][175][176][177][178][179][180][181][182][183][184]; two additional loci await to be confirmed [185,186]. The PD genes and loci are described in Table 4.…”

Section: Genes and Loci In Familial Pdmentioning

confidence: 99%

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

et al. 2011

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“…The identification of rare highly penetrant mutations in genes causing familial and early onset Parkinson disease (PD)1, 2, 3, 4, 5 has considerably improved our understanding of disease pathogenesis. Recently, our understanding of idiopathic PD has been enhanced by genome‐wide association (GWA) studies6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 that have collectively identified PD risk variants at >18 loci 6, 7.…”

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confidence: 99%

Polygenic risk of Parkinson disease is correlated with disease age at onset

Escott‐Price¹,

Nalls

Morris

et al. 2015

Annals of Neurology

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126

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ObjectiveWe have investigated the polygenic architecture of Parkinson disease (PD) and have also explored the potential relationship between an individual's polygenic risk score and their disease age at onset.MethodsThis study used genotypic data from 4,294 cases and 10,340 controls obtained from the meta‐analysis of PD genome‐wide association studies. Polygenic score analysis was performed as previously described by the International Schizophrenia Consortium, testing whether the polygenic score alleles identified in 1 association study were significantly enriched in the cases relative to the controls of 3 independent studies. Linear regression was used to investigate the relationship between an individual's polygenic score for PD risk alleles and disease age at onset.ResultsOur polygenic score analysis has identified significant evidence for a polygenic component enriched in the cases of each of 3 independent PD genome‐wide association cohorts (minimum p = 3.76 × 10−6). Further analysis identified compelling evidence that the average polygenic score in patients with an early disease age at onset was significantly higher than in those with a late age at onset (p = 0.00014).InterpretationThis provides strong support for a large polygenic contribution to the overall heritable risk of PD and also suggests that early onset forms of the illness are not exclusively caused by highly penetrant Mendelian mutations, but can also be contributed to by an accumulation of common polygenic alleles with relatively low effect sizes. Ann Neurol 2015;77:582–591

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Hereditary Early-Onset Parkinson's Disease Caused by Mutations in PINK1

Cited by 3,144 publications

References 16 publications

Syndromic parkinsonism and dementia associated with OPA1 missense mutations

Syndromic parkinsonism and dementia associated with OPA1 missense mutations

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

Polygenic risk of Parkinson disease is correlated with disease age at onset

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