Journal article
A heterozygous effect for PINK1 mutations in Parkinson's disease
Annals of Neurology, Vol.60(4), pp.414-419
2006
Abstract
Objective: To investigate the significance of PINK1 mutations in sporadic Parkinson's disease (PD). Methods: We determined the frequency of PINK1 mutations by direct sequencing in a large series of PD patients with apparently sporadic disease (n = 768). Results: Twelve heterozygous mutations were identified, nine in PD patients and three in control subjects. Interpretation: Given the difficulty in interpreting the pathogenic significance of the heterozygous mutations that have already been reported in parkin and DJ-1, we first determined the frequency of heterozygous PINK1 mutations in the general population by sequencing a large number of control subjects (n = 768), then subsequently assessed their functional significance by examining their effects on stress-induced alterations to the mitochondrial membrane potential (ΔΨm). We demonstrate an enrichment of heterozygous mutations in sporadic PD patients compared with matched control subjects (1.2% in PD vs 0.4% in control subjects). Furthermore, we show that they adversely affect ΔΨm in a similar way to the familial G309D mutation. Although it remains difficult to conclusively demonstrate the pathogenicity of heterozygous mutations, the results of this study and the previously reported subclinical nigrostriatal dysfunction in carriers of heterozygous PINK1 mutations suggest the possibility that these heterozygous mutations are a significant risk factor in the development of later onset PD. © 2006 American Neurological Association Published by Wiley-Liss, Inc., through Wiley Subscription Services.
Details
- Title
- A heterozygous effect for PINK1 mutations in Parkinson's disease
- Authors
- P M Abou-Sleiman (Author) - Department of Molecular Neuroscience, Institute of NeurologyM M K Muqit (Author) - Department of Molecular Neuroscience, Institute of NeurologyN Q McDonald (Author) - Structural Biology Laboratory, United KingdomY X Yang (Author) - Institute of Child HealthS Gandhi (Author) - Department of Molecular Neuroscience, Institute of NeurologyD G Healy (Author) - Department of Molecular Neuroscience, Institute of NeurologyK Harvey (Author) - Department of Pharmacology, School of PharmacyRobert J Harvey (Author) - Department of Pharmacology, School of PharmacyE Deas (Author) - Department of Pharmacology, School of PharmacyK Bhatia (Author) - Sobell Department of Motor Neu-roscience and Movement Disorders, Institute of NeurologyN Quinn (Author) - Sobell Department of Motor Neu-roscience and Movement Disorders, Institute of NeurologyA Lees (Author) - Department of Molecular Neuroscience, Institute of NeurologyD S Latchman (Author) - Institute of Child HealthN W Wood (Author) - Department of Molecular Neuroscience, Institute of Neurology
- Publication details
- Annals of Neurology, Vol.60(4), pp.414-419
- Publisher
- John Wiley & Sons Inc.
- Date published
- 2006
- DOI
- 10.1002/ana.20960
- ISSN
- 0364-5134
- Organisation Unit
- School of Health; University of the Sunshine Coast, Queensland; School of Health and Sport Sciences - Legacy; Centre for Bioinnovation; School of Health and Behavioural Sciences - Legacy
- Language
- English
- Record Identifier
- 99450430402621
- Output Type
- Journal article
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