A heterozygous effect for PINK1 mutations in Parkinson's disease?
Article first published online: 12 SEP 2006
Copyright © 2006 American Neurological Association
Annals of Neurology
Volume 60, Issue 4, pages 414–419, October 2006
How to Cite
Abou-Sleiman, P. M., Muqit, M. M. K., McDonald, N. Q., Yang, Y. X., Gandhi, S., Healy, D. G., Harvey, K., Harvey, R. J., Deas, E., Bhatia, K., Quinn, N., Lees, A., Latchman, D. S. and Wood, N. W. (2006), A heterozygous effect for PINK1 mutations in Parkinson's disease?. Ann Neurol., 60: 414–419. doi: 10.1002/ana.20960
- Issue published online: 26 OCT 2006
- Article first published online: 12 SEP 2006
- Manuscript Accepted: 17 JUL 2006
- Manuscript Revised: 12 JUN 2006
- Manuscript Received: 21 OCT 2005
- Medical Research Council (MRC) program. Grant Number: G0400000
- Parkinson's Disease Society, United Kingdom
- Brain Research Trust
- Medical Research Council Clinical Research Training Fellowship
- Wellcome Trust Research Training Fellowship
To investigate the significance of PINK1 mutations in sporadic Parkinson's disease (PD).
We determined the frequency of PINK1 mutations by direct sequencing in a large series of PD patients with apparently sporadic disease (n = 768).
Twelve heterozygous mutations were identified, nine in PD patients and three in control subjects.
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. Ann Neurol 2006