A heterozygous effect for PINK1 mutations in Parkinson's disease?
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.


CONCLUSIONS
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 (DeltaPsim). 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 DeltaPsim 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.
Abou-Sleiman
Patrick M
PM
Department of Molecular Neuroscience, Institute of Neurology, London, United Kingdom.
Muqit
Miratul M K
MM
McDonald
Neil Q
NQ
Yang
Yan Xiang
YX
Gandhi
Sonia
S
Healy
Daniel G
DG
Harvey
Kirsten
K
Harvey
Robert J
RJ
Deas
Emma
E
Bhatia
Kailash
K
Quinn
Niall
N
Lees
Andrew
A
Latchman
David S
DS
Wood
Nicholas W
NW
D000328:Adult; D017668:Age of Onset; D000368:Aged; D000483:Alleles; D002478:Cells, Cultured; D002875:Chromosomes / Q000235:genetics; D019295:Computational Biology; D004252:DNA Mutational Analysis; D005260:Female; D005434:Flow Cytometry; D005787:Gene Frequency; D006579:Heterozygote; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D008875:Middle Aged; D008928:Mitochondria / Q000502:physiology; D009154:Mutation / Q000502:physiology*; D016366:Open Reading Frames / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics*; D011494:Protein Kinases / Q000235:genetics*; D014162:Transfection; D000099202:PTEN-Induced Putative Kinase
D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase