title: A heterozygous effect for PINK1 mutations in Parkinson's disease?
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.
  
  
  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.
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, London, United Kingdom.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Abou-Sleiman
authors.forename: Miratul M K
authors.initials: MM
authors.lastname: Muqit
authors.forename: Neil Q
authors.initials: NQ
authors.lastname: McDonald
authors.forename: Yan Xiang
authors.initials: YX
authors.lastname: Yang
authors.forename: Sonia
authors.initials: S
authors.lastname: Gandhi
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Healy
authors.forename: Kirsten
authors.initials: K
authors.lastname: Harvey
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Harvey
authors.forename: Emma
authors.initials: E
authors.lastname: Deas
authors.forename: Kailash
authors.initials: K
authors.lastname: Bhatia
authors.forename: Niall
authors.initials: N
authors.lastname: Quinn
authors.forename: Andrew
authors.initials: A
authors.lastname: Lees
authors.forename: David S
authors.initials: DS
authors.lastname: Latchman
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Wood
mesh_terms: 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
chemical_list: D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase