title: Early-onset Parkinson's disease due to PINK1 p.Q456X mutation--clinical and functional study.
abstract: BACKGROUND
  Recessive mutations in the PTEN-induced putative kinase 1 (PINK1) gene cause early-onset Parkinson's disease (EOPD). The clinical phenotype of families that have this PINK1-associated disease may present with different symptoms, including typical PD. The loss of the PINK1 protein may lead to mitochondrial dysfunction, which causes dopaminergic neuron death.
  
  
  METHODS
  The clinical phenotypes of a large Polish family with EOPD and an identified PINK1 homozygous nonsense mutation were assessed. Ubiquitination and degradation of mitochondrial parkin substrates as well as mitochondrial bioenergetics were investigated as direct functional readouts for PINK1's kinase activity in biopsied dermal fibroblasts.
  
  
  RESULTS
  A four-generation family was genealogically evaluated. Genetic screening identified two affected subjects who were both homozygous carriers of the pathogenic PINK1 p.Q456X substitution. Both patients presented with dystonia and gait disorders at symptom onset. Seven heterozygous mutation carriers remained unaffected. Functional studies revealed that the PINK1 p.Q456X protein is non-functional in activating the downstream ubiquitin ligase parkin and priming the ubiquitination of its substrates, and that the RNA levels of PINK1 were significantly reduced.
  
  
  CONCLUSIONS
  The PINK1 p.Q456X mutation leads to a decrease in mRNA and a loss of protein function. The foot dystonia and gait disorders seen at disease onset in affected members of our family, which were accompanied by parkinsonism had a similar clinical presentation to what has been described in previous reports of PINK1 mutation carriers.
authors.affiliation: Department of Neurology, Silesian Medical University, Katowice, Poland; Department of Neuroscience, Mayo Clinic Jacksonville, Florida, USA.
authors.forename: Joanna
authors.initials: J
authors.lastname: Siuda
authors.affiliation: Department of Neurology, Silesian Medical University, Katowice, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Jasinska-Myga
authors.affiliation: Department of Neurology, Silesian Medical University, Katowice, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Boczarska-Jedynak
authors.affiliation: Department of Neurology, Silesian Medical University, Katowice, Poland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Opala
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, Florida, USA.
authors.forename: Fabienne C
authors.initials: FC
authors.lastname: Fiesel
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, Florida, USA.
authors.forename: Elisabeth L
authors.initials: EL
authors.lastname: Moussaud-Lamodière
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns, Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Scarffe
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns, Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.
authors.forename: Valina L
authors.initials: VL
authors.lastname: Dawson
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, Florida, USA.
authors.forename: Owen A
authors.initials: OA
authors.lastname: Ross
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, Florida, USA.
authors.forename: Wolfdieter
authors.initials: W
authors.lastname: Springer
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns, Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Ted M
authors.initials: TM
authors.lastname: Dawson
authors.affiliation: Department of Neurology, Mayo Clinic Jacksonville, Florida, USA. Electronic address: wszolek.zbigniew@mayo.edu.
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics*; D011494:Protein Kinases / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D000099202:PTEN-Induced Putative Kinase
chemical_list: D011494:Protein Kinases; D012333:RNA, Messenger; D000099202:PTEN-Induced Putative Kinase
keywords: Autosomal recessive parkinsonism; Clinical characteristic; Familial Parkinson's disease; Mitochondrial dysfunction; PINK1 p.Q456X mutation