title: PINK1 mutations and parkinsonism.
abstract: BACKGROUND
  PINK1 loss-of-function causes recessive, early-onset parkinsonism. In Tunisia there is a high rate of consanguineous marriage but PINK1 carrier frequency and disease prevalence have yet to be assessed.
  
  
  OBJECTIVE
  The frequency of PINK1 mutations in familial parkinsonism, community-based patients with idiopathic Parkinson disease (PD) (non-familial PD), and control subjects was determined. Demographic and clinical characteristics of individuals with PINK1 homozygous or heterozygous variants, or without PINK1 mutations, were compared.
  
  
  METHODS
  A total of 92 kindreds (with 208 affected and 340 unaffected subjects), 240 nonfamilial PD, and 368 control participants were recruited from the Institut National de Neurologie, Tunis. Clinical examinations included Hoehn &Yahr, UPDRS, and Epworth scales. PINK1 sequencing and dosage analysis was performed in familial index patients, the variants identified screened in all subjects. Parkin and LRRK2 genes were also examined.
  
  
  RESULTS
  Four PINK1 homozygous mutations, three novel (Q129X, Q129fsX157, G440E, and one previously reported; Q456X), segregate with parkinsonism in 46 individuals in 14 of 92 families (15%). Six of 240 patients with nonfamilial PD were found with either homozygous Q456X or Q129X (2.5%) substitutions. In patients with familial disease, PINK1 homozygotes were younger at disease onset (36 +/- 12 years) than noncarriers (57 +/- 15 years) and more often had an akinetic-rigid presentation at examination and slow progression.
  
  
  CONCLUSIONS
  Segregation of PINK1 mutations with parkinsonism within families, and frequency estimates within population controls, suggested only four PINK1 mutations were pathogenic. Several PINK1 sequence variants are potentially benign and there was no evidence that PINK1 heterozygosity increases susceptibility to idiopathic Parkinson disease.
authors.affiliation: Research and Development, GlaxoSmithKline Pharmaceuticals, Harlow, Greenford, Hammersmith, UK.
authors.forename: L
authors.initials: L
authors.lastname: Ishihara-Paul
authors.forename: M M
authors.initials: MM
authors.lastname: Hulihan
authors.forename: J
authors.initials: J
authors.lastname: Kachergus
authors.forename: R
authors.initials: R
authors.lastname: Upmanyu
authors.forename: L
authors.initials: L
authors.lastname: Warren
authors.forename: R
authors.initials: R
authors.lastname: Amouri
authors.forename: R
authors.initials: R
authors.lastname: Elango
authors.forename: R K
authors.initials: RK
authors.lastname: Prinjha
authors.forename: A
authors.initials: A
authors.lastname: Soto
authors.forename: M
authors.initials: M
authors.lastname: Kefi
authors.forename: M
authors.initials: M
authors.lastname: Zouari
authors.forename: S B
authors.initials: SB
authors.lastname: Sassi
authors.forename: S B
authors.initials: SB
authors.lastname: Yahmed
authors.forename: G
authors.initials: G
authors.lastname: El Euch-Fayeche
authors.forename: P M
authors.initials: PM
authors.lastname: Matthews
authors.forename: L T
authors.initials: LT
authors.lastname: Middleton
authors.forename: R A
authors.initials: RA
authors.lastname: Gibson
authors.forename: F
authors.initials: F
authors.lastname: Hentati
authors.forename: M J
authors.initials: MJ
authors.lastname: Farrer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020734:Parkinsonian Disorders / Q000235:genetics*; D010375:Pedigree; D011494:Protein Kinases / Q000235:genetics*; D014416:Tunisia; D000099202:PTEN-Induced Putative Kinase
chemical_list: D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase