title: Case-control study of the parkin gene in early-onset Parkinson disease.
abstract: BACKGROUND
  Mutations in parkin are estimated to account for as much as 50% of familial Parkinson disease (PD) and 18% of sporadic PD. Single heterozygous mutations in parkin in both familial and sporadic cases may also increase susceptibility to PD. To our knowledge, all previous studies have been restricted to PD cases; this is the first study to systematically screen the parkin coding regions and exon deletions and duplications in controls.
  
  
  OBJECTIVE
  To determine the frequency and spectrum of parkin variants in early-onset PD cases (aged < or =50 years) and controls participating in a familial aggregation study.
  
  
  METHODS
  We sequenced the parkin gene in 101 cases and 105 controls. All cases and controls were also screened for exon deletions and duplications by semiquantitative multiplex polymerase chain reaction.
  
  
  RESULTS
  Thirteen (12.9% [95% confidence interval, 7%-21%]) of the 101 cases had a previously described parkin mutation: 1 was homozygous, 11 were heterozygous, and 1 was a compound heterozygote. The mutations Arg42Pro (exon 2) and Arg275Trp (exon 7) were recurrent. The previously reported synonymous substitution Leu261Leu (c.884A>G) was identified in 4 (3.9%) of 101 cases and 2 (2%) of 105 controls (P = .44). Excluding the synonymous substitution Leu261Leu (heterozygotes), 10 (9.9% [95% confidence interval, 4.6%-17.5%]) carried mutations.
  
  
  CONCLUSIONS
  The frequency of mutations among cases that were not selected based on family history of PD is similar to what has previously been reported in sporadic PD. The similar frequency of Leu261Leu in cases and controls suggests it is a normal variant rather than a disease-associated mutation. We confirmed that heterozygous parkin mutations may increase susceptibility for early-onset PD.
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. lc654@columbia.edu
authors.forename: Lorraine N
authors.initials: LN
authors.lastname: Clark
authors.forename: Shehla
authors.initials: S
authors.lastname: Afridi
authors.forename: Eric
authors.initials: E
authors.lastname: Karlins
authors.forename: Yuanjia
authors.initials: Y
authors.lastname: Wang
authors.forename: Helen
authors.initials: H
authors.lastname: Mejia-Santana
authors.forename: Juliette
authors.initials: J
authors.lastname: Harris
authors.forename: Elan D
authors.initials: ED
authors.lastname: Louis
authors.forename: Lucien J
authors.initials: LJ
authors.lastname: Cote
authors.forename: Howard
authors.initials: H
authors.lastname: Andrews
authors.forename: Stanley
authors.initials: S
authors.lastname: Fahn
authors.forename: Cheryl
authors.initials: C
authors.lastname: Waters
authors.forename: Blair
authors.initials: B
authors.lastname: Ford
authors.forename: Steven
authors.initials: S
authors.lastname: Frucht
authors.forename: Ruth
authors.initials: R
authors.lastname: Ottman
authors.forename: Karen
authors.initials: K
authors.lastname: Marder
mesh_terms: D017668:Age of Onset; D000368:Aged; D019943:Amino Acid Substitution / Q000235:genetics; D016022:Case-Control Studies; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010300:Parkinson Disease / Q000175:diagnosis* / Q000235:genetics* / Q000503:physiopathology; D017354:Point Mutation / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D044767:Ubiquitin-Protein Ligases; C111567:parkin protein