title: Influence of heterozygosity for parkin mutation on onset age in familial Parkinson disease: the GenePD study.
abstract: BACKGROUND
  The PARK2 gene at 6q26 encodes parkin, whose inactivation is implicated in an early-onset autosomal recessive form of Parkinson disease (PD).
  
  
  OBJECTIVE
  To evaluate the influence of heterozygosity for parkin mutation on onset age in a sample of families with at least 2 PD-affected members.
  
  
  METHODS
  Clinical and genetic study.
  
  
  METHODS
  Twenty collaborative clinical sites.
  
  
  METHODS
  Patients with familial PD collected in the GenePD study. Studied families were selected for (1) affected sibling pairs sharing 2 alleles identical by state at PARK2 (D6S305) or (2) 1 or more family members with onset age younger than 54 years, regardless of D6S305 status. At least 1 member from each of 183 families underwent comprehensive screening for deletion/insertion variants and point mutations in PARK2.
  
  
  METHODS
  Mutations in the parkin gene were screened by means of single-stranded conformation polymorphism and sequencing in all 12 coding exons and flanking intronic sequences for point mutations and duplex quantitative polymerase chain reaction in all exons for rearrangement, duplication, and deletion.
  
  
  RESULTS
  Mutations were found in 23 families (12.6% of those screened). Among the mutation-positive families, 10 (43%) contained compound heterozygotes; 3 (13%), homozygotes; and 10 (43%), heterozygotes. The onset age in patients with parkin gene mutations ranged from 20 to 76 years. Patients with 1 parkin mutation had an 11.7-year age at onset than did patients with none (P = .04), and patients with 2 or more parkin mutations had a 13.2-year decrease in age at onset compared with patients with 1 mutation (P = .04).
  
  
  CONCLUSIONS
  These data indicate that parkin mutations are not rare in multiply affected sibships, and that heterozygous mutation carrier status in PARK2 significantly influences age at onset of PD.
authors.affiliation: Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Sun
authors.forename: Jeanne C
authors.initials: JC
authors.lastname: Latourelle
authors.forename: G Frederick
authors.initials: GF
authors.lastname: Wooten
authors.forename: Mark F
authors.initials: MF
authors.lastname: Lew
authors.forename: Christine
authors.initials: C
authors.lastname: Klein
authors.forename: Holly A
authors.initials: HA
authors.lastname: Shill
authors.forename: Lawrence I
authors.initials: LI
authors.lastname: Golbe
authors.forename: Margery H
authors.initials: MH
authors.lastname: Mark
authors.forename: Brad A
authors.initials: BA
authors.lastname: Racette
authors.forename: Joel S
authors.initials: JS
authors.lastname: Perlmutter
authors.forename: Abbas
authors.initials: A
authors.lastname: Parsian
authors.forename: Mark
authors.initials: M
authors.lastname: Guttman
authors.forename: Garth
authors.initials: G
authors.lastname: Nicholson
authors.forename: Gang
authors.initials: G
authors.lastname: Xu
authors.forename: Jemma B
authors.initials: JB
authors.lastname: Wilk
authors.forename: Marie H
authors.initials: MH
authors.lastname: Saint-Hilaire
authors.forename: Anita L
authors.initials: AL
authors.lastname: DeStefano
authors.forename: Ranjana
authors.initials: R
authors.lastname: Prakash
authors.forename: Sally
authors.initials: S
authors.lastname: Williamson
authors.forename: Oksana
authors.initials: O
authors.lastname: Suchowersky
authors.forename: Nancy
authors.initials: N
authors.lastname: Labelle
authors.forename: John H
authors.initials: JH
authors.lastname: Growdon
authors.forename: Carlos
authors.initials: C
authors.lastname: Singer
authors.forename: Ray L
authors.initials: RL
authors.lastname: Watts
authors.forename: Stefano
authors.initials: S
authors.lastname: Goldwurm
authors.forename: Gianni
authors.initials: G
authors.lastname: Pezzoli
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Baker
authors.forename: Peter P
authors.initials: PP
authors.lastname: Pramstaller
authors.forename: David J
authors.initials: DJ
authors.lastname: Burn
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
authors.forename: Scott
authors.initials: S
authors.lastname: Sherman
authors.forename: Peter
authors.initials: P
authors.lastname: Vieregge
authors.forename: Irene
authors.initials: I
authors.lastname: Litvan
authors.forename: Tammy
authors.initials: T
authors.lastname: Gillis
authors.forename: Marcy E
authors.initials: ME
authors.lastname: MacDonald
authors.forename: Richard H
authors.initials: RH
authors.lastname: Myers
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D004252:DNA Mutational Analysis / Q000379:methods; D005091:Exons; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006579:Heterozygote; D006801:Humans; D007391:International Cooperation; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010300:Parkinson Disease / Q000453:epidemiology / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D044767:Ubiquitin-Protein Ligases; C111567:parkin protein