Influence of heterozygosity for parkin mutation on onset age in familial Parkinson disease: the GenePD study

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. Design Clinical and genetic study. Setting Twenty collaborative clinical sites. Patients Patients with familial PD collected in the Gene PD 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 . Main Outcome Measures 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.