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 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. 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.
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 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. 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.
Authors: D M Kay; C F Stevens; T H Hamza; J S Montimurro; C P Zabetian; S A Factor; A Samii; A Griffith; J W Roberts; E S Molho; D S Higgins; S Gancher; L Moses; S Zareparsi; P Poorkaj; T Bird; J Nutt; G D Schellenberg; H Payami Journal: Neurology Date: 2010-09-28 Impact factor: 9.910
Authors: Lorena de Mena; L Luís Samaranch; Eliecer Coto; Lucía F Cardo; René Ribacoba; Oswaldo Lorenzo-Betancor; Pau Pastor; Li Wang; Jaione Irigoyen; Ignacio F Mata; Marta Díaz; Germán Moris; Manuel Menéndez; Ana I Corao; Elena Lorenzo; Victoria Alvarez Journal: J Mol Neurosci Date: 2012-12-30 Impact factor: 3.444
Authors: L N Clark; B M Ross; Y Wang; H Mejia-Santana; J Harris; E D Louis; L J Cote; H Andrews; S Fahn; C Waters; B Ford; S Frucht; R Ottman; K Marder Journal: Neurology Date: 2007-09-18 Impact factor: 9.910
Authors: Liyong Wang; Karen Nuytemans; Guney Bademci; Cherylyn Jauregui; Eden R Martin; William K Scott; Jeffery M Vance; Stephan Zuchner Journal: Hum Mutat Date: 2013-05-28 Impact factor: 4.878
Authors: Anita L DeStefano; Jeanne Latourelle; Mark F Lew; Oksana Suchowersky; Christine Klein; Lawrence I Golbe; Margery H Mark; John H Growdon; G Fredrick Wooten; Ray Watts; Mark Guttman; Brad A Racette; Joel S Perlmutter; Lynn Marlor; Holly A Shill; Carlos Singer; Stefano Goldwurm; Gianni Pezzoli; Marie H Saint-Hilaire; Audrey E Hendricks; Adam Gower; Sally Williamson; Michael W Nagle; Jemma B Wilk; Tiffany Massood; Karen W Huskey; Kenneth B Baker; Ilia Itin; Irene Litvan; Garth Nicholson; Alastair Corbett; Martha Nance; Edward Drasby; Stuart Isaacson; David J Burn; Patrick F Chinnery; Peter P Pramstaller; Jomana Al-Hinti; Anette T Moller; Karen Ostergaard; Scott J Sherman; Richard Roxburgh; Barry Snow; John T Slevin; Franca Cambi; James F Gusella; Richard H Myers Journal: Hum Genet Date: 2008-06-29 Impact factor: 4.132
Authors: Jeanne C Latourelle; Nathan Pankratz; Alexandra Dumitriu; Jemma B Wilk; Stefano Goldwurm; Gianni Pezzoli; Claudio B Mariani; Anita L DeStefano; Cheryl Halter; James F Gusella; William C Nichols; Richard H Myers; Tatiana Foroud Journal: BMC Med Genet Date: 2009-09-22 Impact factor: 2.103