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.


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.
Sun
Mei
M
Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA.
Latourelle
Jeanne C
JC
Wooten
G Frederick
GF
Lew
Mark F
MF
Klein
Christine
C
Shill
Holly A
HA
Golbe
Lawrence I
LI
Mark
Margery H
MH
Racette
Brad A
BA
Perlmutter
Joel S
JS
Parsian
Abbas
A
Guttman
Mark
M
Nicholson
Garth
G
Xu
Gang
G
Wilk
Jemma B
JB
Saint-Hilaire
Marie H
MH
DeStefano
Anita L
AL
Prakash
Ranjana
R
Williamson
Sally
S
Suchowersky
Oksana
O
Labelle
Nancy
N
Growdon
John H
JH
Singer
Carlos
C
Watts
Ray L
RL
Goldwurm
Stefano
S
Pezzoli
Gianni
G
Baker
Kenneth B
KB
Pramstaller
Peter P
PP
Burn
David J
DJ
Chinnery
Patrick F
PF
Sherman
Scott
S
Vieregge
Peter
P
Litvan
Irene
I
Gillis
Tammy
T
MacDonald
Marcy E
ME
Myers
Richard H
RH
Gusella
James F
JF
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*
D044767:Ubiquitin-Protein Ligases; C111567:parkin protein