Parkin mutations and susceptibility alleles in late-onset Parkinson's disease.
Parkin, an E2-dependent ubiquitin protein ligase, carries pathogenic mutations in patients with autosomal recessive juvenile parkinsonism, but its role in the late-onset form of Parkinson's disease (PD) is not firmly established. Previously, we detected linkage of idiopathic PD to the region on chromosome 6 containing the Parkin gene (D6S305, logarithm of odds score, 5.47) in families with at least one subject with age at onset (AAO) younger than 40 years. Mutation analysis of the Parkin gene in the 174 multiplex families from the genomic screen and 133 additional PD families identified mutations in 18% of early-onset and 2% of late-onset families (5% of total families screened). The AAO of patients with Parkin mutations ranged from 12 to 71 years. Excluding exon 7 mutations, the mean AAO of patients with Parkin mutations was 31.5 years. However, mutations in exon 7, the first RING finger (Cys253Trp, Arg256Cys, Arg275Trp, and Asp280Asn) were observed primarily in heterozygous PD patients with a much later AAO (mean AAO, 49.2 years) but were not found in controls in this study or several previous reports (920 chromosomes). These findings suggest that mutations in Parkin contribute to the common form of PD and that heterozygous mutations, especially those lying in exon 7, act as susceptibility alleles for late-onset form of Parkinson disease.
Department of Medicine and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC 27710, USA.
Sofia A
SA
Oliveira
William K
WK
Scott
Eden R
ER
Martin
Martha A
MA
Nance
Ray L
RL
Watts
Jean P
JP
Hubble
William C
WC
Koller
Rajesh
R
Pahwa
Matthew B
MB
Stern
Bradley C
BC
Hiner
William G
WG
Ondo
Fred H
FH
Allen
Burton L
BL
Scott
Christopher G
CG
Goetz
Gary W
GW
Small
Frank
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Mastaglia
Jeffrey M
JM
Stajich
Fengyu
F
Zhang
Michael W
MW
Booze
Michelle P
MP
Winn
Lefkos T
LT
Middleton
Jonathan L
JL
Haines
Margaret A
MA
Pericak-Vance
Jeffery M
JM
Vance
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D002648:Child; D002851:Chromatography, High Pressure Liquid; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008025:Ligases / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000235:genetics*; D017354:Point Mutation / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D044767:Ubiquitin-Protein Ligases
D017931:DNA Primers; D012333:RNA, Messenger; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D008025:Ligases