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Parkin mutations and susceptibility alleles in late‐onset Parkinson's disease
Author(s) -
Oliveira Sofia A.,
Scott William K.,
Martin Eden R.,
Nance Martha A.,
Watts Ray L.,
Hubble Jean P.,
Koller William C.,
Pahwa Rajesh,
Stern Matthew B.,
Hiner Bradley C.,
Ondo William G.,
Allen Fred H.,
Scott Burton L.,
Goetz Christopher G.,
Small Gary W.,
Mastaglia Frank,
Stajich Jeffrey M.,
Zhang Fengyu,
Booze Michael W.,
Winn Michelle P.,
Middleton Lefkos T.,
Haines Jonathan L.,
PericakVance Margaret A.,
Vance Jeffery M.
Publication year - 2003
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.10524
Subject(s) - parkin , genetics , allele , exon , biology , mutation , parkinson's disease , age of onset , compound heterozygosity , parkinsonism , disease , medicine , gene
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. Ann Neurol 2003