Parkin mutations and susceptibility alleles in late-onset Parkinson's disease

Sofia A. Oliveira, William K. Scott, Eden R. Martin, Martha A. Nance, Ray L. Watts, Jean P. Hubble, William C. Koller, Rajesh Pahwa, Matthew B. Stern, Bradley C. Hiner, William G. Ondo, Fred H. Allen, Burton L. Scott, Christopher G. Goetz, Gary W. Small, Frank Mastaglia, Jeffrey M. Stajich, Fengyu Zhang, Michael W. Booze, Michelle P. WinnLefkos T. Middleton, Jonathan L. Haines, Margaret A. Pericak-Vance, Jeffery M. Vance

Research output: Contribution to journalArticle

160 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)624-629
Number of pages6
JournalAnnals of neurology
Volume53
Issue number5
DOIs
StatePublished - May 1 2003
Externally publishedYes

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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  • Cite this

    Oliveira, S. A., Scott, W. K., Martin, E. R., Nance, M. A., Watts, R. L., Hubble, J. P., Koller, W. C., Pahwa, R., Stern, M. B., Hiner, B. C., Ondo, W. G., Allen, F. H., Scott, B. L., Goetz, C. G., Small, G. W., Mastaglia, F., Stajich, J. M., Zhang, F., Booze, M. W., ... Vance, J. M. (2003). Parkin mutations and susceptibility alleles in late-onset Parkinson's disease. Annals of neurology, 53(5), 624-629. https://doi.org/10.1002/ana.10524