Heterozygous parkin point mutations are as common in control subjects as in Parkinson's patients

Denise M. Kay, Dawn Moran, Lina Moses, Parvoneh Poorkaj, Cyrus P. Zabetian, John Nutt, Stewart A. Factor, Chang En Yu, Jennifer S. Montimurro, Robert G. Keefe, Gerard D. Schellenberg, Haydeh Payami

Research output: Contribution to journalArticlepeer-review

106 Scopus citations


Objective: Homozygous or compound heterozygous parkin mutations cause juvenile parkinsonism. Heterozygous parkin mutations are also found in patients with typical Parkinson's disease (PD), but it is unclear whether a single "mutation" in a patient is related to disease or is coincidental, because the mutation frequency in control subjects is unknown. We present a comprehensive sequence analysis of parkin in control subjects. Methods: A total of 302 patients and 301 control subjects were sequenced, and findings were replicated in 1,260 additional patients and 1,657 control subjects. Results: Thirty-four variants were detected, of which 21 were novel; 12 were polymorphisms and 22 were rare variants. Patients and control subjects did not differ in the frequency, type, or functional location of the variants. Even P437L, a common mutation thought to be pathogenic, was present in unaffected control subjects. Interpretation: parkin point mutations are not exclusive to PD. The mere presence of a single point mutation in a patient, in the absence of a second mutation, should not be taken as a cause of disease unless corroborated by family data and functional studies. This study does not support the notion that heterozygous parkin sequence variants (mutations or polymorphisms) are risk factors for PD. Whether heterozygous dosage anomalies are associated with PD remains to be determined.

Original languageEnglish (US)
Pages (from-to)47-54
Number of pages8
JournalAnnals of Neurology
Issue number1
StatePublished - Jan 2007

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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