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

Authors

  • Denise M. Kay PhD,

    1. Wadsworth Center, New York State Department of Health, Albany, NY
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  • Dawn Moran BS,

    1. Geriatric Research Education and Clinical Center, Veterans Administration Puget Sound Health Care System, Seattle, WA
    2. Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA
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  • Lina Moses BS,

    1. Wadsworth Center, New York State Department of Health, Albany, NY
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  • Parvoneh Poorkaj PhD,

    1. Geriatric Research Education and Clinical Center, Veterans Administration Puget Sound Health Care System, Seattle, WA
    2. Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA
    3. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA
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  • Cyrus P. Zabetian MD, MS,

    1. Geriatric Research Education and Clinical Center, Veterans Administration Puget Sound Health Care System, Seattle, WA
    2. Department of Neurology, University of Washington School of Medicine, Seattle, WA
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  • John Nutt MD,

    1. Department of Neurology, Oregon Health and Science University, Portland, OR
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  • Stewart A. Factor DO,

    1. Parkinson's Disease and Movement Disorder Clinic, Albany Medical Center, Albany, NY
    2. Department of Neurology, Emory University School of Medicine, Atlanta, GA
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  • Chang-En Yu PhD,

    1. Geriatric Research Education and Clinical Center, Veterans Administration Puget Sound Health Care System, Seattle, WA
    2. Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA
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  • Jennifer S. Montimurro BS,

    1. Wadsworth Center, New York State Department of Health, Albany, NY
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  • Robert G. Keefe PhD,

    1. Wadsworth Center, New York State Department of Health, Albany, NY
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  • Gerard D. Schellenberg PhD,

    1. Geriatric Research Education and Clinical Center, Veterans Administration Puget Sound Health Care System, Seattle, WA
    2. Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA
    3. Departments of Neurology and Pharmacology, University of Washington, Seattle, WA
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  • Haydeh Payami PhD

    Corresponding author
    1. Wadsworth Center, New York State Department of Health, Albany, NY
    • Wadsworth Center, New York State Department of Health, PO Box 22002, Albany, NY 12201-2002
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Abstract

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. Ann Neurol 2006

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