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Case-Control Study of the Parkin Gene in Early-Onset Parkinson Disease
Lorraine N. Clark, PhD;
Shehla Afridi, MS;
Eric Karlins, MS;
Yuanjia Wang, PhD;
Helen Mejia-Santana, MS;
Juliette Harris, PhD;
Elan D. Louis, MD, MS;
Lucien J. Cote, MD;
Howard Andrews, PhD;
Stanley Fahn, MD;
Cheryl Waters, MD, FRCP;
Blair Ford, MD, FRCP;
Steven Frucht, MD;
Ruth Ottman, PhD;
Karen Marder, MD, MPH
Arch Neurol. 2006;63:548-552.
Background Mutations in parkin are estimated to account for as much as 50% of familial Parkinson disease (PD) and 18% of sporadic PD. Single heterozygous mutations in parkin in both familial and sporadic cases may also increase susceptibility to PD. To our knowledge, all previous studies have been restricted to PD cases; this is the first study to systematically screen the parkin coding regions and exon deletions and duplications in controls.
Objective To determine the frequency and spectrum of parkin variants in early-onset PD cases (aged  50 years) and controls participating in a familial aggregation study.
Patients and Methods We sequenced the parkin gene in 101 cases and 105 controls. All cases and controls were also screened for exon deletions and duplications by semiquantitative multiplex polymerase chain reaction.
Results Thirteen (12.9% [95% confidence interval, 7%-21%]) of the 101 cases had a previously described parkin mutation: 1 was homozygous, 11 were heterozygous, and 1 was a compound heterozygote. The mutations Arg42Pro (exon 2) and Arg275Trp (exon 7) were recurrent. The previously reported synonymous substitution Leu261Leu (c.884A>G) was identified in 4 (3.9%) of 101 cases and 2 (2%) of 105 controls (P = .44). Excluding the synonymous substitution Leu261Leu (heterozygotes), 10 (9.9% [95% confidence interval, 4.6%-17.5%]) carried mutations.
Conclusions The frequency of mutations among cases that were not selected based on family history of PD is similar to what has previously been reported in sporadic PD. The similar frequency of Leu261Leu in cases and controls suggests it is a normal variant rather than a disease-associated mutation. We confirmed that heterozygous parkin mutations may increase susceptibility for early-onset PD.
Author Affiliations: Taub Institute for Research on Alzheimer's Disease and the Aging Brain (Drs Clark, Louis, and Marder and Ms Afridi), Departments of Pathology (Dr Clark), Statistics (Dr Wang), Neurology (Drs Harris, Louis, Cote, Fahn, Waters, Ford, Frucht, and Marder), and Psychiatry (Dr Marder) and Gertrude H. Sergievsky Center (Mr Karlins, Ms Mejia-Santana, and Drs Louis, Cote, Andrews, Ottman, and Marder), College of Physicians and Surgeons, Epidemiology Department, Mailman School of Public Health (Drs Andrews and Ottman), and The Epidemiology of Brain Disorders Department, New York State Psychiatric Institute (Dr Ottman), Columbia University, New York, NY.
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