This Article  • Full text  • PDF  • Reply to article  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Citing articles on ISI (20)  • Contact me when this article is cited  Related Content  • Related articles  • Similar articles in this journal  Topic Collections  • Neurogenetics  • Movement Disorders  • Parkinson Disease/ Parkinsonian Disorders  • Neurology, Other  • Alert me on articles by topic  Social Bookmarking   What's this?

The GenePD Study

Mei Sun, MD, PhD; Jeanne C. Latourelle, MS; G. Frederick Wooten, MD; Mark F. Lew, MD; Christine Klein, MD; Holly A. Shill, MD; Lawrence I. Golbe, MD; Margery H. Mark, MD; Brad A. Racette, MD; Joel S. Perlmutter, MD; Abbas Parsian, PhD; Mark Guttman, MD; Garth Nicholson, PhD; Gang Xu, PhD; Jemma B. Wilk, DSc; Marie H. Saint-Hilaire, MD; Anita L. DeStefano, PhD; Ranjana Prakash, MS; Sally Williamson, BS; Oksana Suchowersky, MD; Nancy Labelle, BN, BSc; John H. Growdon, MD; Carlos Singer, MD; Ray L. Watts, MD; Stefano Goldwurm, MD, PhD; Gianni Pezzoli, MD; Kenneth B. Baker, PhD; Peter P. Pramstaller, MD; David J. Burn, MD; Patrick F. Chinnery, MD; Scott Sherman, MD; Peter Vieregge, MD; Irene Litvan, MD; Tammy Gillis, BS; Marcy E. MacDonald, PhD; Richard H. Myers, PhD; James F. Gusella, PhD

Arch Neurol. 2006;63:826-832.

Background  The PARK2 gene at 6q26 encodes parkin, whose inactivation is implicated in an early-onset autosomal recessive form of Parkinson disease (PD).

Objective  To evaluate the influence of heterozygosity for parkin mutation on onset age in a sample of families with at least 2 PD-affected members.

Design  Clinical and genetic study.

Setting  Twenty collaborative clinical sites.

Patients  Patients with familial PD collected in the GenePD study. Studied families were selected for (1) affected sibling pairs sharing 2 alleles identical by state at PARK2 (D6S305) or (2) 1 or more family members with onset age younger than 54 years, regardless of D6S305 status. At least 1 member from each of 183 families underwent comprehensive screening for deletion/insertion variants and point mutations in PARK2.

Main Outcome Measures  Mutations in the parkin gene were screened by means of single-stranded conformation polymorphism and sequencing in all 12 coding exons and flanking intronic sequences for point mutations and duplex quantitative polymerase chain reaction in all exons for rearrangement, duplication, and deletion.

Results  Mutations were found in 23 families (12.6% of those screened). Among the mutation-positive families, 10 (43%) contained compound heterozygotes; 3 (13%), homozygotes; and 10 (43%), heterozygotes. The onset age in patients with parkin gene mutations ranged from 20 to 76 years. Patients with 1 parkin mutation had an 11.7-year age at onset than did patients with none (P = .04), and patients with 2 or more parkin mutations had a 13.2-year decrease in age at onset compared with patients with 1 mutation (P = .04).

Conclusions  These data indicate that parkin mutations are not rare in multiply affected sibships, and that heterozygous mutation carrier status in PARK2 significantly influences age at onset of PD.

Author Affiliations: Molecular Neurogenetics Unit (Drs Sun, MacDonald, and Gusella and Ms Gillis) and Department of Neurology (Dr Growden), Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Department of Neurology, Boston University School of Medicine (Mss Latourelle, Prakash, and Williamson and Drs Xu, Wilk, Saint-Hilaire, DeStefano, and Myers), and Department of Biostatistics, Boston University School of Public Health (Dr DeStefano), Boston, Mass; Departments of Neurology, University of Virginia Health System, Charlottesville, Va (Dr Wooten), University of Southern California, Los Angeles (Dr Lew), University of Lübeck, Lübeck, Germany (Dr Klein), University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, New Brunswick (Drs Golbe and Mark), Washington University School of Medicine, St Louis, Mo (Drs Racette and Perlmutter), Molecular Medicine Laboratory, University of Sydney, Concord Hospital, Sydney, Australia (Dr Nicholson), University of Miami, Miami, Fla (Dr Singer), University of Alabama at Birmingham (Dr Watts), General Regional Hospital Bolzano, Bolzano, Italy (Dr Pramstaller), University of Arizona, Tucson (Dr Sherman), and University of Louisville School of Medicine, Louisville, Ky (Dr Litvan); Muhammad Ali Parkinson Research Center, Barrow Neurological Institute, Phoenix, Ariz (Dr Shill); Department of Pediatrics, Human Genomics Laboratories, University of Arkansas for Medical Sciences, Little Rock (Dr Parsian); Department of Medicine, University of Toronto, Toronto, Ontario (Dr Guttman); Departments of Clinical Neurosciences and Medical Genetics, University of Calgary, Calgary, Alberta (Dr Suchowersky and Ms Labelle); Parkinson Institute, Istituti Clinici di Perfezionamento, Milano, Italy (Drs Goldwurm and Pezzoli); Departments of Neurology and Neuroscience, Cleveland Clinic Foundation, Cleveland, Ohio (Dr Baker); Regional Neurosciences Centre, Newcastle General Hospital, Newcastle upon Tyne, England (Drs Burn and Chinnery); and Klinik für Neurologie, Klinikum Lippe-Lemgo, Lemgo, Germany (Dr Vieregge).

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati     What's this?

RELATED ARTICLES

Increased Risk for Heterozygotes in Recessive Parkinson Disease
Uwe Beffert and Roger N. Rosenberg
Arch Neurol. 2006;63(6):807-808.
EXTRACT | FULL TEXT  

Clinical Spectrum of Homozygous and Heterozygous PINK1 Mutations in a Large German Family With Parkinson Disease: Role of a Single Hit?
Katja Hedrich, Johann Hagenah, Ana Djarmati, Anja Hiller, Thora Lohnau, Kathrin Lasek, Anne Grünewald, Rüdiger Hilker, Susanne Steinlechner, Heather Boston, Norman Kock, Christiane Schneider-Gold, Wolfram Kress, Hartwig Siebner, Ferdinand Binkofski, Rebekka Lencer, Alexander Münchau, and Christine Klein
Arch Neurol. 2006;63(6):833-838.
ABSTRACT | FULL TEXT  

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Parkin and PINK1 mutations in early-onset Parkinson's disease: comprehensive screening in publicly available cases and control
Brooks et al.
J. Med. Genet. 2009;46:375-381.
ABSTRACT | FULL TEXT  

Bacterial Artificial Chromosome Transgenic Mice Expressing a Truncated Mutant Parkin Exhibit Age-Dependent Hypokinetic Motor Deficits, Dopaminergic Neuron Degeneration, and Accumulation of Proteinase K-Resistant {alpha}-Synuclein
Lu et al.
J. Neurosci. 2009;29:1962-1976.
ABSTRACT | FULL TEXT  

Haplotypes and gene expression implicate the MAPT region for Parkinson disease: The GenePD Study
Tobin et al.
Neurology 2008;71:28-34.
ABSTRACT | FULL TEXT  

Risk of Parkinson Disease in Carriers of Parkin Mutations: Estimation Using the Kin-Cohort Method
Wang et al.
Arch Neurol 2008;65:467-474.
ABSTRACT | FULL TEXT  

Rare heterozygous parkin variants in French early-onset Parkinson disease patients and controls
Lesage et al.
J. Med. Genet. 2008;45:43-46.
ABSTRACT | FULL TEXT  

Mutations in the glucocerebrosidase gene are associated with early-onset Parkinson disease
Clark et al.
Neurology 2007;69:1270-1277.
ABSTRACT | FULL TEXT  

Drosophila Overexpressing Parkin R275W Mutant Exhibits Dopaminergic Neuron Degeneration and Mitochondrial Abnormalities
Wang et al.
J. Neurosci. 2007;27:8563-8570.
ABSTRACT | FULL TEXT  

A Drosophila Model of Mutant Human Parkin-Induced Toxicity Demonstrates Selective Loss of Dopaminergic Neurons and Dependence on Cellular Dopamine
Sang et al.
J. Neurosci. 2007;27:981-992.
ABSTRACT | FULL TEXT  

Papers of Note
Sci Aging Knowl Environ 2006;2006:nw10-nw10.
FULL TEXT  

Increased risk for heterozygotes in recessive Parkinson disease.
Beffert and Rosenberg
Arch Neurol 2006;63:807-808.
FULL TEXT