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From the Neurogenetic Laboratories (Dr. Farrer, S. Lincoln, G. Bisceglio, J. Hussey, A. West, and M. Hulihan), Department of Neuroscience, Mayo Clinic, Jacksonville, FL; Department of Neurology (Dr. Harris), Columbia University, and Taub Institute for Research on Alzheimer’s Disease and the Aging Brain (Dr. Marder), New York; Laboratory of Neurogenetics (Dr. Hardy), National Institute on Aging, NIH, Bethesda, MD; Parkinson’s Institute (Drs. Langston and Chen), Sunnyvale, CA; Department of Neurology (Drs. Wiley and Lynch), Mater Misericordiae Hospital, University College Dublin, Ireland; Department of Medicine (Division of Neurology) (Drs. Lang, Rogaeva, Sa, and Munhoz), Toronto Western Hospital and Centre for Research in Neurodegenerative Diseases, University of Toronto, Ontario, Canada; and Department of Neurology (Dr. Klein), Medical University of Luebeck, Germany.
Address correspondence and reprint requests to Dr. M. Farrer, Genetics of Neurodegeneration, Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224; e-mail: farrer.matthew{at}mayo.edu
Objective: To compare and contrast clinical and genetic findings in six probands with parkinsonism with a parkin exon 3 438- to 477-bp deletion (Ex3
40) to search for evidence of a common founder.
Method: Clinical review, parkin gene sequencing, dosage studies, and high-resolution genotype/haplotype analysis were performed.
Results: All subjects had two or more signs consistent with a diagnosis of possible or probable PD with age at onset younger than 45 years (mean ± SD 29.3 ± 10.2 years, range 16 to 42 years). Affected individuals were either homozygotes, compound heterozygotes, or Ex340 carriers with one normal parkin allele. Haplotype analysis revealed both Ex340 and Ex7 924 C
T (R275W) mutations originated from common founders, the former most probably of Irish descent. Although three cases had Ex7 924 CT (R275W) and Ex340 mutations, their clinical presentation and mode of inheritance were variable.
Conclusion: Parkin mutations on common parkin haplotypes provide testable hypotheses of parkin function in genetically defined parkinsonism.
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