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© 2009 American Academy of Neurology Parkin dosage mutations have greater pathogenicity in familial PD than simple sequence mutationsFrom the Indiana University Medical Center (N.P., C.A.H., T.F.), Indianapolis, IN; Cincinnati Children’s Hospital Medical Center (D.K.K., M.W.P., W.C.N.), OH; University of Rochester (A.R.), Rochester, NY; University of Tennessee Health Science Center (R.F.P.), Memphis, TN; Columbia University and The Taub Institute (K.S.M.), New York, NY; and University of Cincinnati School of Medicine (W.C.N.), Cincinnati, OH. Address correspondence and reprint requests to Dr. Tatiana Foroud, Medical and Molecular Genetics, Indiana University, School of Medicine, Hereditary Genomics Division, 410 W. 10th St., MI-4000, Indianapolis, IN 46202 tforoud{at}iupui.edu Objective: Mutations in both alleles of parkin have been shown to result in Parkinson disease (PD). However, it is unclear whether haploinsufficiency (presence of a mutation in only 1 of the 2 parkin alleles) increases the risk for PD. Methods: We performed comprehensive dosage and sequence analysis of all 12 exons of parkin in a sample of 520 independent patients with familial PD and 263 controls. We evaluated whether presence of a single parkin mutation, either a sequence (point mutation or small insertion/deletion) or dosage (whole exon deletion or duplication) mutation, was found at increased frequency in cases as compared with controls. We then compared the clinical characteristics of cases with 0, 1, or 2 parkin mutations.
Results: We identified 55 independent patients with PD with at least 1 parkin mutation and 9 controls with a single sequence mutation. Cases and controls had a similar frequency of single sequence mutations (3.1% vs 3.4%, p = 0.83); however, the cases had a significantly higher rate of dosage mutations (2.6% vs 0%, p = 0.009). Cases with a single dosage mutation were more likely to have an earlier age at onset (50% with onset at Conclusions: Parkin haploinsufficiency, specifically for a dosage mutation rather than a point mutation or small insertion/deletion, is a risk factor for familial PD and may be associated with earlier age at onset.
Abbreviations: ADL = Activities of Daily Living; GDS = Geriatric Depression Scale; MLPA = multiplex ligation-dependent probe amplification; MMSE = Mini-Mental State Examination; PD = Parkinson disease; UPDRS = Unified Parkinson’s Disease Rating Scale.
Supplemental data at www.neurology.org *Parkinson Study Group–PROGENI Investigators are listed in the appendix. Supported by NIH R01 NS37167 (N.P., D.K.K., M.W.P., C.A.H., A.R., R.F.P., K.S.M., T.F., W.C.N.) and M01 RR-00750. Disclosure: Author disclosures are provided at the end of the article. Received January 14, 2009. Accepted in final form April 17, 2009.
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45 years) compared with those with no parkin mutations (10%, p = 0.00002); this was not true for cases with only a single sequence mutation (25% with onset at