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From the Molecular Genetics Unit (Drs. Paisán-Ruíz and Singleton), National Institute on Aging, National Institutes of Health, Porter Neuroscience Research Center, Bethesda, MD; Unitat de Genètica Molecular (Dr. Paisán-Ruíz), Departament de Genòmica i Proteòmica, Institut de Biomedicina de València-CSIC, València, Spain; and Toronto Western Hospital Research Institute, Movement Disorders Centre, Toronto Western Hospital (Drs. Lang, Fisman, Al-Khairallah, and St George-Hyslop), and Centre for Research in Neurodegenerative Diseases (Drs. Kawarai, St George-Hyslop, and Rogaeva, and C. Sato and S. Salehi-Rad), Department of Medicine, Division of Neurology (Drs. Lang, St George-Hyslop, and Rogaeva), University of Toronto, Ontario, Canada.
Address correspondence and reprint requests to Dr. Rogaeva, Department of Medicine, University of Toronto, 6 Queen’s Park Crescent West, Toronto, ON, Canada M5S; e-mail: ekaterina.rogaeva{at}utoronto.ca
Background: In addition to the four well-confirmed genes linked to early-onset Parkinson disease (PD) (SNCA, PARKIN, DJ-1, and PINK1), mutations in the leucine-rich repeat kinase 2 gene (LRRK2) have recently been identified in families with autosomal dominant late-onset PD.
Objective: To perform mutation analysis of LRRK2 in probands of families showing dominant inheritance of PD and to conduct a case control association study to test the hypothesis that common coding variations might be associated with increased susceptibility to PD.
Methods: All 51 LRRK2 coding exons were sequenced in 23 probands and the mutation frequencies were evaluated in 180 neurologically normal control subjects. For the association study the authors genotyped four coding LRRK2 polymorphisms in 250 normal control subjects and 121 patients with PD (predominantly white patients of Canadian origin), 84% of whom had age at onset before 50 years and 42% had a positive family history.
Results: The authors identified three probands with heterozygous LRRK2 mutations: two of them have the known G2019S substitution and one proband has a novel I1371V substitution. Mutation analysis of a large family demonstrated complete segregation of the G2019S with PD. However, there was no association between PD and any of the four polymorphisms at the allelic or genotypic levels (p > 0.17). Furthermore, the authors did not detect a modifying effect for any genotype or of APOE genotypes upon the age at onset in the PD group (p > 0.20).
Conclusions: The results support the prior suggestion that LRRK2 mutations cause PD. The disease in the families reported here presents a phenotype indistinguishable from typical PD. All three families demonstrate a very variable age at onset that is not explained by APOE genotypes. The common coding variations in the LRRK2 gene neither constitute strong PD risk factors nor modify the age at onset; however, the possibility of a modest risk effect remains to be assessed in large datasets.
Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the September 13 issue to find the title link for this article.
Editoral, see page 664
See also pages 738 and 741
This article was previously published in electronic format as an Expedited E-Pub on June 15, 2005, at www.neurology.org.
Supported by grants from the Canadian Institutes of Health Research, Howard Hughes Medical Institute (P.S.G.-H.), a Center of Excellence award from the National Parkinson Foundation (Miami) (A.E.L.), the Connaught Grant (E.R.), and the Nakabayashi Trust (T.A.-K.). C.P.-R. is a recipient of an FPI fellowship from the Ministerio de Educación y Ciencia (GEN2001-4851-C06-01).
Received December 16, 2004. Accepted in final form March 14, 2005.
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