LRRK2 haplotype-sharing analysis in Parkinson's disease reveals a novel p.S1761R mutation

Authors

  • Oswaldo Lorenzo-Betancor,

    1. Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
    2. Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain
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  • Lluís Samaranch,

    1. Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
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  • Mario Ezquerra,

    1. Parkinson's Disease and Movement Disorders Unit, Neurology Service, Institut Clínic de Neurociències, Hospital Clínic de Barcelona, Spain
    2. CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Spain
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  • Eduardo Tolosa,

    1. Parkinson's Disease and Movement Disorders Unit, Neurology Service, Institut Clínic de Neurociències, Hospital Clínic de Barcelona, Spain
    2. CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Spain
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  • Elena Lorenzo,

    1. Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
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  • Jaione Irigoyen,

    1. Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
    2. Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain
    3. CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Spain
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  • Carles Gaig,

    1. Parkinson's Disease and Movement Disorders Unit, Neurology Service, Institut Clínic de Neurociències, Hospital Clínic de Barcelona, Spain
    2. CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Spain
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  • María A. Pastor,

    1. Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
    2. Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain
    3. CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Spain
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  • Alexandra I. Soto-Ortolaza,

    1. Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, USA
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  • Owen A. Ross,

    1. Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, USA
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  • María C. Rodríguez-Oroz,

    1. Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
    2. Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain
    3. CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Spain
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  • Francesc Valldeoriola,

    1. Parkinson's Disease and Movement Disorders Unit, Neurology Service, Institut Clínic de Neurociències, Hospital Clínic de Barcelona, Spain
    2. CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Spain
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  • María J. Martí,

    1. Parkinson's Disease and Movement Disorders Unit, Neurology Service, Institut Clínic de Neurociències, Hospital Clínic de Barcelona, Spain
    2. CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Spain
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  • María R. Luquin,

    1. Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
    2. Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain
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  • Jordi Perez-Tur,

    1. CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Spain
    2. Unitat de Genètica Molecular, Institut de Biomedicina de València-CSIC, Valencia, Spain
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  • Juan A. Burguera,

    1. Service of Neurology, Hospital Universitario “La Fe”, Valencia, Spain
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  • José A. Obeso,

    1. Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
    2. Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain
    3. CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Spain
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  • Pau Pastor

    Corresponding author
    1. Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
    2. Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain
    3. CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Spain
    • Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pío XII 55, 31008 Pamplona, Spain
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  • Relevant conflicts of interest/financial disclosures: The authors declare no conflicts of interest to report. L.S. held a “Torres Quevedo” fellowship from the Spanish Ministry of Science and Technology, co-financed by the European Social Fund. This study was supported by grants from the Spanish Ministry of Science and Innovation SAF2006-10126 (2006-2009) and SAF2010-22329-C02-01 (2011-2013) to P.P. and SAF2010-10434 (2010-2012) to J.P.T., by the project 061131 from the “Fundació La Marató de TV3” and by the UTE project FIMA, Spain to P.P. Sample collection at Nodo ENAE was partially funded by a grant from the Generalitat Valenciana (07/2008) to J.A.B.

Abstract

Background and objective.

Mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene at chromosome 12q12 are the most common genetic cause of sporadic and familial late-onset Parkinson's disease. Our aim was to identify novel LRRK2 mutations in late-onset Parkinson's disease families.

Design.

We analyzed chromosome 12p11.2-q13.1 haplotypes in 14 late-onset Parkinson's disease families without known LRRK2 mutations.

Results.

Haplotype analysis identified 12 families in which the affected subjects shared chromosome 12p11.2-q13.1 haplotypes. LRRK2 sequencing revealed a novel co-segregating missense mutation in exon 36 (c.5281A>C; p.S1761R) located within a highly conserved region of the COR [C-terminal of ROC (Ras of complex proteins)] domain wherein it could deregulate LRRK2 kinase activity by modifying ROC-COR dimer stability. p.S1761R was present in a late-onset Parkinson's disease family and in 2 unrelated Parkinson's disease subjects, but not in 2491 healthy controls. LRRK2 p.S1761R carriers developed levodopa-responsive asymmetrical parkinsonism, with variable age at onset (range: 37–72 years) suggesting age-dependent penetrance. These findings indicate that mutations interfering with LRRK2 ROC-COR domain dimerization lead to typical Parkinson's disease. © 2011 Movement Disorder Society

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