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Lrrk2 R1441G-related Parkinson’s disease: evidence of a common founding event in the seventh century in Northern Spain

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Abstract

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene together represent the most common genetic determinant of Parkinson’s disease (PD) identified to date. The vast majority of patients with LRRK2-related PD reported in the literature carry one of three pathogenic substitutions: G2019S, R1441C, or R1441G. While G2019S and R1441C are geographically widespread, R1441G is most prevalent in the Basque Country and is rare outside of Northern Spain. We sought to better understand the processes that have shaped the current distribution of R1441G. We performed a haplotype analysis of 29 unrelated PD patients heterozygous for R1441G and 85 wild-type controls using 20 markers that spanned 15.1 Mb across the LRRK2 region. Nine of the patients were of Basque origin and 20 were non-Basques. We inferred haplotypes using a Bayesian approach and utilized a maximum-likelihood method to estimate the age of the most recent common ancestor. Significant but incomplete allele sharing was observed over a distance of 6.0 Mb and a single, rare ten-marker haplotype 5.8 Mb in length was seen in all mutation carriers. We estimate that the most recent common ancestor lived 1,350 (95% CI, 1,020–1,740) years ago in approximately the seventh century. We hypothesize that R1441G originated in the Basque population and that dispersion of the mutation then occurred through short-range gene flow that was largely limited to nearby regions in Spain.

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Acknowledgements

We dedicate this paper to our dear colleague, Dr. Luis M. Guisasola, a superb clinician, researcher, and educator, who recently passed away. We thank the individuals who participated in the study. This work was supported by the Basque Government and University of the Basque Country (grant S-PE07UN44, M.M.P. and M.C.G-F.); the NIH (NINDS, K08 NS044138, C.P.Z.); the Department of Veterans Affairs (Merit Review Award, C.P.Z.); the Parkinson’s Disease Foundation (Fellowship Award, I.F.M.); the Spanish Fondo de Investigacion Sanitaria (grant FIS PI070014, J.I; grant 05/008, V.A.); and the Veterans Integrated Service Network 20 Geriatric, Mental Illness, and Parkinson’s Disease Research, Education, and Clinical Centers.

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Authors and Affiliations

  1. Geriatric Research Education and Clinical Center S-182, Veterans Affairs Puget Sound Health Care System, 1660 South Columbian Way, Seattle, WA, 98108, USA

    Ignacio F. Mata & Cyrus P. Zabetian

  2. Department of Neurology, University of Washington, Seattle, WA, USA

    Ignacio F. Mata & Cyrus P. Zabetian

  3. Department of Epidemiology, University of Washington, Seattle, WA, USA

    Carolyn M. Hutter & Karen L. Edwards

  4. Servicio General de Investigación Genómica: Banco de ADN, Universidad del País Vasco, Vitoria-Gasteiz, Spain

    María C. González-Fernández & Marian M. de Pancorbo

  5. Unidad de trastornos del movimiento, Hospital de Cruces, Baracaldo, Spain

    Elena Lezcano, Juan C. Gómez-Esteban & Juan J. Zarranz

  6. Genética Molecular-Instituto de Investigacion Nefrológica, Hospital Universitario Central de Asturias, Oviedo, Spain

    Cecilia Huerta & Victoria Alvarez

  7. Servicio de Neurología, Hospital Universitario Central de Asturias, Oviedo, Spain

    Marta Blazquez, Luis M. Guisasola & Carlos Salvador

  8. Servicio de Neurología, Hospital Alvarez-Buylla, Mieres, Spain

    Renee Ribacoba

  9. Servicio de Neurología, Hospital Universitario “Marqués de Valdecilla”, Universidad de Cantabria, Santander, Spain

    Jon Infante

  10. Department of Neurology, Baylor College of Medicine, Houston, TX, USA

    Joseph Jankovic & Hao Deng

  11. Center for Experimental Medicine, The Third Xiangya Hospital, Central South University, Changsha, China

    Hao Deng

Authors
  1. Ignacio F. Mata
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  2. Carolyn M. Hutter
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  3. María C. González-Fernández
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  4. Marian M. de Pancorbo
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  5. Elena Lezcano
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  6. Cecilia Huerta
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  7. Marta Blazquez
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  9. Luis M. Guisasola
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  10. Carlos Salvador
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  11. Juan C. Gómez-Esteban
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  13. Jon Infante
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  14. Joseph Jankovic
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  15. Hao Deng
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  16. Karen L. Edwards
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  17. Victoria Alvarez
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  18. Cyrus P. Zabetian
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Corresponding author

Correspondence to Cyrus P. Zabetian.

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Ignacio F. Mata and Carolyn M. Hutter contributed equally to this work

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Mata, I.F., Hutter, C.M., González-Fernández, M.C. et al. Lrrk2 R1441G-related Parkinson’s disease: evidence of a common founding event in the seventh century in Northern Spain. Neurogenetics 10, 347–353 (2009). https://doi.org/10.1007/s10048-009-0187-z

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