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Leucine-rich repeat kinase 1: a paralog of LRRK2 and a candidate gene for Parkinson’s disease

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Abstract

Leucine-rich repeat kinase 1 gene (LRRK1) on chromosome 15q26.3 is a paralog of LRRK2 in which multiple substitutions were recently linked to Parkinson’s disease. We have examined the exon–intron structure of the gene and the expressed mRNA sequence in brain. LRRK1 sequencing analysis in 95 probands from families with autosomal dominant Parkinson’s disease identified 23 variants, 14 of which are novel, with four resulting in non-synonymous amino acid substitutions. These four substitutions are rare and do not clearly segregate with disease within our families or associate with sporadic Parkinson’s disease in a US case-control series. Subsequent sequencing of exon 26 encoding the kinase activation segment in an additional 360 probands identified one further synonymous variant, suggesting that LRRK1 variants are not a frequent cause of Parkinson’s disease. The relative absence of substitutions within LRRK1 highlights a greater conservation of sequence than observed for LRRK2. Comparison of evolutionary interspecies sequences of LRRK1 and LRRK2 suggests they diverged from a common founder gene.

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Acknowledgements

We thank all clinicians and their patients for their participation in this study, without whom this work could not have been completed. In addition, we thank all collaborating investigators and physicians of the Udall Center, Mayo Clinic (Jacksonville, FL) for their continued effort. Minnie Schreiber is thanked for laboratory support. NINDS P50 NS40256 funded the Udall Clinical and Genetic Cores and R01 NS36960 (HP). This work was supported by a Robert H. and Clarice Smith Fellowship (OAR) and the National Parkinson’s Foundation (JPT).

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Authors and Affiliations

  1. Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL, 32224, USA

    Julie P. Taylor, Mary M. Hulihan, Jennifer M. Kachergus, Heather L. Melrose, Sarah J. Lincoln, Kelly M. Hinkle, Jeremy T. Stone, Owen A. Ross & Matthew J. Farrer

  2. Department of Neurology, University of South Florida, Tampa, FL, USA

    Robert Hauser

  3. Department of Neurology, St. Olav’s Hospital, Trondheim, Norway

    Jan Aasly

  4. Hertie-Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, Center for Neurology, University of Tübingen, Tübingen, Germany

    Thomas Gasser

  5. Wadsworth Center, New York State Department of Health, Albany, NY, USA

    Haydeh Payami

  6. Department of Neurology, Mayo Clinic College of Medicine, Jacksonville, FL, USA

    Zbigniew K. Wszolek

  7. Division of Neurogenetics, Department of Neuroscience, Morris K. Udall Parkinson’s Disease Research Center of Excellence, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA

    Matthew J. Farrer

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  1. Julie P. Taylor
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  2. Mary M. Hulihan
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  3. Jennifer M. Kachergus
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  4. Heather L. Melrose
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  9. Robert Hauser
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  11. Thomas Gasser
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  12. Haydeh Payami
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  13. Zbigniew K. Wszolek
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  14. Matthew J. Farrer
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Correspondence to Matthew J. Farrer.

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Taylor, J.P., Hulihan, M.M., Kachergus, J.M. et al. Leucine-rich repeat kinase 1: a paralog of LRRK2 and a candidate gene for Parkinson’s disease. Neurogenetics 8, 95–102 (2007). https://doi.org/10.1007/s10048-006-0075-8

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  • DOI: https://doi.org/10.1007/s10048-006-0075-8

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