• Open Access

The glucocerobrosidase E326K variant predisposes to Parkinson's disease, but does not cause Gaucher's disease

Authors

  • Raquel Duran PhD,

    1. Reta Lila Weston Laboratories and Departments of Molecular Neuroscience, UCL Institute of Neurology, London, UK
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    • Drs. Duran and Mencacci made equal contributions.

  • Niccolo E. Mencacci MD,

    1. Reta Lila Weston Laboratories and Departments of Molecular Neuroscience, UCL Institute of Neurology, London, UK
    2. Department of Neurology and Laboratory of Neuroscience, “Dino Ferrari” Center, Università degli Studi di Milano, IRCCS Istituto Auxologico Italiano, Milan, Italy
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    • Drs. Duran and Mencacci made equal contributions.

  • Aikaterini V. Angeli MD,

    1. Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, UK
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  • Maryam Shoai PhD,

    1. Reta Lila Weston Laboratories and Departments of Molecular Neuroscience, UCL Institute of Neurology, London, UK
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  • Emma Deas PhD,

    1. Reta Lila Weston Laboratories and Departments of Molecular Neuroscience, UCL Institute of Neurology, London, UK
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  • Henry Houlden MD, MRCP, PhD,

    1. Reta Lila Weston Laboratories and Departments of Molecular Neuroscience, UCL Institute of Neurology, London, UK
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  • Atul Mehta FRCP,

    1. Lysosomal Storage Disorders Unit, Department of Haematology, UCL Medical School, Royal Free Hospital, London, UK
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  • Derralynn Hughes MA, DPhilN FRCP, FRCPath,

    1. Lysosomal Storage Disorders Unit, Department of Haematology, UCL Medical School, Royal Free Hospital, London, UK
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  • Timothy M. Cox MD, FRCP, FMedSci,

    1. Lysosomal Diseases Unit, Addenbrookes Hospital, Department of Medicine, University of Cambridge, Cambridge, UK
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  • Patrick Deegan MD, FRCP Edin, FRCPath,

    1. Lysosomal Diseases Unit, Addenbrookes Hospital, Department of Medicine, University of Cambridge, Cambridge, UK
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  • Anthony H. Schapira MD, FRCP, FMedSci,

    1. Department of Clinical Neurosciences, Institute of Neurology, UCL Medical School, Royal Free Hospital, London, UK
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  • Andrew J. Lees MD, FRCP,

    1. Reta Lila Weston Laboratories and Departments of Molecular Neuroscience, UCL Institute of Neurology, London, UK
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  • Patricia Limousin MN, PhD,

    1. Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, UK
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  • Paul R. Jarman PhD, FRCP,

    1. Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, UK
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  • Kailash P. Bhatia MD, DM, FRCP,

    1. Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, UK
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  • Nicholas W. Wood PhD FRCP FMedSci,

    1. Reta Lila Weston Laboratories and Departments of Molecular Neuroscience, UCL Institute of Neurology, London, UK
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  • John Hardy PhD, FMedSci, FRS,

    Corresponding author
    1. Reta Lila Weston Laboratories and Departments of Molecular Neuroscience, UCL Institute of Neurology, London, UK
    • Correspondence to: Prof. John Hardy, Reta Lila Weston Research Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; j.hardy@ucl.ac.uk

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  • Tom Foltynie PhD, MRCP

    1. Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, UK
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  • Re-use of this article is permitted in accordance with the Terms and Conditions set out at http://olabout.wiley.com/WileyCDA/Section/id-817008.html

  • Funding agencies: R.D. received a postdoctoral fellowship from Alfonso Martin Escudero Foundation (Spain). J.H., N.W., and A.H.S. received research support from the UK Medical Research Council and Wellcome Trust. This work was supported by a Wellcome/MRC Parkinson's Disease Consortium grant to UCL/IoN, the University of Sheffield, and the MRC Protein Phosphorylation Unit at the University of Dundee (grant no.: WT089698). Funding to pay the Open Access publication charges for this article was provided by the Wellcome/MRC Parkinson's Disease Consortium grant to UCL/IoN, the University of Sheffield, and the MRC Protein Phosphorylation Unit at the University of Dundee. The clinical sample collection was supported by Parkinson's UK (K-0901; to T.F. and N.W.). Additional support came from the Reta Lila Trust (to A.J.L. and J.H.).

  • Relevant conflicts of interest/financial disclosures: Nothing to report.

  • Full financial disclosures and author roles may be found in the online version of this article.

Abstract

Background

Heterozygous loss-of-function mutations in the acid beta-glucocerebrosidase (GBA1) gene, responsible for the recessive lysosomal storage disorder, Gaucher's disease (GD), are the strongest known risk factor for Parkinson's disease (PD). Our aim was to assess the contribution of GBA1 mutations in a series of early-onset PD.

Methods

One hundred and eighty-five PD patients (with an onset age of ≤50) and 283 age-matched controls were screened for GBA1 mutations by Sanger sequencing.

Results

We show that the frequency of GBA1 mutations is much higher in this patient series than in typical late-onset patient cohorts. Furthermore, our results reveal that the most prevalent PD-associated GBA1 mutation is E326K, a variant that does not, when homozygous, cause GD.

Conclusions

Our results confirm recent reports that the mutation, E326K, predisposes to PD and suggest that, in addition to reduced GBA1 activity, other molecular mechanisms may contribute to the development of the disease. © 2012 Movement Disorder Society

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