• Open Access

Mutations in the autoregulatory domain of β-tubulin 4a cause hereditary dystonia

Authors

  • Joshua Hersheson MD,

    1. Department of Molecular Neuroscience, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, United Kingdom
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  • Niccolo E. Mencacci MD,

    1. Department of Molecular Neuroscience, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, United Kingdom
    2. Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Universita degli Studi di Milano, Italy
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  • Mary Davis PhD,

    1. Department of Molecular Neuroscience, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, United Kingdom
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  • Nicola MacDonald MD,

    1. Department of Womens Health, UCLH, London, United Kingdom
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  • Daniah Trabzuni MSc,

    1. Department of Molecular Neuroscience, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, United Kingdom
    2. Department of Genetics, King Faisal Specialist Hospital and Research Centre, PO Box 3354, Riyadh 11211, Saudi Arabia
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  • Mina Ryten MD, PhD,

    1. Department of Molecular Neuroscience, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, United Kingdom
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  • Alan Pittman PhD,

    1. Department of Molecular Neuroscience, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, United Kingdom
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  • Reema Paudel PhD,

    1. Department of Molecular Neuroscience, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, United Kingdom
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  • Eleanna Kara MD,

    1. Department of Molecular Neuroscience, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, United Kingdom
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  • Katherine Fawcett PhD,

    1. Department of Molecular Neuroscience, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, United Kingdom
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  • Vincent Plagnol PhD,

    1. Department of Molecular Neuroscience, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, United Kingdom
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  • Kailash P. Bhatia MD,

    1. Department of Molecular Neuroscience, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, United Kingdom
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  • Alan J. Medlar PhD,

    1. Centre for Nephrology, University College London, London, United Kingdom
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  • Horia C. Stanescu MD,

    1. Centre for Nephrology, University College London, London, United Kingdom
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  • John Hardy PhD,

    1. Department of Molecular Neuroscience, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, United Kingdom
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  • Robert Kleta MD,

    1. Centre for Nephrology, University College London, London, United Kingdom
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  • Nicholas W. Wood MD,

    1. Department of Molecular Neuroscience, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, United Kingdom
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  • Henry Houlden MD,

    Corresponding author
    • Department of Molecular Neuroscience, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, United Kingdom
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Address correspondence to Dr Houlden, Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom. E-mail: h.houlden@ucl.ac.uk

Abstract

Dystonia type 4 (DYT4) was first described in a large family from Heacham in Norfolk with an autosomal dominantly inherited whispering dysphonia, generalized dystonia, and a characteristic hobby horse ataxic gait. We carried out a genetic linkage analysis in the extended DYT4 family that spanned 7 generations from England and Australia, revealing a single LOD score peak of 6.33 on chromosome 19p13.12-13. Exome sequencing in 2 cousins identified a single cosegregating mutation (p.R2G) in the β-tubulin 4a (TUBB4a) gene that was absent in a large number of controls. The mutation is highly conserved in the β-tubulin autoregulatory MREI (methionine–arginine–glutamic acid–isoleucine) domain, highly expressed in the central nervous system, and extensive in vitro work has previously demonstrated that substitutions at residue 2, specifically R2G, disrupt the autoregulatory capability of the wild-type β-tubulin peptide, affirming the role of the cytoskeleton in dystonia pathogenesis. Ann Neurol 2013;73:546–553

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