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New mutations in protein kinase Cγ associated with spinocerebellar ataxia type 14

Authors

  • Stephan Klebe MD,

    1. Institut National de la Sante et de la Recherche Médicale U679 (formerly U289) and Institut Fédératif de Recherche en Neurosciences, Paris, France
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  • Alexandra Durr MD, PhD,

    1. Institut National de la Sante et de la Recherche Médicale U679 (formerly U289) and Institut Fédératif de Recherche en Neurosciences, Paris, France
    2. Département de génétique, cytogénétique et embryologie, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
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  • Alexander Rentschler MD,

    1. Department of Medical Genetics, University of Tübingen, Tübingen, Germany
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  • Valerie Hahn-Barma MS,

    1. Fédération de Neurologie, APHP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
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  • Michael Abele MD,

    1. Department of Neurology, University of Bonn, Bonn
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  • Naima Bouslam MS,

    1. Institut National de la Sante et de la Recherche Médicale U679 (formerly U289) and Institut Fédératif de Recherche en Neurosciences, Paris, France
    Current affiliation:
    1. Neurologie B et Laboratoire de Neurogénétique, Hôpital des Spécialités, La Rabta, Rabat, Morocco
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  • Ludger Schöls PhD, MD,

    1. Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
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  • Pierre Jedynak MD,

    1. Département de génétique, cytogénétique et embryologie, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
    2. Fédération de Neurologie, APHP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
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  • Sylvie Forlani PhD,

    1. Institut National de la Sante et de la Recherche Médicale U679 (formerly U289) and Institut Fédératif de Recherche en Neurosciences, Paris, France
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  • Elodie Denis BS,

    1. Institut National de la Sante et de la Recherche Médicale U679 (formerly U289) and Institut Fédératif de Recherche en Neurosciences, Paris, France
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  • Christel Dussert BS,

    1. Institut National de la Sante et de la Recherche Médicale U679 (formerly U289) and Institut Fédératif de Recherche en Neurosciences, Paris, France
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  • Yves Agid MD, PhD,

    1. Institut National de la Sante et de la Recherche Médicale U679 (formerly U289) and Institut Fédératif de Recherche en Neurosciences, Paris, France
    2. Fédération de Neurologie, APHP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
    3. Centre d'Investigation Clinique, APHP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
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  • Peter Bauer MD,

    1. Department of Medical Genetics, University of Tübingen, Tübingen, Germany
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  • Christoph Globas MD,

    1. Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
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  • Ullrich Wüllner MD,

    1. Department of Neurology, University of Bonn, Bonn
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  • Alexis Brice MD,

    Corresponding author
    1. Institut National de la Sante et de la Recherche Médicale U679 (formerly U289) and Institut Fédératif de Recherche en Neurosciences, Paris, France
    2. Département de génétique, cytogénétique et embryologie, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
    3. Fédération de Neurologie, APHP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
    • INSERM U679 (formerly U289), Hôpital de la Salpêtrière, 47 boulevard de l'Hôpital, 75651 Paris Cedex 13, France
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  • Olaf Riess MD,

    1. Department of Medical Genetics, University of Tübingen, Tübingen, Germany
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  • Giovanni Stevanin PhD

    1. Institut National de la Sante et de la Recherche Médicale U679 (formerly U289) and Institut Fédératif de Recherche en Neurosciences, Paris, France
    2. Département de génétique, cytogénétique et embryologie, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
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Abstract

Autosomal dominant cerebellar ataxias (ADCA) are a heterogeneous group of neurological disorders. Point mutations in the gene encoding protein kinase Cγ (PRKCG) are responsible for spinocerebellar ataxia 14 (SCA14). We screened for mutations in the PRKCG gene, in a large series of 284 ADCA index cases, mostly French (n=204) and German (n=48), in whom CAG repeat expansions in the known SCA genes were previously excluded. Six mutations were found that segregated with the disease and were not detected on 560 control chromosomes, including F643L (exon 18), already reported in another French kindred. Five new missense mutations were identified in exons 4 (C114Y/G123R/G123E), 10 (G360S) and 18 (V692G). All but one (V692G) were located in highly conserved regions of the regulatory or catalytic domains of the protein. All six SCA14 families were French and there was no evidence of reduced penetrance. The phenotype consisted in a very slowly progressive cerebellar ataxia with a mean age at onset of 33.5±14.2 years (range 15 to 60 years), occasionally associated with executive dysfunction, myoclonus, myorythmia, tremor or decreased vibration sense. SCA14 represented only 1.5% (7/454) of French ADCA families but none of the German families. It should, however, be considered in patients with slowly progressive ADCA, particularly when myoclonus and cognitive impairment are present. Ann Neurol 2005

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