KCNC3: phenotype, mutations, channel biophysics—a study of 260 familial ataxia patients

Authors

  • Karla P. Figueroa,

    1. Department of Neurology, University of Utah, Salt Lake City, Utah
    Search for more papers by this author
    • Karla P. Figueroa, Natali A. Minassian, and Giovanni Stevanin contributed equally to this work.

  • Natali A. Minassian,

    1. Department of Physiology, University of California, Los Angeles, Los Angeles, California
    Search for more papers by this author
    • Karla P. Figueroa, Natali A. Minassian, and Giovanni Stevanin contributed equally to this work.

  • Giovanni Stevanin,

    1. INSERM, U975, 75013, Paris, France
    2. APHP, Département de Génétique et Cytogénétique, Hôpital de la Salpêtrière, Paris, France
    3. UPMC Univ. Paris 6, UMR_S975, CNRS 7225, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epiniere, Groupe Hospitalier Pitie-Salpetriere, 75013 Paris, France
    Search for more papers by this author
    • Karla P. Figueroa, Natali A. Minassian, and Giovanni Stevanin contributed equally to this work.

  • Michael Waters,

    1. Department of Neurology, University of Florida, Gainesville, Florida
    Search for more papers by this author
  • Vartan Garibyan,

    1. Department of Neurology, University of Utah, Salt Lake City, Utah
    Search for more papers by this author
  • Sylvie Forlani,

    1. INSERM, U975, 75013, Paris, France
    2. UPMC Univ. Paris 6, UMR_S975, CNRS 7225, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epiniere, Groupe Hospitalier Pitie-Salpetriere, 75013 Paris, France
    Search for more papers by this author
  • Adam Strzelczyk,

    1. Department of Neurology, University of Marburg, Marburg, Germany
    Search for more papers by this author
  • Katrin Bürk,

    1. Department of Neurology, University of Marburg, Marburg, Germany
    Search for more papers by this author
  • Alexis Brice,

    1. INSERM, U975, 75013, Paris, France
    2. APHP, Département de Génétique et Cytogénétique, Hôpital de la Salpêtrière, Paris, France
    3. UPMC Univ. Paris 6, UMR_S975, CNRS 7225, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epiniere, Groupe Hospitalier Pitie-Salpetriere, 75013 Paris, France
    Search for more papers by this author
  • Alexandra Dürr,

    1. INSERM, U975, 75013, Paris, France
    2. APHP, Département de Génétique et Cytogénétique, Hôpital de la Salpêtrière, Paris, France
    3. UPMC Univ. Paris 6, UMR_S975, CNRS 7225, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epiniere, Groupe Hospitalier Pitie-Salpetriere, 75013 Paris, France
    Search for more papers by this author
  • Diane M. Papazian,

    1. Department of Physiology, University of California, Los Angeles, Los Angeles, California
    Search for more papers by this author
  • Stefan M. Pulst

    Corresponding author
    1. Department of Neurology, University of Utah, Salt Lake City, Utah
    2. Brain Institute, University of Utah, Salt Lake City, Utah
    • Department of Neurology, University of Utah, Salt Lake City, UT
    Search for more papers by this author

  • Communicated by Michel Goossens

Abstract

We recently identified KCNC3, encoding the Kv3.3 voltage-gated potassium channel, as the gene mutated in SCA13. One g.10684G>A (p.Arg420His) mutation caused late-onset ataxia resulting in a nonfunctional channel subunit with dominant-negative properties. A French early-onset pedigree with mild mental retardation segregated a g.10767T>C (p.Phe448Leu) mutation. This mutation changed the relative stability of the channel's open conformation. Coding exons were amplified and sequenced in 260 autosomal-dominant ataxia index cases of European descent. Functional analyses were performed using expression in Xenopus oocytes. The previously identified p.Arg420His mutation occurred in three families with late-onset ataxia. A novel mutation g.10693G>A (p.Arg423His) was identified in two families with early-onset. In one pedigree, a novel g.10522G>A (p.Arg366His) sequence variant was seen in one index case but did not segregate with affected status in the respective family. In a heterologous expression system, the p.Arg423His mutation exhibited dominant-negative properties. The p.Arg420His mutation, which results in a nonfunctional channel subunit, was recurrent and associated with late-onset progressive ataxia. In two families the p.Arg423His mutation was associated with early-onset slow-progressive ataxia. Despite a phenotype reminiscent of the p.Phe448Leu mutation, segregating in a large early-onset French pedigree, the p.Arg423His mutation resulted in a nonfunctional subunit with a strong dominant-negative effect. Hum Mutat 31:191–196, 2010. © 2009 Wiley-Liss, Inc.

Ancillary