Mutations in KCND3 cause spinocerebellar ataxia type 22

Authors

  • Yi-Chung Lee MD, PhD,

    1. Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan
    2. Brain Research Center, National Yang-Ming University, Taipei, Taiwan
    3. Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan
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  • Alexandra Durr MD, PhD,

    1. National Institute of Health and Medical Research, U975, Paris, France
    2. National Center for Scientific Research, UMR7225, Paris, France
    3. Pierre and Marie Curie University Paris, Brain and Spinal Cord Research Center, Pitie-Salpetriere Hospital, Paris, France
    4. Public Assistance Hospitals of Paris, Department of Genetics, Pitie-Salpetriere Hospital, Paris, France
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  • Karen Majczenko MD,

    1. Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI
    2. Department of Neurology, University of Michigan, Ann Arbor, MI
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  • Yen-Hua Huang MD, PhD,

    1. Department of Biochemistry, Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
    2. Center for Systems and Synthetic Biology, National Yang-Ming University, Taipei, Taiwan
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  • Yu-Chao Liu BS,

    1. Institute of Neuroscience, National Yang-Ming University, Taipei, Taiwan
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  • Cheng-Chang Lien MD, PhD,

    1. Brain Research Center, National Yang-Ming University, Taipei, Taiwan
    2. Institute of Neuroscience, National Yang-Ming University, Taipei, Taiwan
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  • Pei-Chien Tsai PhD,

    1. Brain Research Center, National Yang-Ming University, Taipei, Taiwan
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  • Yaeko Ichikawa MD, PhD,

    1. Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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  • Jun Goto MD, PhD,

    1. Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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  • Marie-Lorraine Monin MD,

    1. National Institute of Health and Medical Research, U975, Paris, France
    2. National Center for Scientific Research, UMR7225, Paris, France
    3. Pierre and Marie Curie University Paris, Brain and Spinal Cord Research Center, Pitie-Salpetriere Hospital, Paris, France
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  • Jun Z. Li PhD,

    1. Department of Human Genetics, University of Michigan, Ann Arbor, MI
    2. Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI
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  • Ming-Yi Chung PhD,

    1. Faculty of Life Sciences and Institute of Genomic Sciences, National Yang-Ming University, Taipei, Taiwan
    2. Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan
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  • Emeline Mundwiller BS,

    1. National Institute of Health and Medical Research, U975, Paris, France
    2. National Center for Scientific Research, UMR7225, Paris, France
    3. Pierre and Marie Curie University Paris, Brain and Spinal Cord Research Center, Pitie-Salpetriere Hospital, Paris, France
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  • Vikram Shakkottai MD, PhD,

    1. Department of Neurology, University of Michigan, Ann Arbor, MI
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  • Tze-Tze Liu PhD,

    1. Genome Research Center, National Yang-Ming University, Taipei, Taiwan
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  • Christelle Tesson MS,

    1. National Institute of Health and Medical Research, U975, Paris, France
    2. National Center for Scientific Research, UMR7225, Paris, France
    3. Pierre and Marie Curie University Paris, Brain and Spinal Cord Research Center, Pitie-Salpetriere Hospital, Paris, France
    4. Practical School of Advanced Studies, Paris, France
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  • Yi-Chun Lu BS,

    1. Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan
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  • Alexis Brice MD,

    1. National Institute of Health and Medical Research, U975, Paris, France
    2. National Center for Scientific Research, UMR7225, Paris, France
    3. Pierre and Marie Curie University Paris, Brain and Spinal Cord Research Center, Pitie-Salpetriere Hospital, Paris, France
    4. Public Assistance Hospitals of Paris, Department of Genetics, Pitie-Salpetriere Hospital, Paris, France
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  • Shoji Tsuji MD, PhD,

    1. Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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  • Margit Burmeister PhD,

    Corresponding author
    1. Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI
    2. Department of Human Genetics, University of Michigan, Ann Arbor, MI
    3. Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI
    4. Department of Psychiatry, University of Michigan, Ann Arbor, MI
    • Department of Neurology, National Yang-Ming University School of Medicine, Taipei Veterans General Hospital, #201, Sec 2, Shipai Road, Peitou District, Taipei, Taiwan 11217.
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  • Giovanni Stevanin PhD,

    Corresponding author
    1. National Institute of Health and Medical Research, U975, Paris, France
    2. National Center for Scientific Research, UMR7225, Paris, France
    3. Pierre and Marie Curie University Paris, Brain and Spinal Cord Research Center, Pitie-Salpetriere Hospital, Paris, France
    4. Public Assistance Hospitals of Paris, Department of Genetics, Pitie-Salpetriere Hospital, Paris, France
    5. Practical School of Advanced Studies, Paris, France
    • UPMC University Paris, Centre de Recherche du Cerveau et de la Moelle épinière, Hopital Pitie-Salpetriere, Paris, France
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  • Bing-Wen Soong MD, PhD

    Corresponding author
    1. Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan
    2. Brain Research Center, National Yang-Ming University, Taipei, Taiwan
    3. Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan
    4. Institute of Neuroscience, National Yang-Ming University, Taipei, Taiwan
    • Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI
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Abstract

Objective:

To identify the causative gene in spinocerebellar ataxia (SCA) 22, an autosomal dominant cerebellar ataxia mapped to chromosome 1p21-q23.

Methods:

We previously characterized a large Chinese family with progressive ataxia designated SCA22, which overlaps with the locus of SCA19. The disease locus in a French family and an Ashkenazi Jewish American family was also mapped to this region. Members from all 3 families were enrolled. Whole exome sequencing was performed to identify candidate mutations, which were narrowed by linkage analysis and confirmed by Sanger sequencing and cosegregation analyses. Mutational analyses were also performed in 105 Chinese and 55 Japanese families with cerebellar ataxia. Mutant gene products were examined in a heterologous expression system to address the changes in protein localization and electrophysiological functions.

Results:

We identified heterozygous mutations in the voltage-gated potassium channel Kv4.3-encoding gene KCND3: an in-frame 3-nucleotide deletion c.679_681delTTC p.F227del in both the Chinese and French pedigrees, and a missense mutation c.1034G>T p.G345V in the Ashkenazi Jewish family. Direct sequencing of KCND3 further identified 3 mutations, c.1034G>T p.G345V, c.1013T>C p.V338E, and c.1130C>T p.T377M, in 3 Japanese kindreds. Immunofluorescence analyses revealed that the mutant p.F227del Kv4.3 subunits were retained in the cytoplasm, consistent with the lack of A-type K+ channel conductance in whole cell patch-clamp recordings.

Interpretation:

Our data identify the cause of SCA19/22 in patients of diverse ethnic origins as mutations in KCND3. These findings further emphasize the important role of ion channels as key regulators of neuronal excitability in the pathogenesis of cerebellar degeneration. ANN NEUROL 2012;72:859–869.

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