Augmented currents of an HCN2 variant in patients with febrile seizure syndromes

Authors

  • Leanne M. Dibbens PhD,

    1. Epilepsy Research Program, SA Pathology at the Women's and Children's Hospital, North Adelaide, South Australia, Australia
    2. School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia
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  • Christopher A. Reid PhD,

    1. Florey Neuroscience Institute, University of Melbourne, Parkville, Victoria, Australia
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  • Bree Hodgson BSc(Hons),

    1. Epilepsy Research Program, SA Pathology at the Women's and Children's Hospital, North Adelaide, South Australia, Australia
    2. School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia
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  • Evan A. Thomas PhD,

    1. Florey Neuroscience Institute, University of Melbourne, Parkville, Victoria, Australia
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  • Alison M. Phillips PhD,

    1. Florey Neuroscience Institute, University of Melbourne, Parkville, Victoria, Australia
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  • Elena Gazina PhD,

    1. Florey Neuroscience Institute, University of Melbourne, Parkville, Victoria, Australia
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  • Brett A. Cromer PhD,

    1. Florey Neuroscience Institute, University of Melbourne, Parkville, Victoria, Australia
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  • Alison L. Clarke PhD,

    1. Florey Neuroscience Institute, University of Melbourne, Parkville, Victoria, Australia
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  • Tallie Z. Baram MD, PhD,

    1. Departments of Pediatrics and Anatomy/Neurobiology, University of California, Irvine, CA
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  • Ingrid E. Scheffer MBBS, PhD,

    1. Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Victoria, Australia
    2. Department of Medicine, Austin Health, University of Melbourne, Heidelberg West, Victoria, Australia
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  • Samuel F. Berkovic MD,

    1. Department of Medicine, Austin Health, University of Melbourne, Heidelberg West, Victoria, Australia
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  • Steven Petrou PhD

    Corresponding author
    1. Florey Neuroscience Institute, University of Melbourne, Parkville, Victoria, Australia
    2. Centre for Neuroscience, University of Melbourne, Parkville, Victoria, Australia
    • Howard Florey Institute, The University of Melbourne, Parkville, Victoria 3010, Australia
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Abstract

The genetic architecture of common epilepsies is largely unknown. HCNs are excellent epilepsy candidate genes because of their fundamental neurophysiological roles. Screening in subjects with febrile seizures and genetic epilepsy with febrile seizures plus revealed that 2.4% carried a common triple proline deletion (delPPP) in HCN2 that was seen in only 0.2% of blood bank controls. Currents generated by mutant HCN2 channels were ∼35% larger than those of controls; an effect revealed using automated electrophysiology and an appropriately powered sample size. This is the first association of HCN2 and familial epilepsy, demonstrating gain of function of HCN2 current as a potential contributor to polygenic epilepsy. ANN NEUROL 2010;67:542–546

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