Congenital insensitivity to pain: novel SCN9A missense and in-frame deletion mutations

Authors

  • James J. Cox,

    1. Department of Medical Genetics, University of Cambridge, UK
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    • These authors equally contributed to this work

  • Jony Sheynin,

    1. Department of Virology and Developmental Genetics, Faculty of Health Sciences, Ben Gurion University of the Negev, Israel
    2. National Institute of Biotechnology in the Negev, Ben Gurion University of the Negev, Israel
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    • These authors equally contributed to this work

  • Zamir Shorer,

    1. Division of Pediatrics, Soroka Medical Center and Faculty of Health Sciences, Ben Gurion University of the Negev, Israel
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    • These authors equally contributed to this work

  • Frank Reimann,

    1. Department of Clinical Biochemistry, University of Cambridge, UK
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    • These authors equally contributed to this work

  • Adeline K. Nicholas,

    1. Department of Medical Genetics, University of Cambridge, UK
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  • Lorena Zubovic,

    1. International Centre for Genetic Engineering and Biotechnology, Trieste, Italy
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  • Marco Baralle,

    1. International Centre for Genetic Engineering and Biotechnology, Trieste, Italy
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  • Elizabeth Wraige,

    1. Guy's and St Thomas' NHS Foundation Trust, London, UK
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  • Esther Manor,

    1. Department of Virology and Developmental Genetics, Faculty of Health Sciences, Ben Gurion University of the Negev, Israel
    2. Institute of Genetics, Soroka Medical Center and Faculty of Health Sciences, Beer Sheva, Israel
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  • Jacov Levy,

    1. Division of Pediatrics, Soroka Medical Center and Faculty of Health Sciences, Ben Gurion University of the Negev, Israel
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  • C. Geoffery Woods,

    Corresponding author
    1. Department of Medical Genetics, University of Cambridge, UK
    • Cambridge Institute for Medical Research, Cambridge, CB2 0XY, UK
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    • These authors equally contributed to this work

  • Ruti Parvari

    Corresponding author
    1. Department of Virology and Developmental Genetics, Faculty of Health Sciences, Ben Gurion University of the Negev, Israel
    2. National Institute of Biotechnology in the Negev, Ben Gurion University of the Negev, Israel
    • Ben Gurion University of the Negev, Beer Sheva 84105, Israel
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    • These authors equally contributed to this work


  • Communicated by Claude Ferec

Abstract

SCN9Aencodes the voltage-gated sodium channel Nav1.7, a protein highly expressed in pain-sensing neurons. Mutations in SCN9A cause three human pain disorders: bi-allelic loss of function mutations result in Channelopathy-associated Insensitivity to Pain (CIP), whereas activating mutations cause severe episodic pain in Paroxysmal Extreme Pain Disorder (PEPD) and Primary Erythermalgia (PE). To date, all mutations in SCN9A that cause a complete inability to experience pain are protein truncating and presumably lead to no protein being produced. Here, we describe the identification and functional characterization of two novel non-truncating mutations in families with CIP: a homozygously-inherited missense mutation found in a consanguineous Israeli Bedouin family (Nav1.7-R896Q) and a five amino acid in-frame deletion found in a sporadic compound heterozygote (Nav1.7-ΔR1370-L1374). Both of these mutations map to the pore region of the Nav1.7 sodium channel. Using transient transfection of PC12 cells we found a significant reduction in membrane localization of the mutant protein compared to the wild type. Furthermore, voltage clamp experiments of mutant-transfected HEK293 cells show a complete loss of function of the sodium channel, consistent with the absence of pain phenotype. In summary, this study has identified critical amino acids needed for the normal subcellular localization and function of Nav1.7. © 2010 Wiley-Liss, Inc.

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