A novel Nav1.7 mutation producing carbamazepine-responsive erythromelalgia

Authors

  • Tanya Z. Fischer MD, PhD,

    1. Department of Neurology, Yale University School of Medicine, New Haven
    2. Center for Neuroscience & Regeneration Research, Yale University School of Medicine, New Haven
    3. Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven
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    • T.Z.F. and E.S.G. contributed equally to this work.

  • Elaine S. Gilmore MD, PhD,

    1. Center for Neuroscience & Regeneration Research, Yale University School of Medicine, New Haven
    2. Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven
    3. Department of Dermatology, Yale University School of Medicine, New Haven, CT
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    • T.Z.F. and E.S.G. contributed equally to this work.

  • Mark Estacion PhD,

    1. Department of Neurology, Yale University School of Medicine, New Haven
    2. Center for Neuroscience & Regeneration Research, Yale University School of Medicine, New Haven
    3. Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven
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  • Emmanuella Eastman BS,

    1. Department of Neurology, Yale University School of Medicine, New Haven
    2. Center for Neuroscience & Regeneration Research, Yale University School of Medicine, New Haven
    3. Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven
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  • Sean Taylor MD,

    1. Department of Neurology, Kingston General Hospital, Kingston, Ontario, Canada
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  • Michel Melanson MD,

    1. Department of Neurology, Kingston General Hospital, Kingston, Ontario, Canada
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  • Sulayman D. Dib-Hajj PhD,

    1. Department of Neurology, Yale University School of Medicine, New Haven
    2. Center for Neuroscience & Regeneration Research, Yale University School of Medicine, New Haven
    3. Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven
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  • Stephen G. Waxman MD, PhD

    Corresponding author
    1. Department of Neurology, Yale University School of Medicine, New Haven
    2. Center for Neuroscience & Regeneration Research, Yale University School of Medicine, New Haven
    3. Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven
    • Department of Neurology, LCI 707, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06510
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  • Potential conflict of interest: Nothing to report.

Abstract

Objective

Human and animal studies have shown that Nav1.7 sodium channels, which are preferentially expressed within nociceptors and sympathetic neurons, play a major role in inflammatory and neuropathic pain. Inherited erythromelalgia (IEM) has been linked to gain-of-function mutations of Nav1.7. We now report a novel mutation (V400M) in a three-generation Canadian family in which pain is relieved by carbamazepine (CBZ).

Methods

We extracted genomic DNA from blood samples of eight members of the family, and the sequence of SCN9A coding exons was compared with the reference Nav1.7 complementary DNA. Wild-type Nav1.7 and V400M cell lines were then analyzed using whole-cell patch-clamp recording for changes in activation, deactivation, steady-state inactivation, and ramp currents.

Results

Whole-cell patch-clamp studies of V400M demonstrate changes in activation, deactivation, steady-state inactivation, and ramp currents that can produce dorsal root ganglia neuron hyperexcitability that underlies pain in these patients. We show that CBZ, at concentrations in the human therapeutic range, normalizes the voltage dependence of activation and inactivation of this inherited erythromelalgia mutation in Nav1.7 but does not affect these parameters in wild-type Nav1.7.

Interpretation

Our results demonstrate a normalizing effect of CBZ on mutant Nav1.7 channels in this kindred with CBZ-responsive inherited erythromelalgia. The selective effect of CBZ on the mutant Nav1.7 channel appears to explain the ameliorative response to treatment in this kindred. Our results suggest that functional expression and pharmacological studies may provide mechanistic insights into hereditary painful disorders. Ann Neurol 2009;65:733–741

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