Neuropathy-associated NaV1.7 variant I228M impairs integrity of dorsal root ganglion neuron axons

Authors

  • Anna-Karin Persson PhD,

    1. Department of Neurology, Yale University School of Medicine, New Haven, CT
    2. Center for Neuroscience and Regeneration Research, Veterans Affairs Medical Center, West Haven, CT
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  • Shujun Liu MS,

    1. Department of Neurology, Yale University School of Medicine, New Haven, CT
    2. Center for Neuroscience and Regeneration Research, Veterans Affairs Medical Center, West Haven, CT
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  • Catharina G. Faber MD, PhD,

    1. Department of Neurology, University Medical Center Maastricht, Maastricht, the Netherlands
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  • Ingemar S. J. Merkies MD, PhD,

    1. Department of Neurology, University Medical Center Maastricht, Maastricht, the Netherlands
    2. Department of Neurology, Spaarne Hospital, Hoofddorp, the Netherlands
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  • Joel A. Black PhD,

    1. Department of Neurology, Yale University School of Medicine, New Haven, CT
    2. Center for Neuroscience and Regeneration Research, Veterans Affairs Medical Center, West Haven, CT
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  • Stephen G. Waxman MD, PhD

    Corresponding author
    1. Department of Neurology, Yale University School of Medicine, New Haven, CT
    2. Center for Neuroscience and Regeneration Research, Veterans Affairs Medical Center, West Haven, CT
    • Neuroscience and Regeneration Research Center, VA Connecticut Healthcare System, 950 Campbell Avenue, Bldg. 34, West Haven, CT 06516
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Abstract

Small-fiber neuropathy (SFN) is characterized by injury to small-diameter peripheral nerve axons and intraepidermal nerve fibers (IENF). Although mechanisms underlying loss of IENF in SFN are poorly understood, available data suggest that it results from axonal degeneration and reduced regenerative capacity. Gain-of-function variants in sodium channel NaV1.7 that increase firing frequency and spontaneous firing of dorsal root ganglion (DRG) neurons have recently been identified in ∼30% of patients with idiopathic SFN. In the present study, to determine whether these channel variants can impair axonal integrity, we developed an in vitro assay of DRG neurite length, and examined the effect of 3 SFN-associated variant NaV1.7 channels, I228M, M932L/V991L (ML/VL), and I720K, on DRG neurites in vitro. At 3 days after culturing, DRG neurons transfected with I228M channels exhibited ∼20% reduced neurite length compared to wild-type channels; DRG neurons transfected with ML/VL and I720K variants displayed a trend toward reduced neurite length. I228M-induced reduction in neurite length was ameliorated by the use-dependent sodium channel blocker carbamazepine and by a blocker of reverse Na-Ca exchange. These in vitro observations provide evidence supporting a contribution of the I228M variant NaV1.7 channel to impaired regeneration and/or degeneration of sensory axons in idiopathic SFN, and suggest that enhanced sodium channel activity and reverse Na-Ca exchange can contribute to a decrease in length of peripheral sensory axons. Ann Neurol 2012

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