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Hyperkalemic periodic paralysis associated with a novel missense variant located in the inner pore of Nav1.4

  • Author Footnotes
    1 These authors contributed to this work equally.
    Kazuki Segawa
    Footnotes
    1 These authors contributed to this work equally.
    Affiliations
    Clinical Neurophysiology, Department of Clinical Laboratory and Biomedical Sciences, Division of Health Sciences, Osaka University Graduate School of Medicine, Japan
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  • Author Footnotes
    1 These authors contributed to this work equally.
    Masahiro Nishiyama
    Footnotes
    1 These authors contributed to this work equally.
    Affiliations
    Department of Pediatrics, Kobe University Graduate School of Medicine, Japan
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  • Itsuki Mori
    Affiliations
    Clinical Neurophysiology, Department of Clinical Laboratory and Biomedical Sciences, Division of Health Sciences, Osaka University Graduate School of Medicine, Japan
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  • Tomoya Kubota
    Correspondence
    Corresponding author at: Clinical Neurophysiology, Department of Clinical Laboratory and Biomedical Sciences, Division of Health Sciences, Osaka University Graduate School of Medicine, 1-7, Yamadaoka, Suita, Osaka 5650871, Japan.
    Affiliations
    Clinical Neurophysiology, Department of Clinical Laboratory and Biomedical Sciences, Division of Health Sciences, Osaka University Graduate School of Medicine, Japan
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  • Masanori P. Takahashi
    Affiliations
    Clinical Neurophysiology, Department of Clinical Laboratory and Biomedical Sciences, Division of Health Sciences, Osaka University Graduate School of Medicine, Japan
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  • Author Footnotes
    1 These authors contributed to this work equally.

      Abstract

      Background

      Hyperkalemic periodic paralysis (HyperPP) is an autosomal dominantly inherited disease characterized by episodic paralytic attacks with hyperkalemia, and is caused by mutations of the SCN4A gene encoding the skeletal muscle type voltage-gated sodium channel Nav1.4. The pathological mechanism of HyperPP was suggested to be associated with gain-of-function changes for Nav1.4 gating, some of which are defects of slow inactivation.

      Case presentation & Methods

      We identified a HyperPP family consisting of the proband and his mother, who showed a novel heterozygous SCN4A variant, p.V792G, in an inner pore lesion of segment 6 in Domain II of Nav1.4. Clinical and neurophysiological evaluations were conducted for the proband and his mother. We explored the pathogenesis of the variant by whole-cell patch clamp technique using HEK293T cells expressing the mutant Nav1.4 channel.

      Results

      Functional analysis of Nav1.4 with the V792G mutation revealed a hyperpolarized shift of voltage-dependent activation and fast inactivation. Moreover, steady-state slow inactivation in V792G was impaired with larger residual currents in comparison with wild-type Nav1.4.

      Conclusion

      V792G in SCN4A is a pathogenic variant associated with the HyperPP phenotype and the inner pore lesion of Nav1.4 plays a crucial role in slow inactivation.

      Keywords

      Abbreviations:

      HEK293T (human embryonic kidney), HyperPP (hyperkalemic periodic paralysis), ORF (open reading frame), PCR (polymerase chain reaction), RP (red fluorescent protein), SB (Sleeping Beauty transposon system), WT (wild-type)
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