What is the clinical evidence from this study?

Study design: Case Report. Population: SCN4A-associated overlap phenotype (periodic paralysis and sodium channel myotonia) (n=2). Intervention: Nav1.4-L1326P variant vs. Wild-type channels. Primary outcome: Nav1.4 channel gating alterations.

What does this research mean for the field?

The previously undescribed Nav1.4-L1326P variant causes multiple gating alterations, including decelerated fast channel inactivation and increased persistent current, leading to an SCN4A-associated overlap phenotype of myotonia and periodic paralysis. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.SUPPORTS_CONSENSUS.

What question did this study set out to answer?

This research aims to characterize a missense mutation in the SCN4A gene that affects the Nav1.4 sodium channel and its gating properties.

April 23, 2026

Missense mutation causes multiple defects in Nav1.4 channel gating and leads to an SCN4A -associated overlap phenotype

Key Result

The Nav1.4-L1326P variant identified in 2 family members caused multiple gating alterations, including decelerated fast channel inactivation and increased persistent current.

Key Points

This research aims to characterize a missense mutation in the SCN4A gene that affects the Nav1.4 sodium channel and its gating properties.
Functional characterization using Xenopus oocytes co-expressing human Nav1.4 and β1 subunits
Two-electrode voltage clamp technique to analyze gating alterations
Comparative analysis between mutant Nav1.4-L1326P and wild-type channels
Voltage dependence of activation shifted towards depolarization in Nav1.4-L1326P
Steady-state inactivation moved towards hyperpolarization
Fast inactivation decelerated and persistent current increased significantly

Study Design

Type

Case Report (n=2)

Structured PICO

Does the p.L1326P mutation in the Nav1.4 channel alter channel gating properties compared to wild-type?

Population

Xenopus oocytes co-expressing human Nav1.4 and β1 subunits; and two members of a family with the p.L1326P variant presenting mild symptoms of periodic paralysis and sodium channel myotonia

Intervention

p.L1326P missense mutation in the SCN4A gene encoding the Nav1.4 channel

Comparator

Wild-type Nav1.4 channels

Outcome

Channel gating alterations (voltage dependence of activation and inactivation, fast channel inactivation, and persistent current)surrogate

The p.L1326P mutation in the Nav1.4 channel causes gain-of-function gating defects that provide a functional and structural basis for the observed overlap phenotype of myotonia and periodic paralysis.

Abstract

Mutations in SCN4A gene encoding the skeletal muscle-type voltage-gated sodium channel Nav1.4 are known to cause neuromuscular disorders. Here, we report a previously undescribed variant affecting the DIII–IV cytoplasmic linker, which is a critically important region participating in channel inactivation. The variant p.L1326P was found in heterozygous state in two members of the same family presenting mild symptoms of periodic paralysis and in vivo electrophysiological features of sodium channel myotonia. Functional characterization was performed using Xenopus oocytes co-expressing human Nav1.4 and β1 subunits, and the two-electrode voltage clamp technique. We recorded gating alterations in Nav1.4-L1326P compared with wild-type channels. (1) The voltage dependence of activation shifted to the depolarizing direction, whereas (2) the voltage dependence of steady-state inactivation moved in the hyperpolarizing direction. (3) Fast channel inactivation was markedly decelerated in Nav1.4-L1326P. In addition, (4) we observed a dramatic increase in persistent current. The gain-of-function effects are consistent with the consensus view on the pathogenesis of myotonia and periodic paralysis. AlphaFold 3 models suggest stronger contacts between the cytoplasmic domain and the DIII–IV linker in the mutant channels offering a possible structural interpretation of the functional changes.

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