Analysis of a rare pathogenic variant of the SCN4A gene (c.4307T>C, L1436P): from clinic to patch-clamp

We report nine index cases with a rare mutation in the SCN4A gene, NM_000334.4( SCN4A ).4307T > C (p.Leu1436Pro), which codes for the muscle Na _v 1.4 channel. Patients were evaluated clinically and by an electrodiagnostic study. In addition, the biophysical characteristics of the mutant channels were compared to those of wild type channels and a better-known mutant, R1448H, using whole-cell patch clamp recordings of hNa _v 1.4 currents in stably transfected HEK293 cells, at near physiological temperature (32°C), room temperature (22°C) and cold temperature (15°C). The phenotypes associated with this SCN4A mutation included one sodium channel myotonia (SCM), six paramyotonia congenita , and one SCM worsened by cold. Regarding the phenotype of hyperkalemic periodic paralysis, three probands described episodes of muscle weakness. Whole-cell recordings showed that the L1436P mutation induced a significant slowing down of fast inactivation of the Na _v current at several voltages, but this effect was less marked than in R1448H. The L1436P mutation also tended to induce a right shift in the steady-state inactivation curve, but only at cold temperature. On the other hand, a leftward shift in the activation curve was seen at cold and room temperatures with R1448H, but not L1436P. Recovery from fast inactivation was slowed down in both mutantsat cold temperature. In conclusion, this report confirms that the L1436P mutation of the SCN4A gene leads to different clinical phenotypes. Epigenetic alterations, modifying genes or environmental factors may influence clinical expression. Our experimental data for L1436P reveals a biophysical phenotype consistent with the clinical phenotype of a majority of patients.