SCN4A as modifier gene in patients with myotonic dystrophy type 2

Abstract

A patient with an early severe myotonia diagnosed for Myotonic Dystrophy type 2 (DM2) was found bearing the combined effects of DM2 mutation and Nav1.4 S906T substitution. To investigate the mechanism underlying his atypical phenotype,whole-cell patch-clamp in voltage- and current-clamp mode was performed in myoblasts and myotubes obtained from his muscle biopsy. Results characterizing the properties of the sodium current and of the action potentials have been compared to those obtained in muscle cells derived from his mother, also affected by DM2, but without the S906T polymorphism. A faster inactivation kinetics and a +5 mV shift in the availability curve were found in the sodium current recorded in patient’s myoblasts compared to his mother. 27% of his myotubes displayed spontaneous activity. Patient’s myotubes showing a stable resting membrane potential had a lower rheobase current respect to the mother’s while the overshoot and the maximum slope of the depolarizing phase of action potential were higher. These findings suggest that SCN4A polymorphisms may be responsible for a higher excitability of DM2 patients sarcolemma, supporting the severe myotonic phenotype observed. We suggest SCN4A as a modifier factor and that its screening should be performed in DM2 patients with uncommon clinical features.

A 14-Year Italian Experience in DM2 Genetic Testing: Frequency and Distribution of Normal and Premutated CNBP Alleles

“…Other symptoms such as cardiac and endocrine dysfunctions are not specifically associated with the DM2 phenotype being present in less than 5% of DM2-positive tests. Recent studies indicate that, unlike DM1, either CLCN1 or SCN4A acts as genetic modifiers in DM2 patients since mutations/polymorphisms in these genes may contribute to exaggerated phenotype with more severe muscle stiffness and myotonia ( Suominen et al, 2008 ; Cardani et al, 2012 ; Bugiardini et al, 2015 ; Peddareddygari et al, 2016 ; Binda et al, 2018 ). This suggests that DM2 patients with co-segregating CLCN1 or SCN4A genetic variants could be more easily identified than DM2 patients without the modifier alleles, and consequently that the majority of patients remain undiagnosed even in clinical centers with considerable experience with DM2.…”

Myotonic Dystrophies: Targeting Therapies for Multisystem Disease

“…However, modifier genes, specifically SCN4A and CLCN1, can change the severity of myotonia in DM2. Cases of both CLCN1 and SCN4A mutations present in DM2 patients have been shown to enhance the myotonic phenotype [24][25][26]. Sodium channel blockers, such as mexiletine, have been used for many years to treat myotonia in both the myotonic dystrophies as well as the nondystrophic myotonias.…”

248th ENMC International Workshop: Myotonic dystrophies: Molecular approaches for clinical purposes, framing a European molecular research network, Hoofddorp, the Netherlands, 11–13 October 2019

“…She then showed the results of a methylation study of DNA regions flanking the (CCTG)n expansion carried out in blood and muscle samples from a large cohort of DM2 patients. Pyrosequencing analysis of two CpG islands, upstream and downstream of the DM2 mutation, did not demonstrate any significant difference in the methylation profile between DM2 patients and controls in both tissues analyzed [20][21][22][23] .…”