Human sodium channel myotonia: slowed channel inactivation due to substitutions for a glycine within the III‐IV linker.

Abstract

SUMMARY1. Three families with a form of myotonia (muscle stiffness due to membrane hyperexcitability) clinically distinct from previously classified myotonias were examined. The severity of the disease greatly differed among the families.2. Three dominant point mutations were discovered at the same nucleotide position of the SCN4A gene encoding the adult skeletal muscle Na+ channel asubunit. They predict the substitution of either glutamic acid, valine or alanine for glycine1306, a highly conserved residue within the supposed inactivation gate.Additional SCN4A mutations were excluded.3. Electrophysiological studies were performed on biopsied muscle specimens obtained for each mutation. Patch clamp recordings on sarcolemmal blebs revealed an increase in the time constant of fast Na+ channel inactivation, Th, and in late channel openings as compared to normal controls. Th was increased from 1-2 to 1-6-2-1 ms and the average late currents from 04 to 1-6 % of the peak early current.4. Intracellular recordings on resealed fibre segments revealed an abnormal tetrodotoxin-sensitive steady-state inward current, and repetitive action potentials. Since K+ and Cl-conductances were normal, only the increase in the number of non-inactivating Na+ channels has to be responsible for the membrane hyperexcitability.5. Length, ramification and charge of the side-chains of the substitutions correlated well with the Na+ channel dysfunction and the severity of myotonia, with alanine as the most benign and glutamic acid as the substitution with a major steric effect.6. Our electrophysiological and molecular genetic studies strongly suggest that these Na+ channel mutations cause myotonia. The naturally occurring mutants allowed us to gain further insight into the mechanism of Na+ channel inactivation. ¶ To whom correspondence should be addressed.MS 2411

Congenital Myasthenic Syndromes - Molecular Bases of Congenital Defects of Proteins at the Neuromuscular Junction

“…Dominant gain-of-function mutations in this gene cause hyperkalemic periodic paralysis (Ptacek et al, 1991), paramyotonia congenita (McClatchey et al, 1992;Ptacek et al, 1992), potassium-aggravated myotonia (Lerche et al, 1993), and hypokalemic periodic paralysis type 2 (Bulman et al, 1999). On the other hand, loss-of-function mutations cause a CMS.…”

The non-dystrophic myotonias: molecular pathogenesis, diagnosis and treatment

“…Given some of the shared clinical features of hyperkalaemic periodic paralysis and paramyotonia congenita and the recognition of abnormal sodium conductance in both (Lehmann-Horn et al, 1981, 1987a it was proposed and subsequently confirmed that paramyotonia congenita and hyperkalaemic periodic paralysis were allelic disorders (Koch et al, 1991a;Ptacek et al, 1991a, b;Rojas et al, 1991;McClatchey et al, 1992a, b). Later the phenotypes grouped together as the potassium aggravated myotonias were also shown to be sodium channel disorders (Lerche et al, 1993;Ptacek et al, 1994;Ricker et al, 1994) All the skeletal muscle sodium channelopathies are autosomal dominant conditions and de novo mutations can occur. In a proportion of patients with a phenotype typical for paramyotonia congenita no mutation has been identified in SCN4A raising the possibility of further genetic heterogeneity (Miller et al, 2004).…”

“…This phenotype was classified as myotonia fluctuans (Ricker et al, 1990(Ricker et al, , 1994Lennox et al, 1992). The term myotonia permanens was introduced to describe patients with a third clinical variant characterized by very severe persistent myotonia which significantly impaired respiration (McClatchey et al, 1992b;Lerche et al, 1993). These three purely myotonic disorders shared the potassium aggravation and the absence of sensitivity to cold.…”

Ranolazine block of human Nav1.4 sodium channels and paramyotonia congenita mutants

“…Gain-of-function mutations in SCN4A, the gene encoding the pore-forming alpha (α) subunit of the human skeletal muscle voltage-gated Na + channel type IV (hNa v 1.4) have been associated with non-dystrophic skeletal muscle pathologies including paramyotonia congenita, 1 hyperkalaemic periodic paralysis, 2 and potassium-aggravated myotonia 3 (reviewed in refs. [4][5][6].…”