Autosomal Recessive Inheritance of Congenital Myasthenic Syndrome is Associated with Skeletal Muscle Sodium Channel Mutations

Abstract

The SCN4A gene, that encodes the pore-forming α-subunit of the skeletal muscle voltage-gated sodium channel, has long been associated with dominantly-inherited myotonia, and periodic paralysis mutations. One single severe case of congenital myasthenic syndrome (CMS) due to a dominantly-inherited SCN4A mutation has been reported. CMS is a clinically and genetically heterogeneous group of rare disorders characterized by muscle weakness and fatigability. They are due to impairment of neuromuscular transmission and result from mutations in genes encoding for proteins critical for the neuromuscular junction. We have identified a novel homozygous SCN4A mutation (p.R1454W) in a patient with a rare form of recessively-inherited CMS. The p.R1454W missense mutation is located on the segment S4 of domain IV of the Nav1.4 channel. Expression of p.R1454W mutant Nav1.4 in the human embryonic kidney 293 cells induced dramatic changes in the biophysical properties of the mutated channel. These include fast and slow inactivation,kinetics of fast inactivation, and recovery from inactivation. A slower current decay combined with a shift in channel availability at resting potentials can ultimately lead to membrane inexcitability and muscle weakness. Our data confirm that this CMS phenotype belongs to the group of sodium channel disorders and question the clinical overlapping between periodic paralyses and CMS. We suggest that while Nav1.4 mutations exerting a dominant-negative effect cause periodic paralysis, a CMS phenotype may result from recessively-inherited mutations that decrease the Nav1.4 availability for muscle action potential genesis at the neuromuscular junction and its propagation along the sarcolemma.