title: Mechanisms underlying a life-threatening skeletal muscle Na+ channel disorder.
abstract: Myotonia is an intrinsic muscular disorder caused by muscle fibre hyperexcitability, which produces a prolonged time for relaxation after voluntary muscle contraction or internal mechanical stimulation. Missense mutations in skeletal muscle genes encoding Cl− or Na+ channels cause non-dystrophic myotonias.Mutations of the SCN4A gene that encodes the skeletal voltage-gated Na+ channel Nav1.4 can produce opposing phenotypes leading to hyperexcitable or inexcitable muscle fibres. Nav1.4 mutations result in different forms of myotonias that can be found in adults. However, the recently reported myotonic manifestations in infants have been shown to be lethal. This was typically the case for children suffering from severe neonatal episodic laryngospasm (SNEL). A novel Nav1.4 channel missense mutation was found in these children that has not yet been analysed. In this study, we characterize the functional consequences of the new A799S Na+ channel mutation that is associated with sodium channel myotonia in newborn babies. We have used mammalian cell expression and patch-clamp techniques to monitor the channel properties.We found that the A799S substitution changes several biophysical properties of the channel by causing a hyperpolarizing shift of the steady-state activation, and slowing the kinetics of fast inactivation and deactivation. In addition, the single channel open probability was dramatically increased, contributing hence to a severe phenotype. We showed that substitutions at position 799 of the Nav1.4 channel favoured the channel open state with sustained activity leading to hyperexcitability of laryngeal muscles that could be lethal during infancy.
authors.affiliation: University of Nice Sophia-Antipolis, and UMR 6097 CNRS-TIANP, Nice, France.
authors.forename: Dina
authors.initials: D
authors.lastname: Simkin
authors.forename: Isabelle
authors.initials: I
authors.lastname: Léna
authors.forename: Pierre
authors.initials: P
authors.lastname: Landrieu
authors.forename: Laurence
authors.initials: L
authors.lastname: Lion-François
authors.forename: Damien
authors.initials: D
authors.lastname: Sternberg
authors.forename: Bertrand
authors.initials: B
authors.lastname: Fontaine
authors.forename: Saïd
authors.initials: S
authors.lastname: Bendahhou
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D002460:Cell Line; D006801:Humans; D007826:Laryngismus / Q000235:genetics; D018482:Muscle, Skeletal / Q000473:pathology / Q000502:physiology*; D020125:Mutation, Missense / Q000235:genetics*; D009222:Myotonia / Q000235:genetics; D062553:NAV1.4 Voltage-Gated Sodium Channel; D012720:Severity of Illness Index; D015222:Sodium Channels / Q000009:adverse effects / Q000235:genetics*
chemical_list: D062553:NAV1.4 Voltage-Gated Sodium Channel; C106251:SCN4A protein, human; D015222:Sodium Channels