A novel mutation, R859C, in the Nav1.1 sodium channel was identified in a 4-generation, 33-member Caucasian family with a clinical presentation consistent with GEFS+. The mutation neutralizes a positively charged arginine in the domain 2 S4 voltage sensor of the Nav1.1 channel Ą subunit. When the mutation was placed in the rat Nav1.1 channel and expressed in Xenopus oocytes, the mutant channel displayed a positive shift in the voltage-dependence of sodium channel activation, slower recovery from slow inactivation, and lower levels of current compared to the wild-type channel. Computational analysis suggests that neurons expressing the mutant channel have higher thresholds for firing a single action potential and for firing multiple action potentials, along with decreased repetitive firing. Therefore, this mutation should lead to decreased neuronal excitability, in contrast to most previous GEFS+ sodium channel mutations that have changes predicted to increase neuronal firing.
Model Type: Neuron or other electrically excitable cell
Currents: I Na,t; I K; I Sodium
Genes: Nav1.1 SCN1A
Model Concept(s): Action Potentials; Epilepsy
Simulation Environment: NEURON
Implementer(s): Lickfett, Jay ; Goldin, Al [agoldin at uci.edu]
References:
Barela AJ et al. (2006). An epilepsy mutation in the sodium channel SCN1A that decreases channel excitability. The Journal of neuroscience : the official journal of the Society for Neuroscience. 26 [PubMed]
Spampanato J, Aradi I, Soltesz I, Goldin AL. (2004). Increased neuronal firing in computer simulations of sodium channel mutations that cause generalized epilepsy with febrile seizures plus. Journal of neurophysiology. 91 [PubMed]