Mice with an Na_V1.4 sodium channel null allele have latent myasthenia, without susceptibility to periodic paralysis

Over 60 mutations of SCN4A encoding the Na_V1.4 sodium channel of skeletal muscle have been identified in patients with myotonia, periodic paralysis, myasthenia, or congenital myopathy. Most mutations are missense with gain-of-function defects that cause susceptibility to myotonia or periodic paralysis. Loss-of-function from enhanced inactivation or null alleles is rare and has been associated with myasthenia and congenital myopathy, while a mix of loss and gain of function changes has an uncertain relation to hypokalaemic periodic paralysis. To better define the functional consequences for a loss-of-function, we generated Na_V1.4 null mice by deletion of exon 12. Heterozygous null mice have latent myasthenia and a right shift of the forcestimulus relation, without evidence of periodic paralysis. Sodium current density was half that of wild-type muscle and no compensation by retained expression of the foetal NaV1.5 isoform was detected. Mice null for Na_V1.4 did not survive beyond the second postnatal day. This mouse model shows remarkable preservation of muscle function and viability for haploinsufficiency of Na_V1.4, as has been reported in humans, with a propensity for pseudo-myasthenia caused by a marginal Na+ current density to support sustained high-frequency action potentials in muscle.