Mice with an NaV1.4 sodium channel null allele have latent myasthenia, without susceptibility to periodic paralysis

Over 60 mutations of SCN4A encoding the Na V 1.4 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 V 1.4 null mice by deletion of exon 12. Heterozygous null mice have latent myasthenia and a right shift of the force-stimulus 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 Na V 1.5 isoform was detected. Mice null for Na V 1.4 did not survive beyond the second postnatal day. This mouse model shows remarkable preservation of muscle function and viability for haploinsufficiency of Na V 1.4, 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. Mutations in Na V 1.4 are most often associated with myotonia or periodic paralysis. Loss of function changes are rare, and are seen in congenital myasthenia, congenital myopathy, and hypokalemic periodic paralysis. Using an NaV1.4 knock-out mouse, Wu et al . show that haploinsufficiency gives rise to latent myasthenia, but not periodic paralysis.