Nav1.4 Loss Of Function Changes For Recessively Inherited Myopathy With Fluctuating Weakness

Mutations in SCNA4, coding for the skeletal muscle specific NaV1.4 sodium channel, are associated with a variety of dominantly inherited disorders in which gain-of-function changes cause myotonia or periodic paralysis. In contrast, very few loss of function NaV1.4 mutations have been identified, and these cause recessively inherited myopathy and fluctuating strength that has features of myasthenia or a variant of periodic paralysis. We report on the functional characterization of two mutations at the same residue in DIVS4 that both produce recessive muscle disorders. R1460W was identified in a 6 y.o. with myopathy, episodes of weakness and breathing difficulties. The patient was homozygous for R1460W, and the parents were both asymptomatic carriers. A heteroallelic mutation R1460Q/null was reported in a child with congenital weakness, ptosis, plus intermittent laryngospasm and painful muscle stiffness suggestive of myotonia. Voltage clamp studies in HEK cells revealed loss of function deficits with a decreased current density and a left shift for the voltage-sensitivity of fast inactivation for both mutant channels. A modest gain-of-function change was also detected, as an accelerated rate of recovery from fast inactivation. Use-dependent inactivation for high frequency pulse trains was reduced for mutant channels, which may explain the myotonic features. Remarkably, the three prior cases of recessive NaV1.4 myopathy / myasthenia plus the two reported here are all in the DIVS4 voltage sensor domain and all cause a prominent left shift of inactivation.