Thor, Michael Gunnar; (2019) Novel pathomechanisms and disease associations of the voltage-gated sodium channel NaV1.4. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Voltage-gated sodium channels initiate and shape the upstroke of the action potential, allowing fast electrical signaling between cells. Mutations in the genes encoding these channels are associated with a group of disorders known as channelopathies. This project aimed to characterize mutations in SCN4A encoding NaV1.4 associated with traditional skeletal muscle channelopathies as well as novel conditions using functional expression in Xenopus oocytes or HEK293T cells. Mutations of gating charges in the voltage sensor domain in the fourth transmembrane segment (S4), such as p.R222W or p.R222G, were found in patients with hypokalemic periodic paralysis. Another mutation, p.R222Q, was found in an individual with myotonia. I found that unlike hypoPP S4 arginine mutations causing gating pore currents, p.R222Q results in gain of function typically associated with sodium-channel myotonia. In another project, novel homozygous or compound heterozygous SCN4A mutations were found in eleven families with congenital myopathy. Each affected individual carried at least one mutation causing full loss of function. In all but one case the mutation in the opposite allele caused full or partial loss of function. The genetic and functional data are consistent with heteroallelic loss of function mutations—one of which confers full loss of function—underlying the clinical presentation by reducing the action potential amplitude in the muscle to a level insufficient to sustain normal muscle function. Some SCN4A mutations are lethal in infants when affecting muscle regulating respiration. Whole-exome sequencing of 434 cases of sudden infant death syndrome (SIDS) identified in six novel and five very rare SCN4A variants. Channel defects were found in four variants, two of which were gain of function and the other two loss of function. Dysfunctional SCN4A variants were also overrepresented in the SIDS cohort compared to controls. These results suggest pathogenic variations in SCN4A may be a genetic risk factor for SIDS.

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