Channel, neuronal and clinical function in sodium channelopathies: from genotype to phenotype

Abstract

What is the relationship between sodium channel function, neuronal function and clinical status in channelopathies of the nervous system? Given the central role of sodium channels in the generation of neuronal activity, channelopathies involving sodium channels might be expected to cause either enhanced sodium channel function and neuronal hyperexcitability associated with positive clinical manifestations such as seizures, or attenuated channel function and neuronal hypoexcitability associated with negative clinical manifestations such as paralysis. In this article, I review observations showing that changes in neuronal function and clinical status associated with channelopathies are not necessarily predictable solely from the altered physiological properties of the mutated channel itself. I discuss evidence showing that cell background acts as a filter that can strongly influence the effects of ion channel mutations.

Inherited Pain

“…A negative shift of the activation of the Nav1.7 channel is currently accepted to cause the clinical picture of IEM (22). Nevertheless, the age of disease onset as a measure for clinical severity correlates best to the sum of the shift of activation and to that of steady-state fast inactivation (23).…”

Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders

“…This illustrates an important principle, that the phenotype associated with a monogenic channelopathy is not predictable on the basis of the changes in physiology of the mutant sodium channel per se. The effect depends on the cell background in which the mutant channel is expressed, so that physiological interactions that are specific to particular types of neurons (in the case of PE, the physiological interaction of Na v 1.7 and Na v 1.8) may better explain the symptoms experienced by patients (45). These data provide an explanation of why PE presents with pain due to…”

SCN5A variant that blocks fibroblast growth factor homologous factor regulation causes human arrhythmia

“…5 | FHF E ncoded by 10 different genes, Na v channel α-subunits regulate excitable membrane depolarization and are therefore central to metazoan physiology (1). Na v channel function is critical for neuronal firing and communication (1,2), cardiac excitationcontraction coupling (3), and skeletal and intestinal function (4,5). The impact of Na v channel function for human biology has been elegantly defined by nearly two decades of studies directly linking Na v channel gene variants with human disease.…”