Ion channelopathies of skeletal muscle.
The primary research interests of our laboratory are how ion channels regulate the electrical excitability of cells and how defects in these channels lead to human disease. In the past three decades, mutations of ion channel genes have been found to be the primary cause for over 100 human diseases. The focus of our laboratory has been to understand the mechanistic basis for a group of inherited disorders of skeletal muscle caused by mutations of voltage-gated ion channels. The derangements in electrical excitability of affected muscle may cause involuntary after-contractions (excess excitability called myotonia) or transient episodes of severe weakness (temporary loss of excitability called periodic paralysis). Our lab studies the consequences of mutations on channel function, uses computational models of muscle excitability to explore the impact of altered channel behavior, and developed genetically-engineered mouse models to gain insights on the pathomechanisms of these disorders and to test pre-clinical strategies for therapeutics and disease modification.
This work has led to the discovery of gain-of-function defects in the NaV1.4 sodium channel that cause a predisposition to myotonia, to periodic paralysis, or to both and thereby provides a mechanistic basis for the genotype-phenotype associations in the allelic disorders hyperkalemic periodic paralysis, paramyotonia congenita, and sodium channel myotonia. More recent work shows that loss-of-function changes for NaV1.4 may cause pseudo-myasthenia or congenital myopathy. We also established the gating pore “leak” resulting from mutations in the voltage-sensor domain of NaV1.4 or CaV1.1 as a major determinant in causing susceptibility to hypokalemic periodic paralysis due to paradoxical depolarization in low K+. Our knock-in mutant mouse models prove these missense mutations are sufficient to cause myotonia or periodic paralysis, have yielded new insights on the mechanisms for triggering attacks, and provided proof-of-principle that inhibitors of the Na-K-2Cl transporter can reverse or prevent acute attacks of weakness in hypokalemic periodic paralysis. Our latest projects are exploring the mechanism by which vigorous exercise is a trigger for eliciting attacks of weakness in periodic paralysis
Periodic Paralysis Association 2021
Repurposing a drug for preventing attacks of periodic paralysis (link to YouTube video)
Channelopathy 2018 Plenary Lecture
Periodic Paralysis of Skeletal Muscle: A Prototypical Ion Channelopathy (vimeo link to Dr. Cannon's talk)
