Many physiological processes depend upon the proper functioning of plasma membrane ion channels. This is most apparent in absorptive and secretory epithelia, and in electrically excitable tissues such as nerve and muscle. Disturbances in the operation of ion channels in these settings can alter normal physiology and cause disease. This review illustrates the use of molecular genetics in identifying hereditary diseases caused by mutations in genes which encode various skeletal muscle ion channels. Recent advances in the discovery of genetic mutations in the skeletal muscle voltage-gated sodium channel in certain forms of periodic paralysis, mutations in the skeletal muscle chloride channel gene in myotonia congenita, and defects in two distinct calcium channels that underlie disorders of excitation-contraction coupling (murine muscular dysgenesis, malignant hyperthermia susceptibility) will be presented. In each case, prior knowledge of abnormal ion channel function prompted the search for mutations in candidate genes. This work is beginning to shed new light on the relationship between ion channel structure and function by studies of naturally occurring channel mutations.
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