Ion channel genes and human neurological disease: recent progress, prospects, and challenges

Abstract

What do epilepsy, migraine headache, deafness, episodic ataxia, periodic paralysis, malignant hyperthermia, and generalized myotonia have in common? These human neurological disorders can be caused by mutations in genes for ion channels. Many of the channel diseases are "paroxysmal disorders" whose principal symptoms occur intermittently in individuals who otherwise may be healthy and active. Some of the ion channels that cause human neurological disease are old acquaintances previously cloned and extensively studied by channel specialists. In other cases, however, disease-gene hunts have led the way to the identification of new channel genes. Progress in the study of ion channels has made it possible to analyze the effects of human neurological disease-causing channel mutations at the level of the single channel, the subcellular domain, the neuronal network, and the behaving organism.

Figure 1

Ion channels of the motor nerve and skeletal muscle involved in human disease. The drawing shows a myelinated axon branching to form synaptic contacts with a muscle fiber. (Upper) The outer surfaces of the axon and muscle. (Lower) The nerve presynaptic terminal and muscle fiber in cut section. (Inset) A magnified view of the nerve fiber, cut lengthwise near a node of Ranvier. Different channel types are identified by number and color, as indicated in the key below the drawing. The contractile proteins of the sarcomere are depicted schematically within the muscle. See text for additional details.

Figure 2

The KCNQ family of voltage-gated potassium channels. Four pore-forming subunit genes (KCNQ1–4) and one small auxiliary subunit gene (KCNE1) are known.