Ion Channels and Human Disorders

The human channelopathies are a rapidly expanding group of primarily genetic conditions. They are characterised by dysfunction of membrane-bound glycoproteins (ion channels). Several neurological and general medical disorders have been shown to be due to underlying ion channel dysfunction and genetic analysis is now often routine clinical practice. These disorders exhibit extensive phenotypic and genetic heterogeneity with many distinct diseases caused by dysfunction of the same channel by differing mechanisms. Our understanding of the mechanisms behind these diseases continues to extend as more mutations are identified and functional analysis is performed. In the future this will lead to the identification of better targeted treatments for these diseases. Key Concepts: Ion channels are transmembrane glycoproteins important in intra- and intercellular processes. Channelopathies are commonly due to mutations in functionally important regions of either pore-forming or auxillary channel subunits. Mutations often cause disease by altering channel gating, voltage dependence and channel assembly. Channelopathies may manifest with intermittent symptoms which may completely recover or have a secondary progression. Channleopathies, like myotonia congenita, have extensive phenotypic variability even within a single pedigree. Genetic heterogeneity occurs in many channelopathies like the episodic ataxias and periodic paralyses. In the calcium channel, CACNA1A, different mutations cause distinct central nervous diseases. Mutations in a number of channel genes can increase the predisposition to epilepsy. Keywords: channelopathy; myotonia; migraine; epilepsy; episodic ataxia; spinocerebellar ataxia