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Ion channels and disease 

Ion channels and disease

Chapter:
Ion channels and disease
Author(s):

Frances M. Ashcroft

DOI:
10.1093/med/9780199204854.003.0404
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date: 25 April 2017

Ion channels are membrane proteins that act as gated pathways for the movement of ions across cell membranes. They are found in both surface and intracellular membranes, and play essential roles in the physiology of all cell types. An ever-increasing number of human diseases are found to be caused by defects in ion channel function. Ion channel diseases may arise in a number of different ways: ◆ From mutations in the coding region of the gene, or its control elements, leading to the gain, or loss, of channel function. Diseases that result from ion-channel mutations are often known as channelopathies. As with all single-gene disorders, their frequency in the general population is usually very low. Many channelopathies are genetically heterogeneous and the same clinical phenotype may be caused by mutations in different genes, as is the case for long QT syndrome. Conversely, mutations in the same gene may produce different phenotypes. For example, gain-of-function mutations in the epithelial sodium channel produce Liddle’s syndrome, whereas loss-of-function mutations cause pseudohypoaldosteronism type 1. Disease severity may also vary with different mutations in the same gene. ◆ From defective regulation of channel activity by intracellular or extracellular ligands, or by channel modulators, due to mutations in the genes encoding the regulatory molecules themselves, or defects in the pathways leading to their production. For instance, glucokinase mutations cause one type of maturity-onset diabetes of the young (MODY2), by impairing the metabolic regulation of ATP-sensitive potassium channels in pancreatic β‎ cells. ◆ From autoantibodies to ion channel proteins, which may either down-regulate or enhance channel function. These diseases are discussed elsewhere. ◆ From ion channels that act as lethal agents. These are secreted by cells and insert into the membrane of the target cell to form large nonselective pores that cause cell lysis and death. Examples include bacterial toxins such as staphylococcal α‎-toxin and the amoebopore of Entamoeba histolytica. The membrane-attack complex of complement, perforin, and the defensins also acts in this way.

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