Paracellular Channel in Human Disease

Abstract Linkage analysis and positional cloning have led to the discovery of TJ genes and mutant alleles that cause various human diseases. More than 10 Mendelian diseases related to paracellular channel dysfunction have been solved on the molecular level. These include genetic disorders affecting the skin, the liver, the kidney, the inner ear, and the blood-brain barrier. In each case, identification of a gene sparks intense investigation of the cellular mechanism that can relate a genotype to a phenotype. Knowledge of the causal mechanism for disease not only facilitates the development of new treatment but also provides critical insight into the basic biology and physiology of paracellular channel. For example, the paracellular pathway in the kidney is particularly important for mineral metabolism. Genetic variations in three claudin genes, claudin-14, claudin-16, and claudin-19, are associated with renal diseases of Ca++ and Mg++ imbalance. Virtually every aspect of claudin biology, e.g. gene transcription, protein translation, trafficking, interaction, and transport function, plays an important role in paracellular channelopathy.