Connexin gene pathology

Gap junctions are formed by a polygenic family of more than 20 different connexin proteins and mediate the direct exchange of ions, metabolites and secondary messengers between adjacent cells. Gap junction intercellular communication coordinates a multitude of cellular activities and is crucial for tissue homeostasis, cell growth, differentiation, and response to stimuli. The identification of a growing number of human connexin defects and the targeted ablation of connexin genes in mice has recently shed light on the importance and functional diversity of the gap junction system in various tissues. This review summarizes the genetic basis and phenotypic spectrum of human connexin disorders affecting skin and its appendages as well as inner ear and cornea. Special emphasis is placed on the pleiotropic effects of mutations in several connexin genes and the genetic diversity of these disorders, which result in intriguing genotype–phenotype correlations. With very few exceptions, almost all cells in the developing and adult mammalian organism directly communicate with their neighbours through gap junctions. Gap junctions are ordered arrays of 10–10 000 intercellular channels that facilitate and regulate the diffusional exchange of ions, secondary messengers and small metabolites (< 1000 Da) between the cytoplasms of adjacent cells.1, 2 Each aqueous channel is formed by end‐to‐end docking of a hexameric hemichannel (‘connexon’) with a partner connexon of the neighbouring cell.2, 3 These hemichannels are formed by connexins, a closely related family of integral membrane proteins that comprise four transmembrane, two extracellular and three cytoplasmic domains (Fig. 1).4 The four α‐helical domains (M1–M4) anchor the polypeptide in the cell membrane, partially form the lining of the channel pore and determine the functional properties of the connexin channel.5, 6 The two extracellular domains (E1, E2) extend about 2 nm into the extracellular space where they couple with those of a partner connexon from an apposing cell.5 E2 is also the major determinant for connexon–connexon compatibility, while E1 is part of a voltage‐sensing mechanism and establishes charge selectivity.7, 8 The cytoplasmic loop (CL) between M2 and M3 and the carboxyl terminus (CT) differ in length and sequence between members of the connexin family and are involved in chemical gating, pH sensitivity and gating through phosphorylation. In contrast, the cytoplasmic amino terminus (NT) is more conserved. It may participate in voltage gating8–10 and forming of the channel pore.11