Chapter 13 - Connexins and Heritable Human Diseases

Abstract

Connexins are tetratransmembrane proteins that assemble into hexameric pore-forming structures known as connexons or hemichannels. Connexons typically dock with their counterparts in adjacent cells to form intercellular gap junction channels, but may remain unpaired as cell surface hemichannels. Gap junction channels and hemichannels allow for the passage of ions, secondary messengers, and other small molecules between cells or between intra- and extracellular compartments, respectively, playing key roles in embryonic development, tissue homeostasis, and response to pathologic stress. The human genome contains 20 genes that encode distinct but structurally related connexin isoforms. Most tissues express multiple connexin types and individual isoforms can assemble into homomeric and heteromeric hemichannels or homotypic and heterotypic gap junction channels. Given the large number of individual connexin genes, the potential combinatorial diversity of encoded channel proteins, and their complex developmental and tissue-restricted patterns of expression, it is not surprising that mutations in connexins are responsible for a significant burden of heritable human diseases. In this chapter we will review the clinical disorders associated with genetic abnormalities of connexins and, where known, the molecular mechanisms responsible for the disease phenotype.