Chapter 20: Hereditary Human Diseases Caused by Connexin Mutations

Abstract

The connexins comprise a family of homologous integral membrane proteins that form channels providing a low resistance pathway for the diffusion of small ions and nonelectrolytes between coupled cells. These channels, generally occurring in clusters that constitute gap junctions, provide an important pathway for intercellular signaling in many tissues. The connexin family contains at least 16 genes, and mutations in five of them have now been shown to be responsible for hereditary human diseases. Thus, connexins join the company of channel-forming proteins, that when mutated cause disease. Mutations in each of the connexin genes will ultimately be found to reduce fitness, to cause a disease, or to lead to embryonic lethality. This chapter discusses disease-causing mutations in connexin genes: mutations in the Cx26 gene cause nonsyndromic deafness; mutations in the Cx31 gene cause erythrokeratodermia or nonsyndromic deafness; mutations in the gene encoding Cx32 lead to a peripheral neuropathy, the X-linked form of Charcot-Marie-Tooth disease (CMTX); and mutations in the Cx46 and Cx50 genes lead to hereditary cataracts. This chapter describes the clinical manifestations of inherited gap junction diseases in humans and comments on the possible molecular and cellular bases for the pathophysiology of these disorders.