Connexin Mutations and Disease
Since connexins are ubiquitously expressed in mammalians and appear to have a unique role in cell and tissue homeostasis, it is expected that mutations in these genes would be associated with a wide variety of diseases. In fact, since the first description of a mutation in the Cx32 in patients with the X-linked Charcot–Marie–Tooth (CMTX) syndrome, disease-causing mutations have been detected in almost every connexin gene. Mutations in a connexin can affect one organ expressing this protein but simultaneously spare another organ expressing the same connexin. This selectivity for organ involvement can partially be explained by redundancy in connexin expression, especially in cells where connexins are indispensable to survival of the organism. It is also quite surprising that some connexin genes harbour hundreds of different mutations in humans whereas in others no mutations have been found so far. This difference in susceptibility to mutagenesis is poorly understood. As connexins have similar gene structure and a high sequence homology, it seems highly unlikely that only some of these genes would contain mutational hotspots, and we can also assume that the mutation rate is comparable in each connexin gene. If mutations in one particular gene would have little consequence on proper cell function, then numerous gene polymorphisms should be found in the human population. This is, however, not the case for connexins, as only a limited number of polymorphisms have been described in screenings of those genes. Some of the mutations in connexin genes and their linkage to diseases are discussed below.