Gap junctions allow the exchange of
ions and small molecules between adjacent cells through intercellular channels formed by
connexin proteins, which can also form functional hemichannels in nonjunctional membranes. Mutations in
connexin genes cause a variety of human diseases. For example, mutations in GJB2, the gene encoding connexin-26 (Cx26), are not only a major cause of
nonsyndromic deafness, but also cause syndromic
deafness associated with skin disorders such as
palmoplantar keratoderma,
keratitis-ichthyosis deafness syndrome,
Vohwinkel syndrome, hystrix-
ichthyosis deafness syndrome and
Bart-Pumphrey syndrome. The most common mutation in the Cx26 gene linked to
nonsyndromic deafness is 35DeltaG, a frameshift mutation leading to an early stop
codon. The large number of deaf individuals homozygous for 35DeltaG do not develop
skin disease. Similarly, there is abundant experimental evidence to suggest that other Cx26 loss-of-function mutations cause
deafness, but not
skin disease. By contrast, Cx26 mutations that cause both
skin diseases and
deafness are all single
amino acid changes. Since
nonsyndromic deafness is predominantly a loss-of-function disorder, it follows that the syndromic mutants must show an alteration, or gain, of function to cause
skin disease. Here, we summarise the functional consequences and clinical phenotypes resulting from Cx26 mutations that cause
deafness and
skin disease.