Human diseases associated with connexin mutations

Abstract

Gap junctions and hemichannels comprised of connexins impact many cellular processes. Significant advances in our understanding of the functional role of these channels have been made by the identification of a host of genetic diseases caused by connexin mutations. Prominent features of connexin disorders are the inability of other connexins expressed in the same cell type to compensate for the mutated one, and the ability of connexin mutants to dominantly influence the activity of other wild-type connexins. Functional studies have begun to identify some of the underlying mechanisms whereby connexin channel mutation contributes to the disease state. Detailed mechanistic understanding of these functional differences will help to facilitate new pathophysiology driven therapies for the diverse array of connexin genetic disorders. This article is part of a Special Issue entitled: Gap Junction Proteins edited by Jean Claude Herve.

Keywords: Connexin; Gap junction; Genetic disease; Hemichannel; Mutation.

Figure 1

A mouse model of KID syndrome. (A). A wild-type mouse of the SKH1 hairless strain. (B). An inducible transgenic SKH1 mouse expressing the Cx26-G45E mutation in keratinocytes develops the epidermal features of KID syndrome. See [166] for details.

Figure 2

Disruption of the epidermal Ca²⁺ gradient by mutant Cx26 hemichannels in KID syndrome. (A). Cx26 KID mutant hemichannels have a higher net flux of Ca²⁺ and broader expression pattern than wild-type Cx26. (B). In normal epidermis, Cx26 is restricted to cells in the basal layer, and there is a gradient of Ca²⁺ with the highest levels in the granular layer, and low levels in the basal layer. In KID epidermis, mutant Cx26 expression expands across the epithelium, increasing Ca²⁺ flux and eliminating the normal Ca²⁺ gradient. The loss of the Ca²⁺ gradient disrupts the normal regulation of keratinocyte proliferation (favored in low Ca²⁺) and differentiation (favored in high Ca²⁺) resulting in a greatly thickened epidermis and a decrease in differentiated cells.

Figure 3

Hemichannel activity of the Cx43-G8V mutation causing PPKCA1 [108]. (A). A recording from a cell attached patch containing a single Cx43-G8V hemichannel obtained in response to an 8s voltage ramp applied between −70 and +70 mV. The leak current was subtracted offline. The hemichannel unitary conductance (γ_hc) was ~215 pS. (B). Another recording from a cell attached patch containing a single Cx43-G8V hemichannel obtained in response to a constant voltage step of −70 mV. At this voltage a sub conductance state was also evident. All currents were filtered at 1 kHz, data were acquired at 5 kHz and the pipette solution contained 140 mM KCl.