Connexin Mutations and Hereditary Diseases

Abstract

Inherited diseases caused by connexin mutations are found in multiple organs and include hereditary deafness, congenital cataract, congenital heart diseases, hereditary skin diseases, and X-linked Charcot-Marie-Tooth disease (CMT1X). A large number of knockout and knock-in animal models have been used to study the pathology and pathogenesis of diseases of different organs. Because the structures of different connexins are highly homologous and the functions of gap junctions formed by these connexins are similar, connexin-related hereditary diseases may share the same pathogenic mechanism. Here, we analyze the similarities and differences of the pathology and pathogenesis in animal models and find that connexin mutations in gap junction genes expressed in the ear, eye, heart, skin, and peripheral nerves can affect cellular proliferation and differentiation of corresponding organs. Additionally, some dominant mutations (e.g., Cx43 p.Gly60Ser, Cx32 p.Arg75Trp, Cx32 p.Asn175Asp, and Cx32 p.Arg142Trp) are identified as gain-of-function variants in vivo, which may play a vital role in the onset of dominant inherited diseases. Specifically, patients with these dominant mutations receive no benefits from gene therapy. Finally, the complete loss of gap junctional function or altered channel function including permeability (ions, adenosine triphosphate (ATP), Inositol 1,4,5-trisphosphate (IP3), Ca²⁺, glucose, miRNA) and electric activity are also identified in vivo or in vitro.

Keywords: congenital cataract; congenital heart diseases; connexin; gap junction; gene mutation; hereditary deafness; hereditary skin diseases.

Figure 1

Main pathophysiological changes associated with human hereditary deafness, congenital cataract, congenital heart diseases, hereditary skin diseases, and CMT1X found in knock-in and knockout mouse models. EP: endolymphatic potential, OHC: outer hair cell, IHC: inner hair cell, SCs: supporting cells, MCP-1: monocyte chemoattractant protein-1, CSF-1: colony-stimulating factor 1.

Figure 2

Diagram of possible pathogenesis of gap junction disorders caused by gene mutations. (a) structure of connexin, hemichannels, and gap junctions; (b) Gene mutations lead to the disruption of translation, assembly, and trafficking of connexins, which results in a loss of gap junction or hemichannel formation; (c,d) Gene mutations reduce the area of gap junction plaques and impair the function of gap junctions and hemichannels. (c) Gene mutations result in aberrant channel permeability and electric activity of hemichannels. (d) Gene mutations result in reduced area of gap junction plaques, altered channel permeability, and abnormal electric activity of gap junctions. WT: wild-type. ER: endoplasmic reticulum, ATP: adenosine triphosphate.