Connexinopathies: a structural and functional glimpse

Abstract

Mutations in human connexin (Cx) genes have been related to diseases, which we termed connexinopathies. Such hereditary disorders include nonsyndromic or syndromic deafness (Cx26, Cx30), Charcot Marie Tooth disease (Cx32), occulodentodigital dysplasia and cardiopathies (Cx43), and cataracts (Cx46, Cx50). Despite the clinical phenotypes of connexinopathies have been well documented, their pathogenic molecular determinants remain elusive. The purpose of this work is to identify common/uncommon patterns in channels function among Cx mutations linked to human diseases. To this end, we compiled and discussed the effect of mutations associated to Cx26, Cx32, Cx43, and Cx50 over gap junction channels and hemichannels, highlighting the function of the structural channel domains in which mutations are located and their possible role affecting oligomerization, gating and perm/selectivity processes.

Keywords: Connexins; gap junction channels; hemichannels; human genetic disease; structure and function.

Fig. 1

Localization of loss-of-function mutations for Cx26 GJC. a Cartoon representation of a Cx26 monomer, colored with a blue-green gradient from the N- to the CT region. Localization of loss-of-function mutations are colored in red. b Lateral (c) Top (d) Bottom view of the same subunit of (a), in the context of the HC assemble. The HC surface is transparent and white. The figure was generated with PyMol and edited with Gimp

Fig. 2

Mutations affecting function of GJCs. Models of single Cxs chains are represented as cartoons, and colored with a blue-green gradient from the N- to the CT region, for (a) Cx26 (b) Cx32, (c) Cx43 and (d) Cx50. Positions of loss of function mutations are colored as red and gain of function mutations as yellow. The figure was generated with Pymol and edited with Gimp

Fig. 3

Mutations affecting function of HCs. Models of single Cxs chains are represented as cartoons, and colored with a blue-green gradient from the N- to the CT region, for (a) Cx26 (b) Cx32, (c) Cx43 and (d) Cx50. Positions of loss of function mutations are colored as red and gain of function mutations as yellow. The figure was generated with PyMol and edited with Gimp