Connexinopathies: a structural and functional glimpse.

Isaac E García,Carolina Soto-Riveros,Carlos González,Paula Mujica,Diana Rojas-Gómez,Mauricio A Retamal,Pavel Prado,Oscar Jara,Jorge González-Casanova,Agustín D Martínez,Carolina Flores-Muñoz,Bernardo I Pinto,Amaury Pupo

doi:10.1186/s12860-016-0092-x

Isaac E García, Carolina Soto-Riveros + Show 11 more

Open Access

https://doi.org/10.1186/s12860-016-0092-x

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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.

Highlights

Connexin gap junction channels (GJCs) and hemichannels (HCs) are critical for cellular communication
Most mutations causing connexinopathies generates total or partial loss of GJCs function. It is unclear if the severity of disease correlates with the level of GJCs loss of function
Mutations associated with loss of function GJCs are distributed along the entire protein sequence with no clear pattern of clustering at any segment, which suggest that GJC functionality is very sensitive to minor changes in Cxs protein, and that subtle changes in GJC functionality are sufficient to cause diseases

Summary

Introduction

Connexin gap junction channels (GJCs) and hemichannels (HCs) are critical for cellular communication. Despite Cxs share high homology, there are important differences in the amino acid sequence of the ICL and CT These segments contain motifs for regulatory kinases and cytoskeletal binding proteins [7, 8]. Oligomerization between suited isoforms contributes to the assortment of Cx-based channels; for instances, heteromeric GJCs (HCs constituted by more than one Cxs type) and/or heterotypic channels (two homomeric HCs each made by a different Cxs type). These combinations may produce GJCs with particular functional and regulatory properties. A salt bridge between residues Glu-146 (TM3) and Arg-32 (TM1) in García et al BMC Cell Biology 2016, 17(Suppl 1):

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