Structural and Functional Diversity of Connexin Genes in the Mouse and Human Genome

Abstract

Gap junctions are clustered channels between contacting cells through which direct intercellular communication via diffusion of ions and metabolites can occur. Two hemichannels, each built up of six connexin protein subunits in the plasma membrane of adjacent cells, can dock to each other to form conduits between cells. We have recently screened mouse and human genomic data bases and have found 19 connexin (Cx) genes in the mouse genome and 20 connexin genes in the human genome. One mouse connexin gene and two human connexin genes do not appear to have orthologs in the other genome. With three exceptions, the characterized connexin genes comprise two exons whereby the complete reading frame is located on the second exon. Targeted ablation of eleven mouse connexin genes revealed basic insights into the functional diversity of the connexin gene family. In addition, the phenotypes of human genetic disorders caused by mutated connexin genes further complement our understanding of connexin functions in the human organism. In this review we compare currently identified connexin genes in both the mouse and human genome and discuss the functions of gap junctions deduced from targeted mouse mutants and human genetic disorders.

Loss-of-function GJA12/Connexin47 mutations cause Pelizaeus–Merzbacher-like disease

“…These would add 6 or 12 (hCx59, NM_030772) or 11 (mCx29, NM_080450) amino acids to the N-terminus. Given the highly conserved N-termini of connexins (Willecke et al 2002), we conclude that all of these potential upstream alternative ATGs are unlikely to be translation initiation codons, including the one for human Cx47.…”

“…The upstream ATG of Cx47, however, would encode an N-terminus with 24 amino acids, which is inconsistent with all other known connexins. Besides Cx47, the other 19 cloned human connexins are predicted to have a 21-23 amino acid N-terminus comparable to the one encoded by the downstream ATG of GJA12/ Cx47 (Willecke et al 2002). We also examined over 70 different human, dog, cow, mouse, rat, hamster, chicken, frog, and zebrafish connexin sequences, nearly all derived from mRNA, contained at least 9 bases of the 5′ UTR, and found only two other examples of one or more in frame potential upstream start codons.…”

“…Two hemichannels (or connexons) on apposing cell membranes form the channel. Hemichannels are composed of six connexins -a family of highly conserved integral membrane proteins that are usually named according to their predicted molecular mass (Willecke et al 2002). Individual hemichannels can be composed of one (homomeric) or more than one (heteromeric) type of connexin.…”

Effect of the tumor promoter phenobarbital on the pattern of global gene expression in liver of connexin32‐wild‐type and connexin32‐deficient mice

“…Cx32ko mice show no severe phenotype but only subtle changes such as a decrease in glucose mobilization from glycogen upon adrenal stimulation of the liver 12,23,24 and increased 5-bromodeoxyuridine-labeling indices, indicating enhanced hepatocyte proliferation. 5,25 Because there is no concomitant increase in liver weight in Cx32ko mice, hepatocyte death rates must be also upregulated, resulting in tissue homeostasis at an elevated level of cell turnover.…”

Expression of a gap junction protein, connexin43, in a large panel of human gliomas: new insights

“…Their structural proteins, connexins (Cx), are members of a multigene family (21 members in human) presenting a specific tissue distribution 3. In brain, 12 members of this multigene family are expressed 4 and some of them are considered as differentiation markers of cell types in which they are expressed (Cx32 in oligodendrocytes, Cx36 in neurons, and Cx43 and Cx30 in astrocytes) 5.…”