Abstract
Twenty-one human genes encode connexins, a family of homologous proteins making gap junction (GJ) channels, which mediate direct intercellular communication to synchronize tissue/organ activities. Genetic variants in more than half of the connexin genes are associated with dozens of different Mendelian inherited diseases. With rapid advances in DNA sequencing technology, more variants are being identified not only in families and individuals with diseases but also in people in the general population without any apparent linkage to Mendelian inherited diseases. Nevertheless, it remains challenging to classify the pathogenicity of a newly identified connexin variant. Here, we analyzed the disease- and Genome Aggregation Database (gnomAD, as a proxy of the general population)-linked variants in the coding region of the four disease-linked α connexin genes. We found that the most abundant and position-sensitive missense variants showed distinct domain distribution preference between disease- and gnomAD-linked variants. Plotting missense variants on topological and structural models revealed that disease-linked missense variants are highly enriched on the structurally stable/resolved domains, especially the pore-lining domains, while the gnomAD-linked missense variants are highly enriched in the structurally unstable/unresolved domains, especially the carboxyl terminus. In addition, disease-linked variants tend to be on highly conserved residues and those positions show evolutionary co-variation, while the gnomAD-linked missense variants are likely on less conserved residue positions and on positions without co-variation. Collectively, the revealed distribution patterns of disease- and gnomAD-linked missense variants further our understanding of the GJ structure–biological function relationship, which is valuable for classifying the pathogenicity of newly identified connexin variants.
Highlights
Gap junction (GJ) channels mediate direct intercellular communication to synchronize tissue/organ activities electrically and metabolically
We analyzed the domain distribution of the most prevalent and position-sensitive missense variants in four α connexins (Cx43, Cx46, Cx40, and Cx50), including those documented to associate with inherited diseases [24,25,26,27,28] and those found in the reference genome/exome database, Genome Aggregation Database (gnomAD) [13,14]
Further dividing the structure-resolved domains into pore and non-pore domains and the structureunresolved domains into cytoplasmic loop (CL) and carboxyl terminus (CT) domains, we found that disease-linked missense variants showed a higher distribution within the pore domain and lower distribution within the CT domain, and reciprocal to these observations, gnomAD-linked missense variants displayed lower distribution within the pore domain and higher probability within the CT domain
Summary
Gap junction (GJ) channels mediate direct intercellular communication to synchronize tissue/organ activities electrically and metabolically. A GJ channel is formed by proper docking of two hemichannels ( known as connexons), and each hemichannel is a hexamer of connexin molecules. Twenty-one genes in the human genome encode connexin molecules, which could be further classified into five groups according to their sequence similarities: α (seven connexins), β (seven connexins), γ (three connexins), δ (three connexins), and ε (one connexin). Every connexin shows a unique tissue distribution pattern, and every cell often expresses more than one type of connexin [1,2]. GJs in cells from the same or different tissues could be homomeric homotypic, homomeric heterotypic, and/or heteromeric heterotypic GJs. Functionally, GJs mediate rapid electrical signals and/or allow the permeation of nutrients, signaling molecules, and metabolic wastes with molecular weights of less than 1 kilodalton [1]
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