Department of Physiology and Pharmacology, University of Western Ontario, London, ON N6A 5C1, Canada.
Int J Mol Sci. 2021 Jul 22;22(15):7832. doi: 10.3390/ijms22157832.
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.
二十一个人类基因编码连接蛋白，这是一类同源蛋白，形成间隙连接 (GJ) 通道，介导直接的细胞间通讯，以协调组织/器官的活动。超过一半的连接蛋白基因中的遗传变异与几十种不同的孟德尔遗传性疾病有关。随着 DNA 测序技术的快速发展，不仅在有疾病的家族和个体中，而且在没有明显与孟德尔遗传性疾病相关的一般人群中，也发现了更多的变异。然而，要对新鉴定的连接蛋白变异的致病性进行分类仍然具有挑战性。在这里，我们分析了四个与疾病相关的α连接蛋白基因编码区中与疾病和基因组聚集数据库（gnomAD，作为一般人群的代表）相关的变异。我们发现，最丰富和位置敏感的错义变异在疾病和 gnomAD 相关变异之间表现出明显的结构域分布偏好。将错义变异绘制在拓扑和结构模型上表明，疾病相关的错义变异在结构稳定/解析的结构域中高度富集，特别是在孔衬结构域中，而 gnomAD 相关的错义变异在结构不稳定/未解析的结构域中高度富集，特别是在羧基末端。此外，疾病相关的变异倾向于高度保守的残基，并且这些位置显示出进化共变，而 gnomAD 相关的错义变异可能位于不太保守的残基位置，并且在没有共变的位置。总之，所揭示的疾病和 gnomAD 相关的错义变异的分布模式进一步加深了我们对 GJ 结构-生物学功能关系的理解，这对于对新鉴定的连接蛋白变异的致病性进行分类是有价值的。
