Richard G, Smith L E, Bailey R A, Itin P, Hohl D, Epstein E H, DiGiovanna J J, Compton J G, Bale S J
Genetic Studies Section, Laboratory of Skin Biology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Nat Genet. 1998 Dec;20(4):366-9. doi: 10.1038/3840.
Erythrokeratodermia variabilis (EKV, OMIM 133200) is an autosomal dominant genodermatosis with considerable intra- and interfamilial variability. It has a disfiguring phenotype characterized by the independent occurrence of two morphologic features: transient figurate red patches and localized or generalized hyperkeratosis. Both features can be triggered by external factors such as trauma to the skin. After initial linkage to the RH locus on 1p, EKV was mapped to an interval of 2.6 cM on 1p34-p35, and a candidate gene (GJA4) encoding the gap junction protein alpha-4 (connexin 31, Cx31) was excluded by sequence analysis. Evidence in mouse suggesting that the EKV region harbours a cluster of epidermally expressed connexin genes led us to characterize the human homologues of GJB3 (encoding Cx31) and GJB5 (encoding Cx31.1). GJB3, GJB5 and GJA4 were localized to a 1.1-Mb YAC in the candidate interval. We detected heterozygous missense mutations in GJB3 in four EKV families leading to substitution of a conserved glycine by charged residues (G12R and G12D), or change of a cysteine (C86S). These mutations are predicted to interfere with normal Cx31 structure and function, possibly due to a dominant inhibitory effect. Our results implicate Cx31 in the pathogenesis of EKV, and provide evidence that intercellular communication mediated by Cx31 is crucial for epidermal differentiation and response to external factors.
可变型红斑角化病(EKV,OMIM 133200)是一种常染色体显性遗传性皮肤病,在家族内和家族间存在显著的变异性。它具有毁容性表型,其特征是两种形态学特征独立出现:短暂性图形红斑和局限性或全身性角化过度。这两种特征均可由皮肤创伤等外部因素触发。在最初将EKV与1p上的RH基因座连锁后,EKV被定位到1p34 - p35上2.6 cM的区间,并且通过序列分析排除了编码缝隙连接蛋白α - 4(连接蛋白31,Cx31)的候选基因(GJA4)。小鼠实验证据表明EKV区域含有一组表皮表达的连接蛋白基因,这促使我们对GJB3(编码Cx31)和GJB5(编码Cx31.1)的人类同源物进行特征分析。GJB3、GJB5和GJA4定位于候选区间内一个1.1 - Mb的酵母人工染色体(YAC)上。我们在四个EKV家族的GJB3中检测到杂合错义突变,这些突变导致保守的甘氨酸被带电荷的残基取代(G12R和G12D),或一个半胱氨酸发生改变(C86S)。这些突变预计会干扰正常的Cx31结构和功能,可能是由于显性抑制作用。我们的结果表明Cx31参与了EKV的发病机制,并提供证据表明由Cx31介导的细胞间通讯对于表皮分化和对外部因素的反应至关重要。