Richard G, Brown N, Smith L E, Terrinoni A, Melino G, Mackie R M, Bale S J, Uitto J
Department of Dermatology and Cutaneous Biology, Jefferson Medical College and Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Hum Genet. 2000 Mar;106(3):321-9. doi: 10.1007/s004390051045.
Intercellular channels in skin are a complex and functionally diverse system formed by at least eight connexins (Cx). Our recent molecular studies implicating Cx defects in inherited skin disorders emphasize the critical role of this signaling pathway in epidermal differentiation. Erythrokeratodermia variabilis (EKV) is an autosomal dominant genodermatosis with a striking phenotype characterized by the independent occurrence of transient localized erythema and hyperkeratosis. The disease maps to 1p34-p35, and recently we identified the causative gene GJB3 encoding Cx31. We have now investigated GJB3 in two families and three sporadic cases with EKV, and report three new heterozygous mutations. In a sporadic case, we detected a mutation leading to substitution of a conserved phenylalanine (F137L) in the third transmembrane domain, which likely interferes with the proper assembly or gating properties of connexons. In another family, all three affected individuals carried two distinct mutations on the same GJB3 allele. However, only a de novo heterozygous missense mutation replacing arginine 42 with proline (R42P) co-segregated with the disease, while a 12 bp deletion predicted to eliminate four amino acid residues in the variable carboxy terminal domain of Cx31 was also found in clinically unaffected relatives but not in 90 unaffected controls. Including the previously published mutations, in toto, five different missense mutations have now been detected in 6 out of 17 families investigated by our laboratory, all of which presumably affect the cytoplasmic amino terminal and transmembrane domains of Cx31. In contrast, two mutations linked to progressive high-tone hearing impairment were located in the second extracellular domain, suggesting that the character and position of Cx mutations determine their phenotypic expression in different tissues. However, the phenotypic spectrum of GJB3 mutations seems not to include progressive symmetric erythrokeratodermia, another dominant genodermatosis with overlapping features, since no mutations were found in six unrelated families tested.
皮肤中的细胞间通道是一个由至少8种连接蛋白（Cx）形成的复杂且功能多样的系统。我们最近的分子研究表明，遗传性皮肤病中存在Cx缺陷，这强调了该信号通路在表皮分化中的关键作用。可变型红斑角化病（EKV）是一种常染色体显性遗传性皮肤病，具有显著的表型，其特征为短暂性局限性红斑和角化过度独立出现。该疾病定位于1p34 - p35，最近我们鉴定出致病基因GJB3，它编码Cx31。我们现在对两个家族和三例散发的EKV病例中的GJB3进行了研究，并报告了三个新的杂合突变。在一例散发病例中，我们检测到一个突变，该突变导致第三个跨膜结构域中一个保守的苯丙氨酸被替代（F137L），这可能会干扰连接子的正确组装或门控特性。在另一个家族中，所有三名受影响个体在同一个GJB3等位基因上携带两个不同的突变。然而，只有一个新生的杂合错义突变，即用脯氨酸替代精氨酸42（R42P）与疾病共分离，而在临床未受影响的亲属中也发现了一个预计会消除Cx31可变羧基末端结构域中四个氨基酸残基的12 bp缺失，但在90名未受影响的对照中未发现。包括之前发表的突变，在我们实验室研究的17个家族中的6个家族中，总共检测到了五种不同的错义突变，所有这些突变可能都影响Cx31的细胞质氨基末端和跨膜结构域。相比之下，与进行性高调听力障碍相关的两个突变位于第二个细胞外结构域，这表明Cx突变的特征和位置决定了它们在不同组织中的表型表达。然而，GJB3突变的表型谱似乎不包括进行性对称性红斑角化病，这是另一种具有重叠特征的显性遗传性皮肤病，因为在测试的六个无关家族中未发现突变。
