Missense mutations in GJB2 encoding connexin-26 cause the ectodermal dysplasia keratitis-ichthyosis-deafness syndrome
Missense mutations in GJB2 encoding connexin-26 cause the ectodermal dysplasia keratitis-ichthyosis-deafness syndrome
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DOI：
10.1086/339986
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发表时间：
2002-05-01
影响因子：
9.8
通讯作者：
Russell, L
中科院分区：
文献类型：
--
作者：
Richard, G;Rouan, F;Russell, L
角膜炎-鱼鳞病-耳聋综合征（KID）是一种罕见的外胚层发育不良，其特征为血管性角膜炎、重度感音神经性听力损失（SNHL）和进行性红角化病，这是一种临床三联征，表明多种分层上皮发育和分化失败。在这里，我们提供了令人信服的证据，证明KID是由连接蛋白26基因GJB2的杂合错义突变引起的。在10例KID患者中，我们发现了一个点突变，导致细胞质氨基端或Cx26的第一胞外结构域的保守残基被取代。其中一种突变在6个不相关的散发病例中检测到，并在一个垂直传播的KID家庭中分离出来。这些结果表明存在一种常见的，复发性突变，并建立其常染色体显性性质。Cx26和密切相关的Cx30在表皮、附件和角膜上皮中表现出差异表达，但在病变皮肤中没有显著改变。然而，突变体Cx26在体外不能诱导细胞间偶联，这表明其功能受损。我们的数据揭示了显著的基因型-表型相关性，并表明显性GJB2突变可以干扰一个或多个外胚层上皮的间隙连接系统，从而产生多种表型：非综合征型SNHL，综合征型SNHL合并掌跖角化皮病和KID。在KID中，宿主防御能力的降低和致癌潜力的增加表明，间隙连接的通讯不仅在上皮稳态和分化中起着至关重要的作用，而且在免疫反应和表皮癌变中也起着至关重要的作用。
Keratitis-ichthyosis-deafness syndrome (KID) is a rare ectodermal dysplasia characterized by vascularizing keratitis, profound sensorineural hearing loss (SNHL), and progressive erythrokeratoderma, a clinical triad that indicates a failure in development and differentiation of multiple stratifying epithelia. Here, we provide compelling evidence that KID is caused by heterozygous missense mutations in the connexin-26 gene, GJB2. In each of 10 patients with KID, we identified a point mutation leading to substitution of conserved residues in the cytoplasmic amino terminus or first extracellular domain of Cx26. One of these mutations was detected in six unrelated sporadic case subjects and also segregated in one family with vertical transmission of KID. These results indicate the presence of a common, recurrent mutation and establish its autosomal dominant nature. Cx26 and the closely related Cx30 showed differential expression in epidermal, adnexal, and corneal epithelia but were not significantly altered in lesional skin. However, mutant Cx26 was incapable of inducing intercellular coupling in vitro, which indicates its functional impairment. Our data reveal striking genotype-phenotype correlations and demonstrate that dominant GJB2 mutations can disturb the gap junction system of one or several ectodermal epithelia, thereby producing multiple phenotypes: nonsyndromic SNHL, syndromic SNHL with palmoplantar keratoderma, and KID. Decreased host defense and increased carcinogenic potential in KID illustrate that gap junction communication plays not only a crucial role in epithelial homeostasis and differentiation but also in immune response and epidermal carcinogenesis.