N-terminal deletion in a desmosomal cadherin causes the autosomal dominant skin disease striate palmoplantar keratoderma
N-terminal deletion in a desmosomal cadherin causes the autosomal dominant skin disease striate palmoplantar keratoderma
复制标题
DOI：
10.1093/hmg/8.6.971
复制
发表时间：
1999-06-01
影响因子：
3.5
通讯作者：
Buxton, RS
中科院分区：
文献类型：
--
作者：
Rickman, L;Simrak, D;Buxton, RS
钙粘附素的N端胞外结构域，钙依赖的细胞黏附分子，已被X射线结晶学证明参与两种类型的相互作用：侧链二聚体和粘附性二聚体，在这里，我们描述了存在于桥粒细胞连接中的第一个人类钙粘附素突变，它移除了这个高度保守的第一个胞外结构域的一部分。这种突变发生在编码桥粒芯糖蛋白(DSG1)的DSG1基因中，导致第一个钙粘附素重复序列的第一条和大部分第二条β链以及第一个钙结合位点的部分缺失，预计会影响链二聚体的形成。它导致一种显性遗传性皮肤病，纹状掌底角化病(SPPK)，定位于18q12.1号染色体，患者的手掌和脚掌上有明显的角化带。在一个三代荷兰SPPK家系中，我们发现DSG1基因内含子2的3‘剪接受体位点G-->；A与疾病表型分离，导致外显子2到外显子4的异常剪接，导致外显子3编码部分前序列、成熟的蛋白裂解位点和部分第一胞外域的缺失。这种突变强调了这部分分子对钙粘素功能的重要性，以及DSG1蛋白和桥粒在表皮功能中的重要性。
The N-terminal extracellular domain of the cadherins, calcium-dependent cell adhesion molecules, has been shown by X-ray crystallography to be involved in two types of interaction: lateral strand dimers and adhesive dimers, Here we describe the first human mutation in a cadherin present in desmosome cell junctions that removes a portion of this highly conserved first extracellular domain. The mutation, in the DSG1 gene coding for a desmoglein (Dsg1), results in the deletion of the first and much of the second beta-strand of the first cadherin repeat and part of the first Ca2+-binding site, and would be expected to compromise strand dimer formation. It causes a dominantly inherited skin disease, striate palmoplantar keratoderma (SPPK), mapping to chromosome 18q12.1, in which affected individuals have marked hyperkeratotic bands on the palms and soles. In a three generation Dutch family with SPPK, we have found a G-->A transition in the 3' splice acceptor site of intron 2 of the DSG1 gene which segregated with the disease phenotype, This causes aberrant splicing of exon 2 to exon 4, which are in-frame, with the consequent removal of exon 3 encoding part of the prosequence, the mature protein cleavage site and part of the first extracellular domain. This mutation emphasizes the importance of this part of the molecule for cadherin function, and of the Dsg1 protein and hence desmosomes in epidermal function.