Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma
Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma
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DOI：
10.1093/hmg/9.18.2761
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发表时间：
2000-11-01
影响因子：
3.5
通讯作者：
Kelsell, DP
中科院分区：
文献类型：
--
作者：
Norgett, EE;Hatsell, SJ;Kelsell, DP
桥粒是主要的细胞粘附连接，在表皮和心脏组织中特别突出，并且对于细胞的刚性和强度是重要的。桥粒由几种蛋白质组成，其中桥粒斑蛋白是最丰富的。在这里，我们描述了第一个隐性的人类突变，7901delG，在桥粒斑蛋白基因，导致广泛的条纹角化病，特别是影响掌跖表皮，羊毛状头发和扩张性左心室心肌病。许多患有这种综合征的患者在青少年时期患有心力衰竭，导致早期发病，来自厄瓜多尔的三个家庭的所有受影响成员都是这种突变的纯合子，这种突变产生过早的终止密码子，导致截短的桥粒斑蛋白缺失尾部区域的C结构域。皮肤的组织学显示在角质形成细胞粘附的罕见位点处有大的细胞间隙和桥粒聚集。来自患者的皮肤的免疫组织化学显示在基底上角质形成细胞中角蛋白的核周定位，表明中间丝网络塌陷。本研究证明了桥粒斑蛋白在中间丝与桥粒的附着中的重要性，与在早期发育中死亡的无桥粒斑蛋白小鼠相反，由于人类中的纯合7901delG突变而导致的截短蛋白不是胚胎致死的。这表明桥粒斑蛋白的尾部结构域在发育过程中不需要建立组织结构。
Desmosomes are major cell adhesion junctions, particularly prominent in the epidermis and cardiac tissue and are important for the rigidity and strength of the cells, The desmosome consists of several proteins, of which desmoplakin is the most abundant. Here, we describe the first recessive human mutation, 7901delG, in the desmoplakin gene which causes a generalized striate keratoderma particularly affecting the palmoplantar epidermis, woolly hair and a dilated left ventricular cardiomyopathy. A number of the patients with this syndromic disorder suffer heart failure in their teenage years, resulting in early morbidity, AII tested affected members of three families from Ecuador were homozygous for this mutation which produces a premature stop codon leading to a truncated desmoplakin protein missing the C domain of the tail region. Histology of the skin revealed large intercellular spaces and clustering of desmosomes at the infrequent sites of keratinocyte adhesion, Immunohistochemistry of skin from the patients showed a perinuclear localization of keratin in suprabasal keratinocytes, suggesting a collapsed intermediate filament network, This study demonstrates the importance of desmoplakin in the attachment of intermediate filaments to the desmosome, In contrast to null Desmoplakin mice which die in early development, the truncated protein due to the homozygous 7901delG mutation in humans is not embryonic lethal. This suggests that the tail domain of desmoplakin is not required for establishing tissue architecture during development.