Deletion of the cytoplasmatic domain of BP180/collagen XVII causes a phenotype with predominant features of epidermolysis bullosa simplex
Deletion of the cytoplasmatic domain of BP180/collagen XVII causes a phenotype with predominant features of epidermolysis bullosa simplex
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DOI：
10.1046/j.0022-202x.2001.01617.x
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发表时间：
2002-01-01
影响因子：
6.5
通讯作者：
Bruckner-Tuderman, L
中科院分区：
文献类型：
--
作者：
Huber, M;Floeth, M;Bruckner-Tuderman, L
BP180/胶原XVII是一种半囊体跨膜分子，作为细胞表面受体。其基因突变可引起大疱性结缔组织表皮松解症。在这里，我们报告了一个BP180/胶原XVII， COL17A1基因突变的患者，但主要的表型特征是单纯大疱性表皮松解症。出生时，先证者在躯干、面部和手部出现大疱性病变。超微结构上半端粒相当正常，但中间丝与半端粒斑块的附着似乎受损。水疱的形成表现为表皮内和连接处的劈裂。角蛋白抗体、几种半粒染色体蛋白抗体和BP180/胶原XVII的细胞外结构域的免疫荧光染色显示正常，而BP180/胶原XVII细胞内结构域的抗体显示阴性免疫荧光信号。对BP180/collagen XVII cDNA的分析显示，该片段有1172 bp的缺失，对应于该多肽胞内结构域从Ile-18到Asn-407的框内缺失。COL17A1基因的突变分析显示，父系无义突变R1226X，以及从内含子2到内含子15的大量母系基因组缺失，但基础角蛋白基因没有突变。这些发现强调了细胞内BP180/胶原XVII结构域对半粒间质与角蛋白中间丝的相互作用和基底角化细胞的空间稳定性的功能重要性，并为表皮松解-大疱-单纯样表型提供了功能上的解释。此外，数据表明，根据受影响的蛋白结构域的功能，特定基因的缺陷可能导致大疱性表皮松解症的意想不到的表型。
BP180/collagen XVII is a hemidesmosomal transmembrane molecule serving as cell-surface receptor. Mutations in its gene cause junctional epidermolysis bullosa. Here, we report a patient with mutations in the gene for BP180/collagen XVII, COL17A1, but predominant phenotypic features of epidermolysis bullosa simplex. At birth, the proband presented with bullous lesions on the trunk, face, and hands. Utrastructurally, hemidesmosomes were fairly normal, but the attachment of intermediate filaments with the hemidesmosomal plaques appeared to be impaired. Blister formation demonstrated both intra-epidermal and junctional cleavage. Immunofluorescence staining with antibodies to keratins, several hemidesmosomal proteins, and the extracellular domain of BP180/collagen XVII showed normal staining patterns, whereas an antibody against the intracellular domain of BP180/collagen XVII yielded a negative immunofluorescence signal. Analysis of BP180/collagen XVII cDNA revealed a 1172 bp deletion corresponding to an in-frame deletion from Ile-18 to Asn-407 from the intracellular domain of the polypeptide. Mutation analysis of the COL17A1 gene disclosed a paternal nonsense mutation, R1226X, and a large maternal genomic deletion extending from intron 2 to intron 15, but no mutations in basal keratin genes. These findings underline the functional importance of the intracellular BP180/collagen XVII domain for the interaction of hemidesmosomes with keratin intermediate filaments and for the spatial stability of basal keratinocytes, and provide a functional explanation for the epidermolysis-bullosa-simplex-like phenotype. Further, the data demonstrate that defects in a given gene can cause unexpected phenotypes of epidermolysis bullosa categories, depending on the function of the affected protein domain.