A ‐96C→T mutation in the promoter of the collagen type VII gene (COL7A1) abolishing transcription in a patient affected by recessive dystrophic epidermolysis bullosa
A ‐96C→T mutation in the promoter of the collagen type VII gene (COL7A1) abolishing transcription in a patient affected by recessive dystrophic epidermolysis bullosa
复制标题
VII 型胶原蛋白基因 (COL7A1) 启动子中的 ‐96C→T 突变导致隐性营养不良性大疱性表皮松解症患者的转录消失
作者：
R. Gardella;S. Barlati;N. Zoppi;G. Tadini;M. Colombi
遗传性营养不良大疱性表皮松解症（DEB）是指一组由胶原蛋白VII型基因（COL7A1）突变引起的临床异质性皮肤起疱性疾病。我们报道了在一名患有最严重形式的DEB的患者中发现的两个新突变，隐性Hallopeau - Siemens变体（HS - RDEB）： R1978X无意义突变，在第72外显子中，以及启动子区域的- 96C→T转变。对患者皮肤成纤维细胞转录本的等位基因特异性分析显示，‐96C→T突变与胶原型VII (COLVII) mRNA的缺失有关。该突变是COL7A1启动子中首次发现的突变，位于Sp1基序中，位于核苷酸- 96和- 91之间。凝胶位移分析表明，‐96/‐91序列是一个功能性Sp1位点，并且‐96C→T过渡抑制了转录因子的结合。这些数据表明‐96/‐91序列是一个至关重要的Sp1位点，其完整性是COL7A1表达所必需的。- 96C→T null突变和R1978X突变的复合杂合性导致皮肤水平COLVII缺失和HS - RDEB患者的严重表型。2000年16点275分。©2000 Wiley‐Liss, Inc。
Hereditary dystrophic epidermolysis bullosa (DEB) refers to a group of clinically heterogeneous skin blistering diseases due to mutations in the collagen type VII gene (COL7A1). We report two novel mutations found in a patient affected by the most severe form of DEB, the recessive Hallopeau‐Siemens variant (HS‐RDEB): the R1978X nonsense mutation, in exon 72, and the ‐96C→T transition, in the promoter region. The allele specific analysis of the transcripts from skin fibroblasts of the patient showed that the ‐96C→T mutation is associated to the absence of collagen type VII (COLVII) mRNA. This mutation, the first one ever identified in the promoter of COL7A1, falls in an Sp1 motif, localized between nucleotides ‐96 and ‐91. Gel shift analysis indicated that the ‐96/‐91 sequence is a functional Sp1 site and that the ‐96C→T transition inhibits the binding of the trascription factor. These data indicate that the ‐96/‐91 sequence is a crucial Sp1 site whose integrity is necessary for COL7A1 expression. The compound heterozygosity for the ‐96C→T null mutation and for the R1978X mutation leads to the absence of COLVII at skin level and to the severe phenotype of the HS‐RDEB patient. Hum Mutat 16:275, 2000. © 2000 Wiley‐Liss, Inc.