Compound heterozygosity for COL7A1 mutations in twins with dystrophic epidermolysis bullosa: a recessive paternal deletion/insertion mutation and a dominant negative maternal glycine substitution result in a severe phenotype.
Compound heterozygosity for COL7A1 mutations in twins with dystrophic epidermolysis bullosa: a recessive paternal deletion/insertion mutation and a dominant negative maternal glycine substitution result in a severe phenotype.
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发表时间：
1996-04
影响因子：
9.8
通讯作者：
A. Christiano;I. Anton‐Lamprecht;S. Amano;U. Ebschner;R. Burgeson;J. Uitto
中科院分区：
文献类型：
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作者：
A. Christiano;I. Anton‐Lamprecht;S. Amano;U. Ebschner;R. Burgeson;J. Uitto
我们以前已经证明了VII型胶原基因（COL 7A 1）和显性（DDEB）和隐性（RDEB）形式的营养不良性大疱性表皮病（DEB）之间的遗传连锁，并随后确定了几个家庭的致病突变。迄今为止鉴定的DDEB突变是COL 7A 1胶原结构域中的甘氨酸取代，而最严重形式的RDEB是由两个等位基因上的提前终止密码子（PTC）突变引起的。在这项研究中，我们进行了突变分析的COL 7A 1基因在双胞胎谁显示了严重的DEB表型。突变分析揭示了在外显子56中的父源2-bp缺失/1-bp插入，命名为5103 CC-->G，其导致移码和下游PTC。对母亲COL 7A 1等位基因的分析揭示了外显子91（G2351 R）的甘氨酸到精氨酸的替换。仔细询问母亲发现，她和她的父亲有脱落的脚趾甲和偶尔愈合不良糜烂的历史，符合轻度DDEB的形式。从双胞胎的成纤维细胞的VII型胶原蛋白的免疫沉淀显示细胞内蛋白质的产生显着减少，与从父系突变等位基因的mRNA转录的急剧减少一致，而大多数的多肽轴承甘氨酸取代似乎是细胞内降解。因此，先证者中的严重RDEB表型是由COL 7A 1中一个甘氨酸取代和一个PTC突变的复合杂合性引起的。
We have previously demonstrated genetic linkage between the type VII collagen gene (COL7A1) and the dominant (DDEB) and recessive (RDEB) forms of dystrophic epidermolysis bullosa (DEB) and have subsequently identified pathogenetic mutations in several families. Mutations in DDEB identified thus far are glycine substitutions in the collagenous domain of COL7A1, while the most severe forms of RDEB result from premature termination codon (PTC) mutations on both alleles. In this study, we performed mutation analysis in the COL7A1 gene in twins who displayed a severe DEB phenotype. Mutational analysis revealed a paternal 2-bp deletion/1-bp insertion in exon 56, designated 5103CC-->G, which results in a frameshift and downstream PTC. Analysis of the maternal COL7A1 allele revealed a glycine-to-arginine substitution in exon 91 (G2351R). Careful questioning of the mother revealed that she and her father had a history of shedding of toenails and occasional poorly healing erosions, consistent with a mild form of DDEB. Immunoprecipitation of type VII collagen from fibroblasts of the twins revealed a marked reduction in intracellular protein production, consistent with the drastic reduction in mRNA transcript from the paternal mutant allele, while the majority of polypeptides bearing the glycine substitution appeared to be degraded intracellularly. Thus, the severe RDEB phenotype in the probands results from compound heterozygosity for one glycine substitution and one PTC mutation in COL7A1.