Natural Gene Therapy in Dystrophic Epidermolysis Bullosa
Natural Gene Therapy in Dystrophic Epidermolysis Bullosa
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DOI：
10.1001/archdermatol.2011.298
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发表时间：
2012-02-01
影响因子：
--
通讯作者：
Pasmooij, Anna M. G.
中科院分区：
文献类型：
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作者：
van den Akker, Peter C.;Nijenhuis, Miranda;Pasmooij, Anna M. G.
背景：营养不良性大疱性表皮松解症是一种由 VII 型胶原基因 COL7A1 突变引起的遗传性水疱性疾病。在回复嵌合体中，种系突变通过体细胞事件纠正，导致嵌合病分布。这种“自然基因疗法”现象早已在其他形式的大疱性表皮松解症中得到认识，但最近才在营养不良性大疱性表皮松解症中得到认识。观察：我们描述了一名患有隐性营养不良性大疱性表皮松解症的 21 岁男性，携带纯合子 c.6508C>T (p.Gln2170X) 无义突变，他报告说他脖子上有一块未受影响的皮肤斑块，但从未出现过水泡。 80% 未受影响的皮肤活检组织的免疫荧光 VII 型胶原染色结果正常；然而，在受影响的皮肤中，它显着减少。在未受影响的皮肤中，体细胞核苷酸取代 c.6510G>T 将无义密码子恢复为酪氨酸 (p.Gln21.70Tyr)，从而恢复功能性蛋白质的产生。结论：恢复镶嵌现象在隐性营养不良性大疱性表皮松解症中被认为是罕见的。然而，这种情况可能比之前预期的更常见，因为我们的患者是第三位在短时间内发现回复嵌合体的患者。纠正机制与之前报道的不同。因此，对患有隐性营养不良性大疱性表皮松解症的患者进行系统检查可能会发现更多患有回复性斑块的患者。这很重要，因为自然基因治疗现象可能为回复细胞治疗提供机会。
Background: Dystrophic epidermolysis bullosa is a genetic blistering disorder caused by mutations in the type VII collagen gene, COL7A1. In revertant mosaicism, germline mutations are corrected by somatic events resulting in a mosaic disease distribution. This "natural gene therapy" phenomenon long has been recognized in other forms of epidermolysis bullosa but only recently in dystrophic epidermolysis bullosa.Observations: We describe a 21-year-old man with recessive dystrophic epidermolysis bullosa carrying the homozygous c.6508C>T (p.Gln2170X) nonsense mutation who reported an unaffected skin patch on his neck where blisters never had occurred. Immunofluorescent type VII collagen staining was normal in 80% of the unaffected skin biopsy; however, it was strongly reduced in the affected skin. In the unaffected skin, the somatic nucleotide substitution c.6510G>T reverted line nonsense codon to tyrosine (p.Gln21.70Tyr), thereby restoring functional protein production.Conclusions: Revertant mosaicism is considered rare in recessive dystrophic epidermolysis bullosa. However, it might be more common than previously anticipated because our patient is the third in whom revertant mosaicism was identified in a short period of time. The correction mechanism is different than that previously reported. Systematic examination of patients with recessive dystrophic epidermolysis bullosa, therefore, will likely reveal more patients with revertant patches. This is important because the natural gene therapy phenomenon may provide opportunities for revertant cell therapy.