Natural Gene Therapy May Occur in All Patients with Generalized Non-Herlitz Junctional Epidermolysis Bullosa with COL17A1 Mutations
Natural Gene Therapy May Occur in All Patients with Generalized Non-Herlitz Junctional Epidermolysis Bullosa with COL17A1 Mutations
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DOI：
10.1038/jid.2011.477
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发表时间：
2012-05-01
影响因子：
6.5
通讯作者：
Jonkman, Marcel F.
中科院分区：
文献类型：
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作者：
Pasmooij, Anna M. G.;Nijenhuis, Miranda;Jonkman, Marcel F.
XVI型胶原基因(COL17A1)突变导致水疱性疾病非Herlitz交界性大疱性表皮松解症(Jeb-NH)。在荷兰由COL17A1突变引起的14例Jeb-NH患者中，发现了突变嵌合体的发生率，也被称为“自然基因疗法”。在4名嵌合型Jeb-NH患者中，发现了5种不同的体内逆转，均纠正了外显子30上的胚系COL17A1突变c.2237delG。纠正DNA改变涉及各种各样的体细胞突变，其中插入突变(c.2228-101_2263+70delins 15)和2,165个碱基对的大缺失(c.2227+153_2336-318del)在回复突变嵌合体患者中以前没有观察到。我们的结果表明，不存在对修复机制的偏好。此外，在10例全身性Jeb-NH患者中，有6例在DNA水平上证实了回复嵌合体。此外，其他四名全身性JEB-NH患者的照片材料和临床病史表明，每个患者都有逆转的皮肤斑块。相反，在4例局限化的JEb-NH患者中未检测到回复嵌合体。这么多，如果不是所有的全身性JEB-NH COL17A1患者都有回复补丁的事实，为使用患者自己的自然校正细胞作为来源的细胞治疗提供了机会。
Mutations in the type XVII collagen gene (COL17A1) result in the blistering disorder non-Herlitz junctional epidermolysis bullosa (JEB-nH). The incidence of revertant mosaicism, also called "natural gene therapy", was identified in a cohort of 14 patients with JEB-nH caused by COL17A1 mutations in the Netherlands. Five different in vivo reversions, all correcting the germ-line COL17A1 mutation c.2237delG in exon 30, were found in four mosaic JEB-nH patients. The correcting DNA changes involved a wide variety of somatic mutations, from which an indel mutation (c.2228-101_2263 + 70delins15) and a large deletion of 2,165 base pairs (c.2227 + 153_2336-318del) have not been previously observed in patients with revertant mosaicism. Our results show that there is no preference for a repair mechanism. Moreover, revertant mosaicism was confirmed on a DNA level in 6 out of 10 generalized JEB-nH patients. Further, photo-material and clinical history of the other four generalized JEB-nH patients demonstrated that each patient has revertant skin patches. In contrast, revertant mosaicism was not detected in the four localized JEB-nH patients. The fact that so many, if not all, generalized JEB-nH COL17A1 patients have revertant patches offers opportunities for cell therapies in which the patient's own naturally corrected cells are used as a source.