Molecular mechanisms of phenotypic variability in junctional epidermolysis bullosa
Molecular mechanisms of phenotypic variability in junctional epidermolysis bullosa
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DOI：
10.1136/jmg.2010.086751
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发表时间：
2011-07-01
影响因子：
4
通讯作者：
Bruckner-Tuderman, Leena
中科院分区：
文献类型：
--
作者：
Kiritsi, Dimitra;Kern, Johannes S.;Bruckner-Tuderman, Leena
背景大疱性交界性表皮松解症(JEIB)是一组遗传性皮肤脆性疾病，尽管所有的类型都以创伤引起的皮肤起泡和真皮-表皮交界区的组织分离为特征，但与多种表型相关。一个亚群，称为JEB-OTHER，与编码XVII胶原蛋白的COL17A1基因突变有关，或者，更罕见的是，与层粘连蛋白332基因LAMA3、LAMB3或LAMC2突变有关。本研究的目的是对具有COL17A1突变的JEB-Other患者进行全面的基因分型和表型分析，阐明不同皮肤表型的发病机制。方法和结果对43例JEB-Other患者的COL17A1突变及其临床和细胞学后果进行了系统分析。应用细胞培养、RT-PCR和蛋白质生物化学来评估剪接位点突变的影响--即合成的转录本和多肽的性质和数量以及它们与表型结果的关系。发现了34个不同的COL17A1突变，其中12个是新的。MRNA和蛋白质分析显示，只有大约12-14%的生理性XVII胶原蛋白水平的患者有轻微的皮肤损害和较长的寿命。结论与完全无效的表型相比，JEB皮肤中微量的XVII胶原蛋白的存在与轻度表型相关。这些数据对JEB分子疗法的设计具有重要意义，因为它们表明，已经很低程度的XVII胶原蛋白修复将改善皮肤稳定性并缓解症状。
Background Junctional epidermolysis bullosa (JEB), a group of hereditary skin fragility disorders, is associated with a wide variety of phenotypes, although all forms are characterised by trauma induced skin blistering and tissue separation at the dermal-epidermal junction zone. A subgroup, coined JEB-other, is associated with mutations in the COL17A1 gene encoding collagen XVII or, more rarely, with mutations in the laminin 332 genes LAMA3, LAMB3, or LAMC2. The objective of this study is comprehensive genotype-phenotype analysis in JEB-other patients with COL17A1 mutations and elucidation of disease mechanisms underlying different skin phenotypes.Methods and results COL17A1 mutations and their clinical and cellular consequences were systematically analysed in 43 patients with JEB-other. Cell culture, RT-PCR, and protein biochemistry were applied to assess the effects of splice site mutations-that is, the nature and amounts of transcripts and polypeptides synthesised and their association with the phenotypic outcome. 34 distinct COL17A1 mutations were disclosed, 12 of them novel. mRNA and protein analyses demonstrated that patients with only about 12-14% of the physiological collagen XVII levels had mild cutaneous involvement and a long life span.Conclusions In contrast to complete null phenotypes, presence of minor amounts of collagen XVII protein in JEB skin is associated with mild phenotypic manifestations. The data have significant implications for design of molecular therapies for JEB, since they suggest that already a low extent of collagen XVII restoration will improve skin stability and alleviate symptoms.