Splicing modulation of integrin β4 pre-mRNA carrying a branch point mutation underlies epidermolysis bullosa with pyloric atresia undergoing spontaneous amelioration with ageing
Splicing modulation of integrin β4 pre-mRNA carrying a branch point mutation underlies epidermolysis bullosa with pyloric atresia undergoing spontaneous amelioration with ageing
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DOI：
10.1093/hmg/8.11.2097
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发表时间：
1999-10-01
影响因子：
3.5
通讯作者：
Meneguzzi, G
中科院分区：
文献类型：
--
作者：
Chavanas, S;Gache, Y;Meneguzzi, G
据报道，在几例伴有幽门闭锁的大疱性表皮病（PA-JEB，一种常染色体隐性皮肤病，特征为上皮细胞广泛脱粘）中，随着年龄的增长，一般情况会有所改善。在一例从重度改善为轻度PA-JEB的患者中，对整合素β 4基因（IGTB 4）突变的搜索检测到新碱基取代3986- 19 T-->的杂合性内含子30供体剪接位点3802+1G →>A点突变。mRNA分析表明，内含子30供体剪接位点3802+1G →>A点突变阻止了β 4前体mRNA的正常剪接。功能性剪接可以通过将先证者的角质形成细胞接种到辐射的成纤维细胞的饲养细胞中而在体外恢复。对用含有内含子31的IGTB 4小基因转染的野生型角质形成细胞中的mRNA的研究，所述内含子31具有或不具有突变3986- 19 T-->A，证实了PA-JEB中内含子突变的致病作用，并强调了饲养细胞对突变的β 4前mRNA的成熟过程的影响，我们的研究结果表明，在β 4 mRNA水平整体下降的背景下，异常β 4前体mRNA中合法剪接位点的激活是该病症短暂严重性的基础，该结果还指出上皮细胞和基质细胞之间的相互作用在调节整合素受体表达中可能具有相关性。
A general improvement with ageing has been reported in a few cases of epidermolysis bullosa with pyloric atresia (PA-JEB), an autosomal recessive skin disease characterized by extensive disadhesion of epithelia, In a patient who improved from severe to mild PA-JEB, a search for mutations in the integrin beta 4 gene (IGTB4) detected heterozygosity for a novel base substitution 3986-19T-->A in the putative branchpoint sequence of intron 31, and a point mutation 3802+1G-->A in the donor splice site of intron 30 previously associated with severe PA-JEB, Analysis of mRNA showed that the intronic mutation prevents legitimate splicing of the beta 4 pre-mRNA. Functional splicing can be restored in vitro by seeding the proband's keratinocytes an feeders of irradiated fibroblasts, Study of mRNA in wild-type keratinocytes transfected with IGTB4 minigenes containing intron 31 with or without mutation 3986-19T-->A, confirmed the causative role of the intronic mutation in PA-JEB, and highlighted the influence of feeders on the maturation process of the mutated beta 4 pre-mRNA, Our results show that in a context of overall reduction of the beta 4 mRNA levels, activation of the legitimate splice site in the aberrant beta 4 pre-mRNA underlies the transient severity of the condition, The results also point to the relevance which the interaction between epithelial and stromal cells may have in modulating expression of integrin receptors.