Specific inhibition of nonsense-mediated mRNA decay components, SMG-1 or Upf1, rescues the phenotype of Ullrich disease fibroblasts
Specific inhibition of nonsense-mediated mRNA decay components, SMG-1 or Upf1, rescues the phenotype of Ullrich disease fibroblasts
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DOI：
10.1016/j.ymthe.2006.04.011
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发表时间：
2006-09-01
影响因子：
12.4
通讯作者：
Ohno, Shigeo
中科院分区：
文献类型：
--
作者：
Usuki, Fusako;Yamashita, Akio;Ohno, Shigeo
无意义介导的信使核糖核酸衰变(NMD)是一种降解含有提前翻译终止密码子(PTCs)的异常mRNAs的信使核糖核酸质量控制机制。NMD的必需蛋白质包括蛋白激酶SMG-1和具有RNA解旋酶活性的SMG-1底物UPF1。在这项研究中，我们评估了siRNA介导的SMG-1或UPF1基因敲除对Ullrich病(一种常染色体隐性遗传性先天性肌营养不良症)表型的影响。这名患者的研究显示了一种纯合子移码突变，其编码的是一种截短但部分有功能的蛋白质。患者的成纤维细胞显示三螺旋VI型胶原蛋白几乎完全丧失，由于VI型胶原α2蛋白的严重缺陷，细胞外基质(ECM)中存在功能缺陷。我们已经证明，siRNA介导的SMG-1或UPF1的敲除导致突变的三螺旋VI型胶原上调，导致部分功能的ECM的形成。我们认为，抑制NMD可能是治疗某些由NMD加重的人类遗传病的有效方法。
Nonsense-mediated mRNA decay (NMD) is an mRNA quality-control mechanism that degrades aberrant mRNAs containing premature translation termination codons (PTCs). The essential proteins for NMD include SMG-1, a protein kinase, and Upf1, a substrate of SMG-1 with RNA helicase activity. In this study, we evaluated the effects of NMD inhibition by siRNA-mediated knockdown of SMG-1 or Upf1 on the phenotype of Ullrich disease, an autosomal recessive congenital muscular dystrophy. The patient studied showed a homozygous frameshift mutation with a PTC in the collagen VI alpha 2 gene, which encodes a truncated but partially functional protein. The patient's fibroblasts showed a nearly complete loss of the triple-helical collagen VI protein and functional defects in the extracellular matrix (ECM) due to the crucial deficiency of the collagen VI alpha 2 protein. We have shown that siRNA-mediated knockdown of SMG-1 or Upf1 causes the upregulation of the mutant triple-helical collagen VI, resulting in the formation of partially functional ECM. We suggest that the inhibition of NMD may be useful as a therapeutic approach to treat some human genetic diseases exacerbated by NMD.