Usuki Fusako, Yamashita Akio, Kashima Isao, Higuchi Itsuro, Osame Mitsuhiro, Ohno Shigeo
Department of Clinical Medicine, National Institute for Minamata Disease, 4058-18 Hama, Minamata 867-0008, Japan.
Mol Ther. 2006 Sep;14(3):351-60. doi: 10.1016/j.ymthe.2006.04.011. Epub 2006 Jun 27.
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 alpha2 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 alpha2 protein. We have shown that siRNA-mediated knockdown of SMG-1 or Upf1 causes the up-regulation 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.
无义介导的mRNA衰变（NMD）是一种mRNA质量控制机制，可降解含有提前翻译终止密码子（PTC）的异常mRNA。NMD的必需蛋白包括蛋白激酶SMG-1和具有RNA解旋酶活性的SMG-1底物Upf1。在本研究中，我们评估了通过小干扰RNA（siRNA）介导的SMG-1或Upf1敲低抑制NMD对常染色体隐性先天性肌营养不良——乌尔里希病表型的影响。所研究的患者在编码截短但部分有功能的蛋白质的胶原蛋白VIα2基因中出现了带有PTC的纯合移码突变。患者的成纤维细胞显示三螺旋胶原蛋白VI蛋白几乎完全缺失，并且由于胶原蛋白VIα2蛋白的关键缺陷，细胞外基质（ECM）存在功能缺陷。我们已经表明，siRNA介导的SMG-1或Upf1敲低会导致突变的三螺旋胶原蛋白VI上调，从而形成部分有功能的ECM。我们认为，抑制NMD可能作为一种治疗方法，用于治疗因NMD而加剧的某些人类遗传疾病。
