Specific inhibition of nonsense-mediated mRNA decay components, SMG-1 or Upf1, rescues the phenotype of Ullrich disease fibroblasts.

Abstract

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.

• Authors: Fusako Usuki, Akio Yamashita, Isao Kashima, Itsuro Higuchi, Mitsuhiro Osame, Shigeo Ohno
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 14 Issue 3 Pg. 351-60 (Sep 2006) ISSN: 1525-0016 [Print] United States
• PMID: 16807116 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Codon, Nonsense
• Collagen Type VI
• Phosphoinositide-3 Kinase Inhibitors
• RNA, Messenger
• RNA, Small Interfering
• Trans-Activators
• Protein Serine-Threonine Kinases
• SMG1 protein, human
• RNA Helicases
• UPF1 protein, human

Topics

• Adult
• Cells, Cultured
• Codon, Nonsense
• Collagen Type VI (analysis, genetics, metabolism)
• Fibroblasts (chemistry, metabolism)
• Genetic Vectors (genetics)
• Humans
• Male
• Muscular Dystrophies (genetics, metabolism, therapy)
• Mutation
• Phenotype
• Phosphatidylinositol 3-Kinases (genetics)
• Phosphoinositide-3 Kinase Inhibitors
• Plasmids (genetics)
• Protein Serine-Threonine Kinases
• RNA Helicases
• RNA Interference
• RNA Stability
• RNA, Messenger (metabolism)
• RNA, Small Interfering (genetics, metabolism)
• Trans-Activators (antagonists & inhibitors, genetics)
• Transfection
• Up-Regulation