title: [Specific inhibition of nonsense-mediated mRNA decay has the potential to rescue the phenotype of muscular dystrophy].
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 Upf, a substrate of SMG-1 with RNA helicase activity. In this study, we evaluated the effect of NMD inhibition on the phenotype of Ullrich disease, an autosomal recessive congenital muscular dystrophy, by pharmacological inhibition of SMG-1 or siRNA-mediated knockdown of SMG-1 or Upf1. The patient studied, showed a homozygous frame-shift 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 NMD inhibition causes the up-regulation of the mutant collagen VI a2 subunit, resulting in the assembly of mutant triple-helical collagen VI and the formation of partially functional ECM. The results suggest that specific inhibition of NMD may be useful as a therapeutic approach to treat some human genetic diseases exacerbated by NMD.
authors: Department of Clinical Medicine, National Institute for Minamata Disease.
authors: Fusako
authors: F
authors: Usuki
mesh_terms: D018389:Codon, Nonsense; D006801:Humans; D009136:Muscular Dystrophies / Q000235:genetics* / Q000628:therapy*; D010641:Phenotype; D012333:RNA, Messenger
chemical_list: D018389:Codon, Nonsense; D012333:RNA, Messenger