title: 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.affiliation: Department of Clinical Medicine, National Institute for Minamata Disease, 4058-18 Hama, Minamata 867-0008, Japan. usuki@nimd.go.jp
authors.forename: Fusako
authors.initials: F
authors.lastname: Usuki
authors.forename: Akio
authors.initials: A
authors.lastname: Yamashita
authors.forename: Isao
authors.initials: I
authors.lastname: Kashima
authors.forename: Itsuro
authors.initials: I
authors.lastname: Higuchi
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Osame
authors.forename: Shigeo
authors.initials: S
authors.lastname: Ohno
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D018389:Codon, Nonsense; D024142:Collagen Type VI / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000737:chemistry / Q000378:metabolism; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008297:Male; D009136:Muscular Dystrophies / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D009154:Mutation; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010957:Plasmids / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D020365:RNA Helicases; D034622:RNA Interference; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000235:genetics; D014162:Transfection; D015854:Up-Regulation
chemical_list: D018389:Codon, Nonsense; D024142:Collagen Type VI; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D020365:RNA Helicases; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D015534:Trans-Activators; C514704:SMG1 protein, human; C101828:UPF1 protein, human