Inhibition of nonsense-mediated mRNA decay rescues the phenotype in Ullrich's disease.
Nonsense-mediated mRNA decay (NMD) is an mRNA surveillance system that eliminates aberrant mRNAs containing premature translation termination codons (PTCs). We evaluated the role of NMD in of Ullrich's disease. The patient has a frameshift mutation with a PTC in the collagen VI alpha2 gene causing the loss of collagen VI and functional defects in extracellular matrix (ECM). The pharmacological block of NMD caused upregulation of the mutant collagen VI alpha2 subunit, resulting in collagen VI assembly and partially functional ECM formation. Our results suggest that NMD inhibitors can be used as a therapeutic tool to rescue some human genetic diseases exacerbated by NMD.
Usuki
Fusako
F
Department of Clinical Medicine, National Institute for Minamata Disease, Hama, Minamata, Japan. usuki@mind.go.jp
Yamashita
Akio
A
Higuchi
Itsuro
I
Ohnishi
Tetsuo
T
Shiraishi
Tadafumi
T
Osame
Mitsuhiro
M
Ohno
Shigeo
S
D000730:Androstadienes / Q000494:pharmacology; D002110:Caffeine / Q000494:pharmacology; D018389:Codon, Nonsense / Q000037:antagonists & inhibitors* / Q000502:physiology; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D016368:Frameshift Mutation; D006801:Humans; D008297:Male; D009136:Muscular Dystrophies / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D020871:RNA Stability / Q000187:drug effects / Q000235:genetics*; D000077191:Wortmannin
D000730:Androstadienes; D018389:Codon, Nonsense; D002110:Caffeine; D000077191:Wortmannin