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.