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Translation from a DMD exon 5 IRES results in a functional dystrophin isoform that attenuates dystrophinopathy in humans and mice

2014; Nature Portfolio; Volume: 20; Issue: 9 Linguagem: Inglês

10.1038/nm.3628

1546-170X

Nicolas Wein, Adeline Vulin, Maria Sofia Falzarano, Cristina Al‐Khalili Szigyarto, Baijayanta Maiti, Andrew R. Findlay, Kristin N. Heller, Mathias Uhlén, Baskar Bakthavachalu, Sonia Messina, Giuseppe Vita, Chiara Passarelli, Simona Passarelli, Matteo Bovolenta, Marcella Neri, Francesca Gualandi, Steve D. Wilton, Louise R. Rodino‐Klapac, Lin Yang, Diane M. Dunn, Daniel R. Schoenberg, Robert B. Weiss, Michael Howard, Alessandra Ferlini, Kevin M. Flanigan,

Viral Infections and Immunology Research

A novel internal ribosomal entry site in the 5' end of the dystrophin gene allows for expression of a form of the protein that could be therapeutic for certain forms of Duchenne muscular dystrophy. Most mutations that truncate the reading frame of the DMD gene cause loss of dystrophin expression and lead to Duchenne muscular dystrophy. However, amelioration of disease severity has been shown to result from alternative translation initiation beginning in DMD exon 6 that leads to expression of a highly functional N-truncated dystrophin. Here we demonstrate that this isoform results from usage of an internal ribosome entry site (IRES) within exon 5 that is glucocorticoid inducible. We confirmed IRES activity by both peptide sequencing and ribosome profiling in muscle from individuals with minimal symptoms despite the presence of truncating mutations. We generated a truncated reading frame upstream of the IRES by exon skipping, which led to synthesis of a functional N-truncated isoform in both human subject–derived cell lines and in a new DMD mouse model, where expression of the truncated isoform protected muscle from contraction-induced injury and corrected muscle force to the same level as that observed in control mice. These results support a potential therapeutic approach for patients with mutations within the 5′ exons of DMD.