Wein et al. 2014 (PRJNA242628)

General Details

Title	A novel IRES identified in DMD results in a functional N-truncated dystrophin, providing a potential route to therapy for patients with 5’ mutations.
Organism
Number of Samples	2
Release Date	2014/03/24 00:00
Sequencing Types
Protocol Details

Study Links

GWIPS-viz	Trips-Viz

Repository Details

SRA	SRP040550
ENA	SRP040550
GEO	GSE56148
BioProject	PRJNA242628

Publication

Title
Authors	Wein N, Vulin A, Falzarano MS, Szigyarto CA, Maiti B, Findlay A, Heller KN, Uhlén M, Bakthavachalu B, Messina S, Vita G, Passarelli C, Brioschi S, Bovolenta M, Neri M, Gualandi F, Wilton SD, Rodino-Klapac LR, Yang L, Dunn DM, Schoenberg DR, Weiss RB, Howard MT, Ferlini A, Flanigan KM
Journal	Nature medicine
Publication Date	2014 Sep
Abstract	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.
PMC	PMC4165597
PMID	25108525
DOI

	Run Accession	Study Accession	Scientific Name	Cell Line	Library Type	Treatment	GWIPS-viz	Trips-Viz	Reads	BAM	BigWig (F)	BigWig (R)
	SRR1204655	PRJNA242628	Homo sapiens	0.0	Ribo-Seq	Cycloheximide
	SRR1204656	PRJNA242628	Homo sapiens	0.0	Ribo-Seq	Cycloheximide
	Run Accession	Study Accession	Scientific Name	Cell Line	Library Type	Treatment	GWIPS-viz	Trips-Viz	Reads	BAM	BigWig (F)	BigWig (R)

ⓘ For more Information on the columns shown here see: About