The lack of the Celf2a splicing factor converts a Duchenne genotype into a Becker phenotype

Nature Communications
J MartoneIrene Bozzoni

Abstract

Substitutions, deletions and duplications in the dystrophin gene lead to either the severe Duchenne muscular dystrophy (DMD) or mild Becker muscular dystrophy depending on whether out-of-frame or in-frame transcripts are produced. We identified a DMD case (GSΔ44) where the correlation between genotype and phenotype is not respected, even if carrying a typical Duchenne mutation (exon 44 deletion) a Becker-like phenotype was observed. Here we report that in this patient, partial restoration of an in-frame transcript occurs by natural skipping of exon 45 and that this is due to the lack of Celf2a, a splicing factor that interacts with exon 45 in the dystrophin pre-mRNA. Several experiments are presented that demonstrate the central role of Celf2a in controlling exon 45 splicing; our data point to this factor as a potential target for the improvement of those DMD therapeutic treatments, which requires exon 45 skipping.

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Citations

Jun 10, 2017·Human Genetics·Sylvie Tuffery-GiraudMireille Claustres
Sep 7, 2016·F1000Research·Hayder Abdul-RazakGeorge Dickson
Mar 8, 2018·Skeletal Muscle·Kiran NakkaF Jeffrey Dilworth
Mar 3, 2018·PloS One·Yeong-Hwan LimYoung-Kook Kim
May 12, 2020·Journal of Neuromuscular Diseases·Kristin StrandbergCristina Al-Khalili Szigyarto
Nov 5, 2019·Molecular Therapy. Nucleic Acids·Florian BarthélémyM Carrie Miceli
Nov 6, 2018·Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society·A BergougnouxM Taulan-Cadars

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Datasets Mentioned

BETA
GSE70389

Methods Mentioned

BETA
antisense oligonucleotides
biopsy
biopsies
PCR
RNA-seq
RNAseq
cross-linking immunoprecipitation
CLIP
transfection
immunoprecipitation

Software Mentioned

ESE Finder
Cutadapt
Casava
TransFac
Encode browser
TopHat
MATS

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