title: The lack of the Celf2a splicing factor converts a Duchenne genotype into a Becker phenotype.
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.
authors.affiliation: Department of Biology and Biotechnology Charles Darwin, Sapienza University of Rome, P.le A. Moro 5, Rome 00185, Italy.
authors.forename: J
authors.initials: J
authors.lastname: Martone
authors.affiliation: Department of Biology and Biotechnology Charles Darwin, Sapienza University of Rome, P.le A. Moro 5, Rome 00185, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Briganti
authors.affiliation: Department of Biology and Biotechnology Charles Darwin, Sapienza University of Rome, P.le A. Moro 5, Rome 00185, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Legnini
authors.affiliation: Department of Biology and Biotechnology Charles Darwin, Sapienza University of Rome, P.le A. Moro 5, Rome 00185, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Morlando
authors.affiliation: Department of Experimental Medicine, Cardiomyology and Medical Genetics, Second University of Napoli, I Policlinico, Piazza Miraglia, Napoli 80138, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Picillo
authors.affiliation: Department of Biology and Biotechnology Charles Darwin, Sapienza University of Rome, P.le A. Moro 5, Rome 00185, Italy.
authors.forename: O
authors.initials: O
authors.lastname: Sthandier
authors.affiliation: Department of Experimental Medicine, Cardiomyology and Medical Genetics, Second University of Napoli, I Policlinico, Piazza Miraglia, Napoli 80138, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Politano
authors.affiliation: Department of Biology and Biotechnology Charles Darwin, Sapienza University of Rome, P.le A. Moro 5, Rome 00185, Italy.|Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, Rome 00161, Italy.|Institute Pasteur Fondazione Cenci-Bolognetti, Sapienza University of Rome, P.le A. Moro 5, Rome 00185, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Bozzoni
mesh_terms: D000293:Adolescent; D000067878:CELF Proteins / Q000235:genetics* / Q000378:metabolism; D016189:Dystrophin / Q000235:genetics / Q000378:metabolism; D005091:Exons; D005838:Genotype; D006801:Humans; D008297:Male; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D012326:RNA Splicing
chemical_list: D000067878:CELF Proteins; C117363:CELF2 protein, human; D016189:Dystrophin; D009419:Nerve Tissue Proteins