title: Pseudoexon activation increases phenotype severity in a Becker muscular dystrophy patient.
abstract: We report a dystrophinopathy patient with an in-frame deletion of DMD exons 45-47, and therefore a genetic diagnosis of Becker muscular dystrophy, who presented with a more severe than expected phenotype. Analysis of the patient DMD mRNA revealed an 82 bp pseudoexon, derived from intron 44, that disrupts the reading frame and is expected to yield a nonfunctional dystrophin. Since the sequence of the pseudoexon and canonical splice sites does not differ from the reference sequence, we concluded that the genomic rearrangement promoted recognition of the pseudoexon, causing a severe dystrophic phenotype. We characterized the deletion breakpoints and identified motifs that might influence selection of the pseudoexon. We concluded that the donor splice site was strengthened by juxtaposition of intron 47, and loss of intron 44 silencer elements, normally located downstream of the pseudoexon donor splice site, further enhanced pseudoexon selection and inclusion in the DMD transcript in this patient.
authors.affiliation: Centre for Comparative Genomics, Murdoch University 90 South St, Murdoch, Western Australia, 6150, Australia ; The University of Western Australia 35 Stirling Highway, Crawley, Western Australia, 6009, Australia.
authors.forename: Kane
authors.initials: K
authors.lastname: Greer
authors.affiliation: The University of Western Australia 35 Stirling Highway, Crawley, Western Australia, 6009, Australia.
authors.forename: Kayla
authors.initials: K
authors.lastname: Mizzi
authors.affiliation: The University of Western Australia 35 Stirling Highway, Crawley, Western Australia, 6009, Australia.
authors.forename: Emily
authors.initials: E
authors.lastname: Rice
authors.affiliation: The University of Western Australia 35 Stirling Highway, Crawley, Western Australia, 6009, Australia.
authors.forename: Lukas
authors.initials: L
authors.lastname: Kuster
authors.affiliation: Centre for Comparative Genomics, Murdoch University 90 South St, Murdoch, Western Australia, 6150, Australia.
authors.forename: Roberto A
authors.initials: RA
authors.lastname: Barrero
authors.affiliation: Centre for Comparative Genomics, Murdoch University 90 South St, Murdoch, Western Australia, 6150, Australia.
authors.forename: Matthew I
authors.initials: MI
authors.lastname: Bellgard
authors.affiliation: Children's University Hospital Temple Street, Dublin, Ireland.
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Lynch
authors.affiliation: Children's University Hospital Temple Street, Dublin, Ireland.
authors.forename: Aileen Reghan
authors.initials: AR
authors.lastname: Foley
authors.affiliation: Department of Physiotherapy, Central Remedial Clinic Dublin, Ireland.
authors.forename: Eoin
authors.initials: E
authors.lastname: O Rathallaigh
authors.affiliation: Centre for Comparative Genomics, Murdoch University 90 South St, Murdoch, Western Australia, 6150, Australia ; The University of Western Australia 35 Stirling Highway, Crawley, Western Australia, 6009, Australia ; Western Australian Neuroscience Institute Nedlands, Western Australia, 6009, Australia.
authors.forename: Steve D
authors.initials: SD
authors.lastname: Wilton
authors.affiliation: Centre for Comparative Genomics, Murdoch University 90 South St, Murdoch, Western Australia, 6150, Australia ; The University of Western Australia 35 Stirling Highway, Crawley, Western Australia, 6009, Australia ; Western Australian Neuroscience Institute Nedlands, Western Australia, 6009, Australia.
authors.forename: Sue
authors.initials: S
authors.lastname: Fletcher
keywords: Cryptic splicing; Duchenne/Becker muscular dystrophy; dystrophin; exon splicing enhancer; pseudoexon