Pseudoexon activation increases phenotype severity in a Becker muscular dystrophy patient

Kane Greer; Kayla Mizzi; Emily Rice; Lukas Kuster; Roberto A Barrero; Matthew I Bellgard; Bryan J Lynch; Aileen Reghan Foley; Eoin O Rathallaigh; Steve D Wilton; Sue Fletcher

doi:10.1002/mgg3.144

Pseudoexon activation increases phenotype severity in a Becker muscular dystrophy patient

Mol Genet Genomic Med. 2015 Jul;3(4):320-6. doi: 10.1002/mgg3.144. Epub 2015 Apr 15.

Authors

Affiliations

¹ 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.
² The University of Western Australia 35 Stirling Highway, Crawley, Western Australia, 6009, Australia.
³ Centre for Comparative Genomics, Murdoch University 90 South St, Murdoch, Western Australia, 6150, Australia.
⁴ Children's University Hospital Temple Street, Dublin, Ireland.
⁵ Department of Physiotherapy, Central Remedial Clinic Dublin, Ireland.
⁶ 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.

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.

Keywords: Cryptic splicing; Duchenne/Becker muscular dystrophy; dystrophin; exon splicing enhancer; pseudoexon.