Abstract
Duchenne muscular dystrophy is an inherited muscle wasting disease with severe symptoms and onset in early childhood. Duchenne muscular dystrophy is caused by loss-of-function mutations, most commonly deletions, within the DMD gene. Characterizing the junction points of large genomic deletions facilitates a more detailed model of the origins of these mutations and allows for a greater understanding of phenotypic variations associated with particular genotypes, potentially providing insights into the deletion mechanism. Here, we report sequencing of breakpoint junctions for seven patients with intragenic, whole-exon DMD deletions. Of the seven junction sequences identified, we found one instance of a “clean” break, three instances of microhomology (2–5 bp) at the junction site, and three complex rearrangements involving local sequences. Bioinformatics analysis of the upstream and downstream breakpoint regions revealed a possible role of short inverted repeats in the initiation of some of these deletion events.
Highlights
1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Introduction Duchenne muscular dystrophy is an inherited neuromuscular disease arising from loss-of-function mutations in the DMD gene
Each of the donor patients had been diagnosed with a deletion of at least one whole exon in the e45–e51 region of the DMD gene based on sequencing of their mRNA prior to the commencement of this study
In their 2013 study, Verdin et al.[21] cataloged 22 microhomologies in the FOX2 genes of separate patients, ranging in size from 1 to 66 bp. They found that microhomologies occurred at a much higher rate than would be expected if the upstream and downstream breakpoints were completely random (p = 2.28 × 10–8) and noted that the regions around the breakpoints tend to be significantly enriched with repetitive elements
Summary
Duchenne muscular dystrophy is an inherited neuromuscular disease arising from loss-of-function mutations in the DMD gene. On the other hand, the deletion preserves the reading frame, it is far more likely that a functional protein isoform will be produced[7], though this cannot be guaranteed[8]. The phenotype produced by a DMD whole-exon deletion is not predicted solely by the identities of the exons lost. Some intronic DMD sequences serve important regulatory roles both before[14,15] and after mRNA splicing[16], and deletions that affect functional regions such as these are likely to have negative consequences for the patient’s phenotype—consequences that can vary greatly even among patients with identical exon deletions[16].
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