Abstract
Genomic rearrangements such as intragenic deletions and duplications are the most prevalent type of mutations in the dystrophin gene resulting in Duchenne and Becker muscular dystrophy (D/BMD). These copy number variations (CNVs) are nonrecurrent and can result from either nonhomologous end joining (NHEJ) or microhomology-mediated replication-dependent recombination (MMRDR). We characterized five DMD patients with complex genomic rearrangements using a combination of MLPA/mRNA transcript analysis/custom array comparative hybridization arrays (CGH) and breakpoint sequence analysis to investigate the mechanisms for these rearrangements. Two patients had complex rearrangements that involved microhomologies at breakpoints. One patient had a noncontiguous insertion of 89.7 kb chromosome 4 into intron 43 of DMD involving three breakpoints with 2–5 bp microhomology at the junctions. A second patient had an inversion of exon 44 flanked by intronic deletions with two breakpoint junctions each showing 2 bp microhomology. The third patient was a female with an inherited deletion of exon 47 in DMD on the maternal allele and a de novo noncontiguous duplication of exons 45–49 in DMD and MID1 on the paternal allele. The other two patients harbored complex noncontiguous duplications within the dystrophin gene. We propose a replication-based mechanisms for all five complex DMD rearrangements. This study identifies additional underlying mechanisms in DMD, and provides insight into the molecular bases of these genomic rearrangements.
Highlights
Duchenne muscular dystrophy (DMD, MIM 310200), the most common and severe neuromuscular disease in humans, is caused by mutations in the dystrophin gene (DMD, MIM 300377) located on Xp21
We propose that complex genomic rearrangements in the dystrophin gene are a result of microhomology-mediated replication-dependent recombination (MMRDR)
We have presented evidence to suggest that five independent cases of DMD with Complex genomic rearrangements (CGR) involving the dystrophin gene were generated by replication-based mechanisms
Summary
Duchenne muscular dystrophy (DMD, MIM 310200), the most common and severe neuromuscular disease in humans, is caused by mutations in the dystrophin gene (DMD, MIM 300377) located on Xp21. The dystrophin gene, consisting of 79 exons, spans 2.3 Mb of genomic sequence and is one of the largest genes in the genome with 11 kb (0.6%) of coding sequence. Compared with other human genes, the mutation rate in the dystrophin gene is high with approximately 1/3 of the mutations resulting in DMD being de novo with the remaining 2/3 inherited (Cagliani et al 2004). The most prevalent disease-causing mutations in DMD are exonic deletions and duplications accounting for approximately 65% and 10% of the pathogenic alterations, respectively. The remaining mutations are mainly nonsense and indel mutations.
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