DMD – Becker muscular dystrophy

Becker muscular dystrophy (BMD) is caused by hypomorphic variants in the DMD gene leading to partial retention of dystrophin. This X-linked recessive disorder presents with later onset and milder progression than Duchenne muscular dystrophy. The association between DMD (HGNC:2928) and BMD (MONDO:0010311) is definitive based on decades of clinical observations, segregation in multiple families, and functional concordance in animal and cellular models ([PMID:8423832], [PMID:20485447]).

Genetic evidence

DMD variants causing BMD include in-frame exon deletions (particularly exons 45–55), missense substitutions in spectrin-like repeats, splice-site mutations, and deep-intronic pseudoexons. In a Japanese cohort of 442 patients, 61 % carried deletions and 9 % duplications, with 89 % of BMD deletions preserving the reading frame ([PMID:20485447]). Segregation of X-linked variants in multiple pedigrees—including a family with a novel exon 27 frameshift c.3779_3785del (p.Thr1260LysfsTer21) identified in affected male siblings and their nephew—confirms pathogenicity ([PMID:25537791]).

Variant spectrum

More than 500 unrelated BMD probands have been reported with in-frame deletions clustering in two hot spots (exons 3–20 and 45–55) and with missense or splice-site changes elsewhere in the gene. A representative pathogenic allele is c.3779_3785del (p.Thr1260LysfsTer21) ([PMID:25537791]). Carrier frequency is estimated at ~1:5000 males in population-based series, consistent with the X-linked recessive inheritance mode.

Functional evidence

Animal and cellular studies demonstrate that dystrophin deficiency recapitulates muscular dystrophy phenotypes. A zebrafish dmd mutant shows progressive muscle degeneration reflecting human BMD/DMD pathology ([PMID:15298547]). In vitro splicing assays revealed that disruption of an exonic splicing enhancer in exon 27 by a nonsense mutation leads to partial exon skipping and a milder BMD phenotype ([PMID:9410897]). Antisense oligonucleotide-mediated skipping of exon 51 restores in-frame dystrophin and markedly improves muscle histology and function in mdx52 mice, modeling therapeutic exon-skipping approaches ([PMID:20823833]).

Integration & conclusion

DMD gene variants cause BMD via in-frame deletions or splice-modulating mutations that preserve the dystrophin reading frame, producing a truncated but functional protein. Genetic segregation data and functional assays in multiple model systems provide definitive evidence for this gene-disease relationship. This knowledge underpins diagnostic genetic testing, carrier screening, and precision exon-skipping therapies.

Key take-home: Definitive evidence supports DMD as the causative gene for Becker muscular dystrophy, enabling accurate diagnosis and informing mutation-specific therapeutic strategies.

References

• Muscle & nerve | 1993 | A case of myopathy associated with a dystrophin gene deletion and abnormal glycogen storage. PMID:8423832
• Journal of human genetics | 2010 | Mutation spectrum of the dystrophin gene in 442 Duchenne/Becker muscular dystrophy cases from one Japanese referral center. PMID:20485447
• Journal of human genetics | 2015 | Early-progressive dilated cardiomyopathy in a family with Becker muscular dystrophy related to a novel frameshift mutation in the dystrophin gene exon 27. PMID:25537791
• Clinical and experimental pharmacology & physiology | 2004 | Identification of a zebrafish model of muscular dystrophy. PMID:15298547
• Molecular therapy | 2010 | In-frame dystrophin following exon 51-skipping improves muscle pathology and function in the exon 52-deficient mdx mouse. PMID:20823833
• The Journal of clinical investigation | 1997 | Disruption of the splicing enhancer sequence within exon 27 of the dystrophin gene by a nonsense mutation induces partial skipping of the exon and is responsible for Becker muscular dystrophy. PMID:9410897

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