DMD – Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder caused by loss-of-function mutations in the dystrophin gene (Gene Symbol). A multitude of family-based and cohort studies have confirmed that hemizygous males develop progressive muscle wasting, elevated creatine kinase, and premature death, while female carriers may manifest disease through skewed X-inactivation (PMID:2180286).

Inheritance follows an X-linked recessive pattern, with demonstrated segregation of pathogenic alleles in multiple generations. Early reports described a de novo maternal deletion segregating in monozygotic twins and their mother (PMID:2180286), and subsequent pedigree analyses confirm consistent co-segregation in large families.

The spectrum of DMD variants includes large multi-exon deletions (∼61% of cases), duplications (∼13%), nonsense/frameshift mutations (∼16%), splice-site defects (∼5%), and deep-intronic pseudoexon insertions. In 576 dystrophinopathy families, 471 large rearrangements and 105 small mutations were cataloged (PMID:26284620). Point mutation hotspots at CpG sites such as c.8713C>T (p.Arg2905Ter) recur frequently (PMID:15643612).

Mechanistically, pathogenic variants abolish dystrophin’s structural role in linking cytoskeleton to extracellular matrix, resulting in sarcolemmal fragility. The mdx mouse model, bearing a nonsense mutation, exhibits absence of full-length dystrophin and replicates human pathology (PMID:8111539; PMID:8099842). Somatic mosaicism studies reveal that partial preservation of wild-type dystrophin can mitigate muscle symptoms in males, supporting a gene dosage effect (PMID:19530190).

Therapeutically, antisense oligonucleotide-mediated exon 51 skipping in the exon 52-deficient mdx mouse restored an in-frame dystrophin transcript, improved muscle histopathology, and enhanced functional outcomes, underpinning ongoing clinical trials of exon-skipping agents (PMID:20823833).

Taken together, overwhelming genetic and functional data support a Definitive DMD gene–Duchenne muscular dystrophy association. Comprehensive mutation screening informs diagnosis, carrier detection, and personalized therapies.

Key Take-home: Loss-of-function DMD mutations cause Duchenne muscular dystrophy via sarcolemmal destabilization, and exon-skipping strategies can restore functional dystrophin, enabling mutation-specific treatments.

References

• American journal of human genetics • 1990 • Skewed X inactivation in a female MZ twin results in Duchenne muscular dystrophy. PMID:2180286
• PloS one • 2015 • DMD Mutations in 576 Dystrophinopathy Families: A Step Forward in Genotype-Phenotype Correlations. PMID:26284620
• 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
• Human mutation • 2005 • Mutation rates in the dystrophin gene: a hotspot of mutation at a CpG dinucleotide. PMID:15643612
• Molecular and cell biology of human diseases series • 1993 • PCR analysis of muscular dystrophy in mdx mice. PMID:8111539
• Molecular therapy : the journal of the American Society of Gene Therapy • 2010 • In-frame dystrophin following exon 51-skipping improves muscle pathology and function in the exon 52-deficient mdx mouse. PMID:20823833
• American journal of medical genetics. Part A • 2009 • Somatic mosaicism for Duchenne dystrophy: evidence for genetic normalization mitigating muscle symptoms. PMID:19530190

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