Dystrophin – Progressive Muscular Dystrophy

In a six-generation Daghestan kindred, two male siblings exhibited an atypical Duchenne muscular dystrophy variant confirmed by an X-linked deletion in the dystrophin gene, segregating hemizygously (PMID:9009996). No additional unrelated cases of progressive muscular dystrophy have been mapped to DMD, limiting the genetic evidence.

Animal and cellular models of DMD provide concordant functional data: the mdx mouse lacking dystrophin replicates myofiber degeneration and muscle wasting (PMID:8111539; PMID:8099842). Exon-skipping using antisense oligonucleotides restores in-frame dystrophin in mdx52 mice, ameliorating pathology and improving muscle function (PMID:20823833). These studies support a loss-of-function, haploinsufficiency mechanism.

Key take-home: Hemizygous dystrophin deficiency causes progressive muscular dystrophy; molecular diagnosis and exon-skipping therapies are clinically actionable.

References

• Brain • 1996 • Clinical and molecular analysis of a large family with three distinct phenotypes of progressive muscular dystrophy. PMID:9009996
• Molecular and cell biology of human diseases series • 1993 • PCR analysis of muscular dystrophy in mdx mice. PMID:8111539
• Nature genetics • 1993 • New mdx mutation disrupts expression of muscle and nonmuscle isoforms of dystrophin. PMID:8099842
• 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

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