Molecular Genetics of Dystrophinopathies


The term dystrophinopathies includes a spectrum of muscle diseases caused by mutations in the dystrophin (DMD) gene. The commonest mutations are intragenic deletions (65% of cases) and duplications (10%); the remaining 25% are small mutations (missense, nonsense, frameshifting and indels). Atypical mutations (deep intronic, or in 5′/3′ untranslated regions) account for no more than 1%. The functional consequences of mutations are related to the maintenance of the open reading frame, though exceptions to the rule are known. A precise molecular characterisation of dystrophin mutations is nowadays mandatory for the inclusion of patients in therapeutic trials, as the antisense‐mediated targeted exon skipping or the stop codon reversion uses gentamycin and ataluren drugs. Understanding the complexity of the dystrophin gene regulation has provided outstanding information about muscle functions, sarcolemma architecture and signalling circuits, muscle metabolism and other basic science mechanisms.

Key Concepts:

  • The dystrophin gene (DMD) is one of the largest disease genes in the human genome.

  • Dystrophin deficiency accounts for different allelic conditions: Duchenne and Becker muscular dystrophies (DMD/BMD) are X‐linked recessive hereditary myopathies in which the skeletal muscle is affected with a nonreversible, age‐dependent degeneration. Allelic dystrophin mutations can also give rise to isolated cardiac involvement, or X‐linked dilated cardiomyopathy (XLDC).

  • The commonest mutational event in the dystrophin gene is represented by intragenic deletions accounting for 65% of dystrophin mutations. Intragenic duplications account for 10% of all mutations and small mutations represent 25%.

  • The functional consequences of all mutation types are mainly related to the maintenance of the open reading frame: ‘inframe’ mutations result in a shorter but partially functional dystrophin and are associated with BMD. Frame‐shift mutations are related to the absence of protein production and a DMD phenotype.

  • The fine genetic characterisation of dystrophin mutations has become mandatory for making patients eligible for novel personalised trials.

Keywords: dystrophin; muscular dystrophy; X‐linked dilated cardiomyopathy; medical genetics; molecular diagnosis; exon skipping

Figure 1.

Dystrophin gene structure and protein domains. Schematic representation of 79 exons of the dystrophin gene and of the protein domains. Lines in red represent the 5′ full length promoters and their first exons (isoforms Dp427B‐M‐P) and the 3′ promoters and their first exons (isoforms Dp260 retinal, Dp140 brain, Dp116 Schwann cells and Dp71general). Exons alternatively spliced or skipped are represented in light blue. Boxes explain the protein domain corresponding to the different exons.

Figure 2.

(a) Immunolabelling of dystrophin (antiDys antibody) on normal skeletal muscle and heart (left); dystrophin expression is reduced in the BMD muscle and absent in the DMD skeletal muscle compared with control muscle (c) (right). Arrows indicate revertant fibres in the DMD muscle. (b) Immunolabelling of dystrophin on normal (ctrl) human and Duchenne muscular dystrophy (DMD) skin smooth muscle arrector pili. Dystrophin is intensely expressed at the sarcolemma of smooth muscle cells of the arrector pili of the healthy subject, but absent in the DMD patient.

Figure 3.

(a) Interactions of dystrophin with dystrophin‐associated glycoprotein complex and signalling molecules (NOS and syntrophins). Dystrophin is a major component of the subsarcolemmal skeleton of muscle cells, and is part of a molecular multinetwork, the DAGC that links the intracellular cytoskeleton to the extracellular matrix. This protein complex, in addition to dystrophin, encompasses intracellular (α1 and β1 syntrophin, α‐dystrobrevin and nNOS), transmembrane (β‐dystroglycan, α‐, β‐, γ‐ and δ‐sarcoglycan, and sarcospan) and extracellular proteins (α‐dystroglycan and laminin‐2). (b) Pathogenic cascade related to the dystrophin absence. Absence of dystrophin leads to instability of the membrane with a pseudo‐wound state; this is accompanied initially by necrosis, hypertrophy of fibres and regenerations (phase I) but it is followed by a progressive loss of regeneration and muscular degeneration/fibrosis characteristic of DMD (phase II). These processes are not only species specific, being very different in humans, mice and dogs, but also age dependent, as in DMD where the lack (or strong reduction) of regeneration occurs during the prepuberty age.

Figure 4.

Upper figure: Schematic representation of dystrophin mutations. The commonest mutational event in the dystrophin gene is represented by intragenic deletions accounting for 65% of dystrophin mutations. Intragenic duplications account for up to 10% of all mutations and small mutations represent 25%. Lower figure: Cartoon representing the dystrophin frame. (a) Dystrophin normal frame, (b) out‐of‐frame deletion of exons 47–50, (c) additional deletion of exon 51 leads to an inframe deletion.

Figure 5.

DMD–CGH array profiles of deletions and duplications: (a) out‐of‐frame duplication of exons 54–59 of the dystrophin gene (hg18 chrx: 31.676.278–31.828.064 del); (b) out‐of‐frame deletion of exons 48–51 of the dystrophin gene (hg18 chrx 31.665.913–31.380.278 dup).



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Further Reading

Arechavala‐Gomeza V, Anthony K, Morgan J and Muntoni F (2012) Antisense oligonucleotide‐mediated exon skipping for Duchenne muscular dystrophy: progress and challenges. Current Gene Therapy 12(3): 152–160.

Anthony K, Cirak S, Torelli S et al. (2011) Dystrophin quantification and clinical correlations in Becker muscular dystrophy: implications for clinical trials. Brain 134: 3547–3559.

Fletcher S, Adkin CF, Meloni P et al. (2012) Targeted exon skipping to address “leaky” mutations in the dystrophin gene. Molecular Therapy – Nucleic Acids 1: e48.

Muntoni F and Wood MJ (2011) Targeting RNA to treat neuromuscular disease. Nature Reviews Drug Discovery 10(8): 621–637.

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Ferlini, Alessandra, and Neri, Marcella(Mar 2014) Molecular Genetics of Dystrophinopathies. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025342]