The Dystrophin Gene
- Dystrophin is the largest known human gene and is located on the X chromosome.
- The full-length dystrophin protein is normally expressed in striated muscle, smooth muscle, and neurons.
- Multiple smaller forms of dystrophin are expressed in nonmuscle tissues such as the eye, neural tissue, liver and kidney.
- Mutations in the dystrophin gene are responsible for the disease Duchenne’s muscular dystropy (DMD) which is inherited in a sex-linked recessive manner and affects 1 in 3,500 boys worldwide.
- Muscular dystrophy diagnosis can happen at birth from the detection of elevated muscle enzymes in the blood.
Dystrophin Gene Mutation
- Various mutations in the dystrophin gene can cause dystrophin deficiency, which results in Duchenne’s muscular dystrpohy (DMD) or a milder condition, Becker’s muscular dystrophy (BMD).
- Deletions within the dystrophin gene sequence are the most common mutations, occurring in approximately 65% of DMD and BMD patients. Gene duplications, nonsense point mutations and other small mutations account for the remaining cases.
- Disease severity is related to the type of mutation in the dystrophin gene. In-frame mutations result in shortened but partly functional dystrophin proteins and are associated with BMD. Frame shift mutations, which result in a complete absence of the protein, are associated with the more severe condition DMD.
The Result of Dystrophin Gene Mutation - DMD and BMD
- Dystrophin interacts with membrane proteins which collectively constitute the dystrophin glycoprotein complex (DGC).
- In striated and smooth muscles, the dystrophin complex normally spans the plasma membrane and provides a strong connection between the cytoskeleton and extracellular matrix.
- The absence of dystrophin prevents assembly of the DGC. The resulting sarcolemma is fragile and highly susceptible to injuries that can trigger muscle cell death. As muscle tissue is lost, it is gradually replaced by connective tissue and adipose (fat) cells.
- The disease differentially affects different muscles and may completely spare some.
- Some research suggests that secondary responses, such as inflammatory immune reactions, may be involved in exacerbating the degeneration of the dystrophin-deficient muscle.
- The end result is progressive muscle wasting which affects patients’ mobility. DMD patients exhibit muscle weakness by the age of 5. Many lose independent movement and succumb to respiratory failure or cardiomyopathy in their late teens or twenties.
Future Hopes for DMD Patients
At present there is no effective treatment for DMD, but muscular dystrophy research, aimed at replacing or repairing the defective gene, is making progress. Novel treatments include the use of stem cells, gene therapy and transcript repair treatments using exon skipping strategies. Many technical obstacles must be overcome before these therapies are successfully applied to patients. However, early results in animal models of DMD have shown encouraging results and offer hope for the future.
Gene therapy in large animal models of muscular dystrophy by Z.Wang, J.Chamberlain, S.Tapscott & R.Storb. Journal of ILAR, 2009 Vol 50, P187-198.