[Brenner Computational Biology Research Group] [Ed Green] [RUST]

The Dystrophin Story

NMD leads to new understanding of Muscular Dystrophy

    Muscular dystrophy (MD) refers to a group of genetic disorders whose major symptom is muscle wasting.  There are two major forms of MD, differing in severity and age of onset.  In Duchenne muscular dystrophy, symptoms are noticeable in early childhood and quickly become debilitating.  Becker muscular dystrophy, on the other hand, is of later onset and less severe.  Both forms of MD are caused by mutations in the dystrophin gene, a large (2.6Mb) gene comprised of 97 exons.  The dystrophin protein plays an important structural role as part of a large complex in muscle fiber membranes.  When dystrophin is missing or non-functional, the entire complex is compromised, leading to degeneration of muscle tissue.  When the ability to regenerate the muscle is exhausted, muscle wasting occurs.

    Once it was discovered that Duchenne MD and Becker MD were both forms of the same disease, researchers attempted to determine which regions of the dystrophin gene were most important by correlating genotype and phenotype.  It was mystifying that several large deletions were present in patients with the mild, Becker, form, while smaller deletions were sometimes found in patients with Duchenne MD[1-4].

Dystrophin gene

    What seemed to be more important than the amount of coding sequence that was deleted was whether or not the offending mutation resulted in a frameshift or not.  Researchers working on the mouse model of Duchenne MD, mdx mouse, found a similarly puzzling result: a C-terminally truncated version of dystrophin was competent to rescue the MD phenotype in these mice[5].  In 1988, it was entirely unclear how to explain the apparent disconnect between genotype and phenotype.

    In light of NMD, these findings are comprehensible.  Becker MD patients have a partially functional version of dystrophin that leads to less severe symptoms.  Duchenne MD patients, however, have mutations that prevent any functional dystrophin production.  Because of NMD, this includes mutations that introduce premature termination codons.

Dystrphin and NMD

    Appreciation of the role of NMD in MD has led to improved diagnostics and promising new treatment strategies.  For example, the drug gentamicin, which causes translational read-through of stop codons, has shown some effectiveness for restoring dystrophin expression in cultured cells from mdx-mice[6].  Human clinical trials are currently underway.

[1]E. F. Gillard, J. S. Chamberlain, E. G. Murphy, C. L. Duff, B. Smith, A. H. Burghes, M. W. Thompson, J. Sutherland, I. Oss, S. E. Bodrug, and et al., "Molecular and phenotypic analysis of patients with deletions within the deletion-rich region of the Duchenne muscular dystrophy (DMD) gene," Am J Hum Genet, vol. 45, pp. 507-20, 1989.

[2]M. Koenig, A. H. Beggs, M. Moyer, S. Scherpf, K. Heindrich, T. Bettecken, G. Meng, C. R. Muller, M. Lindlof, H. Kaariainen, and et al., "The molecular basis for Duchenne versus Becker muscular dystrophy: correlation of severity with type of deletion," Am J Hum Genet, vol. 45, pp. 498-506, 1989.

[3]R. G. Roberts, R. J. Gardner, and M. Bobrow, "Searching for the 1 in 2,400,000: a review of dystrophin gene point mutations," Hum Mutat, vol. 4, pp. 1-11, 1994.

[4]T. P. Kerr, C. A. Sewry, S. A. Robb, and R. G. Roberts, "Long mutant dystrophins and variable phenotypes: evasion of nonsense-mediated decay?," Hum Genet, vol. 109, pp. 402-7, 2001.

[5]G.E. Crawford, J.A. Faulkner, R.H. Crosbie, K.P. Campbell, S.C. Froehner, and J.S. Chamberlain, "Assembly of the dystrophin-associated protein complex does not require the dystrophin COOH-terminal domain," J Cell Biol, vol. 150, pp. 1399-410, 2000.

[6]E. R. Barton-Davis, L. Cordier, D. I. Shoturma, S. E. Leland, and H. L. Sweeney, "Aminoglycoside antibiotics restore dystrophin function to skeletal muscles of mdx mice," J Clin Invest, vol. 104, pp. 375-81, 1999.

For more information about Muscular Dystrophy:

Muscular Dystrophy Association USA

Duchenne Muscular Dystrophy:Research Approaches Toward a Cure (from Testlaboratorium Breitnau)