Research ArticleMuscular Dystrophy

A Naturally Occurring Human Minidysferlin Protein Repairs Sarcolemmal Lesions in a Mouse Model of Dysferlinopathy

Science Translational Medicine  22 Sep 2010:
Vol. 2, Issue 50, pp. 50ra69
DOI: 10.1126/scitranslmed.3000951

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The Best Things Come in Small Packages

Muscular dystrophies are a group of more than 30 individually rare genetic disorders characterized by progressive muscle wasting, which cause chronic disabilities in both children and adults. Although there is no definitive cure, the genetic cause of many muscular dystrophies is known, and several treatment strategies are currently being investigated. In particular, there are promising possibilities for the development of gene therapy–based treatments to replace the defective proteins that cause these diseases. However, several significant practical hurdles remain, including the packaging size limitation of the most widely used adeno-associated virus (AAV)–derived vector. Dysferlinopathies are a subgroup of muscular dystrophies that usually manifest in the second decade of life. They are caused by mutations in a gene encoding for the large 237-kD plasma membrane protein dysferlin, which plays a role in muscle membrane repair. Unfortunately, the large size of the gene precludes it from being packaged in its entirety into the AAV vector for use in gene therapy. However, partially functional miniature versions of the 427-kD dystrophin protein, which cause a mild form of dystrophy known as Becker muscular dystrophy, have previously been discovered. This helped to overcome the size limitations of the AAV vector and could be used in a gene therapy approach to lessen the severe phenotype associated with the more common Duchenne muscular dystrophy, which is also caused by mutant dystrophin. Now, Krahn et al. have discovered a substantially truncated form of dysferlin in a patient with a moderate form of dysferlinopathy, which may also help pave the way toward the development of a gene therapy–based strategy for treating dysferlinopathies. The authors found that this naturally occurring minidysferlin protein was more than three times smaller than the wild-type protein. This meant it could be successfully packaged into the AAV vector, which was then injected into dysferlin-deficient mice, resulting in stable expression of the truncated protein. Muscle fibers isolated from these mice were efficiently repaired after wound healing, indicating that this miniprotein still retained at least part of its critical function. This work provides an important basis for both minidysferlin and exon-skipping gene therapy strategies, making dysferlinopathies the second group of muscular dystrophies that could be targeted by these approaches.


  • * These authors contributed equally to this work.

  • Citation: M. Krahn, N. Wein, M. Bartoli, W. Lostal, S. Courrier, N. Bourg-Alibert, K. Nguyen, C. Vial, N. Streichenberger, V. Labelle, D. DePetris, C. Pécheux, F. Leturcq, P. Cau, I. Richard, N. Lévy, A Naturally Occurring Human Minidysferlin Protein Repairs Sarcolemmal Lesions in a Mouse Model of Dysferlinopathy. Sci. Transl. Med. 2, 50ra69 (2010).