Correspondence

Serum Antibodies to the Deleted Dystrophin Sequence after Cardiac Transplantation in a Patient with Becker's Muscular Dystrophy

N Engl J Med 1995; 333:732-733September 14, 1995

Article

To the Editor:

Becker's muscular dystrophy and Duchenne's muscular dystrophy are allelic disorders caused by mutations of the dystrophin gene at Xp21.1 The 400-kd dystrophin is expressed most abundantly in the plasma membranes of skeletal and cardiac muscle fibers but is absent in patients with severe Duchenne's muscular dystrophy and in mdx mice. The expression of a truncated, “semifunctional” dystrophin molecule is usually associated with Becker's muscular dystrophy, which is milder than Duchenne's muscular dystrophy.2

It is not clear whether the full-length dystrophin molecule induces a specific immune response against the deleted sequence in a patient with Becker's muscular dystrophy. We tested serum antibodies from a patient with Becker's muscular dystrophy who had undergone cardiac transplantation.

Acute dilated cardiomyopathy led to cardiac transplantation in a man with Becker's muscular dystrophy, in whom exons 4 through 7 of the dystrophin gene were deleted. After only two days, the transplanted heart had to be replaced because of graft failure. Despite immunosuppressive therapy with cyclosporine (1200 mg per day) and prednisone (5 mg per day), the second graft was rejected after two years, and the patient underwent a third cardiac transplantation.

Five years after the first cardiac transplantation, we tested the patient's serum for circulating antibodies. IgG and IgM antibodies in his serum reacted with a 400-kd membrane protein in normal human muscle and a series of animal muscles (Figure 1Figure 1IgG-Specific Reactivity of the Patient's Serum with Various Normal and Truncated Dystrophin Molecules.). No corresponding reactivity was observed in dystrophin-deficient muscle from patients with Duchenne's muscular dystrophy or from mdx mice. Although there was serum reactivity with truncated dystrophin molecules in muscle specimens from a series of patients with Becker's muscular dystrophy who had deletions in regions of the gene other than the region in our patient, there was no corresponding reaction when the serum was incubated with the patient's own heart muscle (Figure 1).

Epitope specificity of the patient's serum antibodies was ruled out when the serum failed to react specifically with muscle from two patients with Becker's muscular dystrophy in whom exons of the dystrophin gene encompassing our patient's deletion were also deleted. In one of these patients, exons 2 through 7 were deleted, and in the other, exons 3 through 7 were deleted (Figure 1).

Our study provides evidence of region-specific dystrophin antibodies in the serum (i.e., antibodies directed against the dystrophin sequence that was deleted in the patient). However, we were not able to determine whether the antibodies were related to the clinical rejection.

Our findings are consistent with the results of studies demonstrating the presence of specific post-transplantation antibodies in patients with hereditary Alport-type nephritis who have received renal allografts4 and in mdx mice after the implantation of dystrophin-expressing muscle from a normal congenic donor.5 Post-transplantation antibodies may represent powerful tools for identifying defective gene products in other inherited diseases.

Reginald E. Bittner, M.D.
Sigrid Shorny, M.D.
Berthold Streubel, M.D.
University of Vienna, 1090 Vienna, Austria

Christoph Hübner, M.D.
University of Berlin, Charité, 10117 Berlin, Germany

Thomas Voit, M.D.
University of Essen, 45122 Essen, Germany

Wolfram Kress, Ph.D.
University of Würzburg, 97074 Würzburg, Germany

5 References

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   Bittner RE, Streubel B, Shorny S, Schaden G, Voit T, Hoger H. Coisogenic all-plus-one immunization: a model for identifying missing proteins in null-mutant conditions: antibodies to dystrophin in mdx mouse after transplantation of muscle from normal coisogenic donor. Neuropediatrics 1994;25:176-182
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Citing Articles (6)

Citing Articles

1. 1

   Jara, Paloma, Hierro, Loreto, Martínez-Fernández, Pilar, Alvarez-Doforno, Rita, Yánez, Francisca, Diaz, María C., Camarena, Carmen, Vega, Angela De la, Frauca, Esteban, Muñoz-Bartolo, Gema, López-Santamaría, Manuel, Larrauri, Javier, Alvarez, Luis, . (2009) Recurrence of Bile Salt Export Pump Deficiency after Liver Transplantation. New England Journal of Medicine 361:14, 1359-1367
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2. 2

   Josef Finsterer, Claudia Stöllberger. (2008) Cardiac involvement in Becker muscular dystrophy. Canadian Journal of Cardiology 24:10, 786-792
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3. 3

   A Zaldumbide, R C Hoeben. (2008) How not to be seen: immune-evasion strategies in gene therapy. Gene Therapy 15:4, 239-246
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4. 4

   Dariusz C Górecki. (2001) Prospects and problems of gene therapy: an update. Expert Opinion on Emerging Drugs 6:2, 187-198
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5. 5

   Dariusz C Górecki. (1999) Gene therapy: prospects and problems. Expert Opinion on Emerging Drugs 4:1, 247-261
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6. 6

   P. Melacini, M. Fanin, A. Angelini, E. Pegoraro, U. Livi, G.A. Danieli, E.P. Hoffman, G. Thiene, S. Dalla Volta, C. Angelini. (1998) Cardiac transplantation in a Duchenne muscular dystrophy carrier. Neuromuscular Disorders 8:8, 585-590
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