Correspondence

Dystrophin, Utrophin, and Muscular Dystrophy

N Engl J Med 1995; 332:612-613March 2, 1995

Article

To the Editor:

Chevron and coworkers (Oct. 27 issue)1 reported the absence of immunostaining for utrophin on the surface of muscle fibers in an unidentified muscle from a boy with a form of muscular dystrophy who died at the age of 15 years. An absence of immunostaining for dystrophin was also observed. These data were interpreted as being indicative of the absence of the expression of both dystrophin and utrophin, possibly because of the absence of a common intramembranous (plasmalemmal) protein that binds both dystrophin and utrophin. The authors correctly point out that in normal skeletal muscle, utrophin is only localized at the postjunctional region of the muscle-fiber surface. However, in the presence of dystrophin deficiency it is also found throughout the extrajunctional region of the surface membrane of muscle fibers,2,3 usually to a much greater extent than is shown in Figure 1D of the article by Chevron et al.1 (The lack of staining of endomysial capillaries in normal muscle [Figure 1B] is also curious.) Quantitative Western blot analysis shows that utrophin levels in the muscles of patients with Duchenne's muscular dystrophy are 15 to 17 times higher than those in normal subjects.3

As the authors indicated, this up-regulation of utrophin may in part compensate for the dystrophin deficiency in Duchenne's muscular dystrophy.3,4 We suggested that without this compensatory mechanism Duchenne's muscular dystrophy could be an even more serious disease than it is.4

The authors' data do not justify their conclusion that there is an absence of utrophin expression in their patient's muscle fibers. At best, their data could be interpreted as being indicative of the absence of the expected up-regulation of utrophin. To demonstrate the absence of utrophin expression, they should have shown a lack of immunostaining for utrophin in the muscle end plates. Demonstrating the presence or absence of utrophin in nonmuscle tissues (where it is normally expressed) would also have been very informative.

George Karpati, M.D.
Paul Holland, Ph.D.
Montreal Neurological Institute, Montreal, QC H3A 2B4, Canada

4 References

1. 1

   Chevron M-P, Echenne B, Damaille J. Absence of dystrophin and utrophin in a boy with severe muscular dystrophy. N Engl J Med 1994;331:1162-1163
   Full Text | Web of Science | Medline

2. 2

   Helliwell TR, Man NT, Morris GE, Davies KE. The dystrophin-related protein, utrophin, is expressed on the sarcolemma of regenerating human skeletal muscle fibres in dystrophies and inflammatory myopathies. Neuromuscul Disord 1992;2:177-184
   CrossRef | Medline

3. 3

   Karpati G, Carpenter S, Morris GE, Davies KE, Guerin C, Holland P. Localization and quantitation of the chromosome 6-encoded dystrophin-related protein in normal and pathological human muscle. J Neuropathol Exp Neurol 1993;52:119-128
   CrossRef | Web of Science | Medline

4. 4

   Karpati G. Recent developments in the biology of dystrophin and related molecules. Curr Opin Neurol Neurosurg 1992;5:615-621
   Medline

Author/Editor Response

Dr. Chevron replies:

To the Editor: In our patient with Duchenne's muscular dystrophy, disease progression was particularly severe. Western blotting and immunostaining, both performed on muscle-biopsy specimens from the legs, demonstrated neither dystrophin nor utrophin on the plasma membrane or in muscle extracts. In the absence of dystrophin in patients with “typical” Duchenne's muscular dystrophy, as during skeletal-muscle development,1 utrophin, which is normally present at the neuromuscular junctions, is expressed throughout the plasma membrane. In contrast, and despite normal levels of messenger RNA, the expression of all the dystrophin-associated proteins is decreased or even absent.2 We have suggested that the absence of dystrophin expression and the overexpression of utrophin on the plasma membrane might arise from the absence of a common sarcolemmal or cytoskeletal protein, which would normally link these proteins to the membrane. We think this hypothesis is still viable and we suggest that to be accurate, the diagnosis of Duchenne's or Becker's muscular dystrophy and other neuromuscular disorders should include a systematic analysis of all the glycoproteins associated with dystrophin and utrophin. Finally, since utrophin is present in smooth muscle and since our patient had severe gastrointestinal disease, it would be of interest to analyze the expression and localization of both dystrophin and utrophin in intestinal smooth muscles in patients with muscular dystrophy and similar clinical symptoms.

Marie-Pierre Chevron, Ph.D.
INSERM Unité 249, 34033 Montpellier CEDEX, France

2 References

1. 1

   Clerk A, Morris GE, Dubowitz V, Davies KE, Sewry CA. Dystrophin-related protein, utrophin, in normal and dystrophic human fetal skeletal muscle. Histochem J 1993;25:554-561
   Medline

2. 2

   Matsumura K, Campbell KP. Dystrophin-glycoprotein complex: its role in the molecular pathogenesis of muscular dystrophies. Muscle Nerve 1994;17:2-15
   CrossRef | Web of Science | Medline