Correspondence
Deficiency of Adhalin in a Patient with Muscular Dystrophy and Cardiomyopathy
N Engl J Med 1996; 334:1610-1611June 13, 1996
- Article
To the Editor:
Deficiency of the dystrophin-associated protein adhalin has been associated with autosomal recessive muscular dystrophy. The report by Fadic et al. (Feb. 8 issue)1 advances our understanding of the dystrophin complex by identifying a child with both cardiomyopathy and muscular dystrophy and a deficiency of adhalin on immunostaining of both the heart and skeletal muscle. However, the authors failed to acknowledge that three different genes have been identified that, when mutated, result in decreased immunostaining for adhalin. The first is the chromosome 17 adhalin gene. The second gene maps to chromosome 13q12 and encodes the 35-kd dystrophin-associated protein that is a common cause of muscular dystrophy in, but not limited to, North Africa.2 The third gene maps to chromosome 4q12, encodes a 43-kd dystrophin-associated protein, and is associated with mild and severe forms of muscular dystrophy.3,4 These genetic data coupled with biochemical studies led to the concept that these three proteins form a subcomplex now referred to as sarcoglycan. Reflecting this, the 50-, 43-, and 35-kd dystrophin-associated proteins have been termed α-, β-, and γ-sarcoglycan, respectively. Mutations in any one of these three genes not only produce muscular dystrophy, but also result in a decrease in immunostaining for all three sarcoglycan components in a fashion very similar to that described by Fadic et al.
Analysis of the BIO14.6 hamster, an animal model for cardiomyopathy and muscular dystrophy, suggests that there is an additional as yet unidentified locus that can also result in muscular dystrophy and cardiomyopathy. Like the patient discussed by Fadic et al., these animals have deficiencies of α-sarcoglycan (adhalin), β-sarcoglycan, and γ-sarcoglycan in both cardiac and skeletal muscle. The gene for α-sarcoglycan is normal in the BIO14.6 hamster.5 We have characterized the β- and γ-sarcoglycan sequences from these animals (GenBank numbers U49791 and U49792) and found that they are also normal. Therefore, there is at least a fourth gene, in addition to the α-, β-, and γ-sarcoglycan genes, that, when mutated, can produce α-sarcoglycan deficiency and myopathy similar to that seen in the patient of Fadic et al. α-Sarcoglycan immunostaining is increasingly being used for diagnostic testing, since this antibody is now commercially available. Because of the implications for prognosis and genetic counseling, deficiency of α-sarcoglycan should not necessarily be equated with a mutation in the α-sarcoglycan gene.
5 ReferencesElizabeth M. McNally, M.D., Ph.D.
Carsten G. Bönnemann, M.D.
Louis Kunkel, Ph.D.
Children's Hospital, Boston, MA 02115Syamal K. Bhattacharya, Ph.D.
University of Tennessee, Memphis, TN 381631
Fadic R ,Sunada Y ,Waclawik AJ , et al. Deficiency of a dystrophin-associated glycoprotein (adhalin) in a patient with muscular dystrophy and cardiomyopathy. N Engl J Med 1996;334:362-366
Full Text | Web of Science | Medline2
Noguchi S ,McNally EM ,Ben Othmane K , et al. Mutations in the dystrophin-associated protein γ-sarcoglycan in chromosome 13 muscular dystrophy. Science 1995;270:819-822
CrossRef | Web of Science | Medline3
Bonnemann CG ,Modi R ,Noguchi S , et al. β-Sarcoglycan (A3b) mutations cause autosomal recessive muscular dystrophy with loss of the sarcoglycan complex. Nat Genet 1995;11:266-273
CrossRef | Web of Science | Medline4
Lim LE ,Duclos F ,Broux O , et al. β-Sarcoglycan: characterization and role in limb-girdle muscular dystrophy linked to 4q12. Nat Genet 1995;11:257-265
CrossRef | Web of Science | Medline5
Roberds SL ,Campbell KP . Adhalin mRNA and cDNA sequence are normal in the cardiomyopathic hamster. FEBS Lett 1995;364:245-249
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Since the submission of our paper describing a possible adhalin deficiency in a patient with muscular dystrophy and cardiomyopathy, papers describing the molecular cloning of β-sarcoglycan1,2 and γ-sarcoglycan3 have been published. McNally and coworkers are correct in pointing out that we now know that mutations in any of the three sarcoglycan genes result in deficiency of immunostaining for adhalin in muscle-biopsy specimens. Thus, our case report does not prove that the defect is necessarily in the adhalin gene, but it still confirms the presence of a defect in the sarcoglycan complex.
Analysis of the sarcoglycan gene for the mutations present in this patient is continuing, and the results should answer the question whether a fourth gene is involved in this case, as suggested by the results in the BIO14.6 hamster model.
3 ReferencesB.P. Lotz, M.D.
A.J. Waclawik, M.D.
University of Wisconsin Hospital and Clinics, Madison, WI 537921
Lim LE ,Duclos F ,Broux O , et al. Beta-sarcoglycan: characterization and role in limb-girdle muscular dystrophy linked to 4q12. Nat Genet 1995;11:257-265
CrossRef | Web of Science | Medline2
Bonnemann CG ,Modi R ,Noguchi S , et al. β-Sarcoglycan (A3b) mutations cause autosomal recessive muscular dystrophy with loss of the sarcoglycan complex. Nat Genet 1995;11:266-273
CrossRef | Web of Science | Medline3
Noguchi S ,McNally EM ,Ben Othmane K , et al. Mutations in the dystrophin-associated protein γ-sarcoglycan in chromosome 13 muscular dystrophy. Science 1995;270:819-822
CrossRef | Web of Science | Medline
- Citing Articles (4)
Citing Articles
1
Laura Broglio, Marta Tentorio, Maria Sofia Cotelli, Michelangelo Mancuso, Valentina Vielmi, Valeria Gregorelli, Alessandro Padovani, Massimiliano Filosto. (2010) Limb-Girdle Muscular Dystrophy-Associated Protein Diseases. The Neurologist 16:6, 340-352
CrossRef2
Weixing Shi, Zaili Chen, Jodi Schottenfeld, Richard C. Stahl, Louis M. Kunkel, Yiu-Mo Chan. (2004) Specific assembly pathway of sarcoglycans is dependent on beta- and delta-sarcoglycan. Muscle & Nerve 29:3, 409-419
CrossRef3
Jeffrey A Towbin. (1998) The role of cytoskeletal proteins in cardiomyopathies. Current Opinion in Cell Biology 10:1, 131-139
CrossRef4
Syamal K. Bhattacharya, Patti L. Johnson, Hua-ju Li, Raj K. Handa, Thomas A. Adamec. (1997) Reduced sarcolemmal dystrophin distribution and upregulation of utrophin in the cardiac and skeletal muscles of CHF-146 dystrophic hamsters. Molecular and Chemical Neuropathology 31:2, 187-206
CrossRef
