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β–sarcoglycan (A3b) mutations cause autosomal recessive muscular dystrophy with loss of the sarcoglycan complex

Nature Genetics volume 11, pages 266–273 (1995)Cite this article

A Correction to this article was published on 01 January 1996

Abstract

The dystrophin associated proteins (DAPs) are good candidates for harboring primary mutations in the genetically heterogeneous autosomal recessive muscular dystrophies (ARMD). The transmembrane components of the DAPs can be separated into the dystroglycan and the sarcoglycan complexes. Here we report the isolation of cDNAs encoding the 43 kD sarcoglycan protein β–sarcoglycan (A3b) and the localization of the human gene to chromosome 4q12. We describe a young girl with ARMD with truncating mutations on both alleles. Immunostaining of her muscle biopsy shows specific loss of the components of the sarcoglycan complex β–sarcoglycan, α–sarcoglycan (adhalin), and 35 kD sarcoglycan). Thus secondary destabilization of the sarcoglycan complex may be an important pathophysiological event in ARMD.

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References

  1. Specht, L.A. & Kunkel, L.M. Duchenne and Becker muscular dystrophies. In The Molecular and Genetic Basis of Neurological Disease (eds Rosenberg, R.N., Prusiner S.B., DiMausro, S., Barchi, R.L & Kunkel, LM.) 613–631 (Butterworth-Heinemann, Boston, 1993).

    Google Scholar 

  2. Koenig, M., Monaco, A.P. & Kunkel, L.M. The complete sequence of dystrophin predicts a rod-shaped cytoskeletal protein. Cell 53, 219–226 (1988).

    Article  CAS  Google Scholar 

  3. Hoffman, E.P., Brown, R.J. & Kunkel, L.M. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 51, 919–928 (1987).

    Article  CAS  Google Scholar 

  4. Campbell, K.P. & Kahl, S.D. Association of dystrophin and an integral membrane glycoprotein. Nature 338, 259–262 (1989).

    Article  CAS  Google Scholar 

  5. Yoshida, M. & Ozawa, E. Glycoprotein complex anchoring dystrophin to sarcolemma. J. Biochem., Tokyo 108, 748–752 (1990).

    Article  CAS  Google Scholar 

  6. Yamamoto, H., Hagiwara, Y., Mizuno, Y., Yoshida, M. & Ozawa, E. Heterogeneity of dystrophin-associated proteins. J. Biochem., Tokyo 114, 132–139 (1993).

    Article  CAS  Google Scholar 

  7. Ervasti, J.M. & Campbell, K.P. Membrane organization of the dystrophin-glycoprotein complex. Cell 66, 1121–1131 (1991).

    Article  CAS  Google Scholar 

  8. Ibraghimov-Beskrovnaya, O. et al. Primary structure of dystrophin-associated glycoproteins linking dystrophin to the extracellular matrix. Nature 355, 696–702 (1992).

    Article  CAS  Google Scholar 

  9. Yoshida, M. et al. Dissociation of the complex of dystrophin and its associated proteins into several unique groups by n-octyl beta-D-glucoside. Eur. J. Biochem. 222, 1055–1061 (1994).

    Article  CAS  Google Scholar 

  10. Ibraghimov-Beskrovnaya, O. et al. Human dystroglycan: skeletal muscle cDNA, genomic structure, origin of tissue specific isoforms and chromosomal localization. Hum. molec. Genet. 2, 1651–1657 (1993).

    Article  CAS  Google Scholar 

  11. Suzuki, A. et al. Molecular organization at the glycoprotein complex-binding site of dystrophin —Three dystrophin-associated proteins bind directly to the carboxy-terminal portion of dystrophin. Eur. J. Biochem. 220, 283–292 (1994).

    Article  CAS  Google Scholar 

  12. Yoshida, M., Mizuno, Y., Nonaka, I. & Ozawa, E. A dystrophin-associated glycoprotein, A3a (one of 43DAG doublets), is retained in Duchenne muscular dystrophy muscle. J. Biochem., Tokyo 114, 634–639 (1993).

    Article  CAS  Google Scholar 

  13. Ben Hamida, M., Fardeau, M. & Attia, N. Severe childhood muscular dystrophy affecting both sexes and frequent in Tunisia. Muscle & Nerve 6, 469–480 (1983).

    Article  CAS  Google Scholar 

  14. Ben Othmane, K. et al. Linkage of Tunisian autosomal recessive Duchenne-like muscular dystrophy to the pericentromeric region of chromosome 13q. Nature Genet. 2, 315–317 (1992).

    Article  CAS  Google Scholar 

  15. EI Kerch, F. et al. Linkage analysis of families with severe childhood autosomal recessive muscular dystrophy in Morocco indicates genetic homogeneity of the disease in North Africa. J. med. Genet. 31, 342–343 (1994).

    Article  Google Scholar 

  16. Passos-Bueno, M.R. et al. Genetic heterogeneity for Duchenne-like muscular dystrophy (DLMD) based on linkage and 50 DAG analysis. Hum. molec. Genet. 2, 1945–1947 (1993).

    Article  CAS  Google Scholar 

  17. Fardeau, M. et al. Deficiency of the 50 kDa dystrophin associated glycoprotein (adhalin) in severe autosomal recessive muscular dystrophies in children native from European countries. C. R. Acad. Sci. Paris 316, 799–804 (1993).

    CAS  PubMed  Google Scholar 

  18. Zatz, M. et al. Assessment of the 50-kDa dystrophin-associated glycoprotein in Brazilian patients with severe childhood autosomal recessive muscular dystrophy. J. Neurol. Sci. 123, 122–128 (1994).

    Article  CAS  Google Scholar 

  19. Passos-Bueno, M.R. et al. A common missense mutation in the adhalin gene in three unrelated Brazilian families with a relatively mild form of autosomal recessive limb-girdle muscular dystrophy. Hum. molec. Genet 4, 1163–1167 (1995).

    Article  Google Scholar 

  20. Matsumura, K. et al. Deficiency of the 50K dystrophin-associated glycoprotein in severe childhood autosomal recessive muscular dystrophy. Nature 359, 320–322 (1992).

    Article  CAS  Google Scholar 

  21. Hayashi, Y.K. et al. The frequency of patients with 50 kDa dystrophin-associated glycoprotein (50 DAG or adhalin) deficiency in a muscular dystrophy patient population in Japan. Neurology 45, 551–554 (1995).

    Article  CAS  Google Scholar 

  22. Mizuno, Y. et al. Selective defect of sarcoglycan complex in severe childhood autosomal recessive muscular dystrophy muscle. Biochem. biophys. Res. Commun. 203, 979–983 (1994).

    Article  CAS  Google Scholar 

  23. McNally, E.M., Yoshida, M., Mizuno, Y., Ozawa, E. & Kunkel, L.M. Human adhalin is alternatively spliced and the gene is located on chromosome 17q21. Proc. natn. Acad. Sci. U.S.A. 91, 9690–9694 (1994).

    Article  CAS  Google Scholar 

  24. Roberds, S.L. et al. Missense mutations in the adhalin gene linked to autosomal recessive muscular dystrophy. Cell 78, 625–633 (1994).

    Article  CAS  Google Scholar 

  25. Piccolo, F. et al. Primary adhalinopathy: a common cause of autosomal recessive muscular dystrophy of variable severity. Nature Genet. 10, 243–245 (1995).

    Article  CAS  Google Scholar 

  26. Ljunggren, A. et al. Primary adhalin deficiency as a cause of muscular dystrophy in patients with normal dystrophin. Ann. Neurol. (in the press).

  27. Kozak, M. Compilation and analysis of sequences upstream from the translational start site in eukaryotic mRNAs. Nucl. Acids Res. 12, 857–872 (1984).

    Article  CAS  Google Scholar 

  28. Roberds, S.L., Anderson, R.D., Ibraghimov-Beskrovnaja, O. & Campbell, K.P. Primary structure and expression of the 50-kDa dystrophin-associated glycoprotein (adhalin). J. biol. Chem. 268, 23739–23742 (1993).

    CAS  Google Scholar 

  29. Ahn, A.H. et al. Cloning of human basic A1, a distinct 59-kDa dystrophin-associated protein encoded on chromosome 8q23–24. Proc. natn. Acad. Sci. U.S.A. 91, 4446–4450 (1994).

    Article  CAS  Google Scholar 

  30. von Heijne, G. Protein targeting signals. Curr. Opin. Cell Biol. 2, 604–608 (1990).

    Article  CAS  Google Scholar 

  31. Beck, J.S., Powers, L.S., Sheffield, V.C. & Murray, J.C. Chromosomal assignment using an efficient monochromosomal hybrid pooling strategy. Hum. Genet 53, A 974 (1993).

    Google Scholar 

  32. Bellanné-Chantelot, C. et al. Mapping the whole human genome by fingerprinting yeast artificial chromosomes. Cell 70, 1059–1068 (1992).

    Article  Google Scholar 

  33. Gyapay, G. et al. The 1993–1994 Généthon human genetic linkage map. Nature Genet. 7, 246–339 (1994).

    Article  CAS  Google Scholar 

  34. Bushby, K.M.D. & Beckmann, J.S. The limb-girdle muscular dystrophies —proposal for a new nomenclature. Neuromusc. Disord. 4, 337–343 (1995).

    Article  Google Scholar 

  35. Yamamoto, H. et al. Expression of dystrophin-associated protein 35DAG (A4) and 50DAG (A2) is confined to striated muscles. J. Biochem., Tokyo 115, 162–167 (1994).

    Article  CAS  Google Scholar 

  36. Ahn, A.H. & Kunkel, L.M. The structural and functional diversity of dystrophin. Nature Genet 3, 283–291 (1993).

    Article  CAS  Google Scholar 

  37. Tinsley, J.M., Blake, D.J., Zuellig, R.A., Davies, K.E. Increasing complexity of the dystrophin-associated protein complex. Proc. natn. Acad. Sci. U.S.A. 91, 8307–6313 (1994).

    Article  CAS  Google Scholar 

  38. Lim, L.E. et al. β-sarcoglycan: characterization and role in limb-girdle muscular dystrophy linked to 4q12. Nature Genet. 11, 257–265 (1995).

    Article  CAS  Google Scholar 

  39. Mizuno, Y. et al. Sarcoglycan complex is selectively lost in dystrophic hamster muscle. Am. J. Pathol. 146, 530–536 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Ozawa, E. et al. Dystrophin-associated proteins in muscular dystrophy. Hum. molec. Genet. (in the press).

  41. Ohlendieck, K. et al. Duchenne muscular dystrophy: deficiency of dystrophin-associated proteins in the sarcolemma. Neurology. 43, 795–800 (1993).

    Article  CAS  Google Scholar 

  42. Mizuno, Y., Yoshida, M., Nonaka, I., Hirai, S. & Ozawa, E. Expression of utrophin (dystrophin-related protein) and dystrophin-associated glycoproteins in muscles from patients with Duchenne muscular dystrophy. Muscle & Nerve 17, 206–216 (1994).

    Article  CAS  Google Scholar 

  43. Yoshida, M., Suzuki, A., Shimizu, T. & Ozawa, E. Proteinase-sensitive sites on isolated rabbit dystrophin. J. Biochem., Tokyo 112, 433–439 (1992).

    Article  CAS  Google Scholar 

  44. Kawasaki, H., Emori, Y. & Suzuki, K. Production and separation of peptides from proteins stained with comassie brilliant blue R-250 after separation by sodium dodecyl sulfate-polyacrykamide gel electrophoresis. Anal. Biochem. 191, 332–336 (1990).

    Article  CAS  Google Scholar 

  45. Sambrook, J., Fritsch, E.F. & Maniatis, T. Molecular Cloning: A Laboratory Manual (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1989).

    Google Scholar 

  46. Altschul, S.F., Gish, W., Miller, W., Meyers, E.W. & Lipman, D.J. Basic local alignment search tool. J mol. Biol. 215, 403–410 (1990).

    Article  CAS  Google Scholar 

  47. Dubois, B.L. & Naylor, S.L. Characterization of NIGMS Human/Rodent Somatic Cell Hybrid Mapping Panel 2 by PCR. Genomics 16, 315–319 (1993).

    Article  CAS  Google Scholar 

  48. Lichter, P. et al. High-resolution mapping of human chromosome 11 by in situ hybridization with cosmid clones. Science 247, 64–69 (1990).

    Article  CAS  Google Scholar 

  49. Tarentino, A.L., Gomez, G.M. & Plummer, J.T.H. Deglycosylation of asparagine-linked glycans by peptide:N-glycosylase F. Biochem. 24, 4665–4671 (1985).

    Article  CAS  Google Scholar 

  50. Hoffman, E.P., Arahata, K., Minetti, C., Bonilla, E. & Rowland, L.P. Dystrophinopathy in isolated cases of myopathy in females. Neurol. 42, 967–975 (1992).

    Article  CAS  Google Scholar 

  51. Miller, S.A., Dykes, D.D. & Polesky, H.F. A simple salting out procedure for extracting DNA from human nucleated cells.Nucl. Acids Res. 16, 1215 (1988).

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Howard Hughes Medical Institute/Division of Genetics, The Children's Hospital and Harvard Medical School, Boston, Massachusetts, 02115, USA

    Carsten G. Bönnemann, Emanuela Gussoni, Elizabeth M. McNally & Louis M. Kunkel

  2. Departments of Molecular Genetics and Biochemistry, Human Genetics, and Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, 15261, USA

    Raju Modi, David J. Duggan & Eric P. Hoffman

  3. Department of Cell Biology, National Institute of Neuroscience, National Center for Neurology and Psychiatry, 4-1-1 Ogawa Higashi, Kodaira, Tokyo, 187, Japan

    Satoru Noguchi, Yuji Mizuno, Mikiharu Yoshida & Eijiro Ozawa

  4. Clinica Neurologica 1, Universita di Padova, Padova, 35128, Italy

    Corrado Angelini

  5. Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, 02114, USA

    Carsten G. Bönnemann

  6. Department of Cardiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15261, USA

    Raju Modi

  7. Department of Neurology, Gunma University, 3-39-22 Showa, Maebashi, Gunma, 371, Japan

    Yuji Mizuno

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  1. Carsten G. Bönnemann
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Bönnemann, C., Modi, R., Noguchi, S. et al. β–sarcoglycan (A3b) mutations cause autosomal recessive muscular dystrophy with loss of the sarcoglycan complex. Nat Genet 11, 266–273 (1995). https://doi.org/10.1038/ng1195-266

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  • DOI: https://doi.org/10.1038/ng1195-266

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