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

  • A Correction to this article was published on 01 January 1996


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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  1. 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).

  2. 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).

  3. 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).

  4. 4

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

  5. 5

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

  6. 6

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

  7. 7

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

  8. 8

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

  9. 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).

  10. 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).

  11. 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).

  12. 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).

  13. 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).

  14. 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).

  15. 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).

  16. 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).

  17. 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).

  18. 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).

  19. 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).

  20. 20

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

  21. 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).

  22. 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).

  23. 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).

  24. 24

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

  25. 25

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

  26. 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. 27

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

  28. 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).

  29. 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).

  30. 30

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

  31. 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).

  32. 32

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

  33. 33

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

  34. 34

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

  35. 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).

  36. 36

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

  37. 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).

  38. 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).

  39. 39

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

  40. 40

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

  41. 41

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

  42. 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).

  43. 43

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

  44. 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).

  45. 45

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

  46. 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).

  47. 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).

  48. 48

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

  49. 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).

  50. 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).

  51. 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).

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