Journal of Neurology

, Volume 240, Issue 2, pp 105–112

The clinical, genetic and dystrophin characteristics of Becker muscular dystrophy

II. Correlation of phenotype with genetic and protein abnormalities
  • K. M. D. Bushby
  • D. Gardner-Medwin
  • L. V. B. Nicholson
  • M. A. Johnson
  • I. D. Haggerty
  • N. J. Cleghorn
  • J. B. Harris
  • S. S. Bhattacharyal
Original Communications

Abstract

We have correlated a detailed clinical assessment of 67 patients with proven Becker muscular dystrophy with the results from genetic and protein analyses. There was an overall deletion frequency of 80%, rising to 92.6% in the large group of patients defined on clinical grounds as being of “typically” mild severity. The deletions in this group were all clustered in the region of the gene between exons 45 and 59; the most common deletion was of exons 45–47 and all but one started at exon 45. No similar deletions were seen in the patients with more severe disease, in whom the diverse genetic defects included a duplication and a very large deletion. Dystrophin patterns in the “typical” group were also very characteristic, and in both groups were as predicted from the genetic defect, the size of deletions being inversely proportional to the size of the protein produced.

Key words

Muscular dystrophy Phenotype-genotype correlation Dystrophin Gene deletions 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Bartlett RJ, Walker AP, Laing NG, Koh J, Secore SL, Speer MC, Pericak-Vance MA, Hung WY, Yamaoka LH, Siddique T, Kandt R, Roses AD (1989) Inherited deletion of Duchenne muscular dystrophy locus in normal male. Lancet 1:496–497Google Scholar
  2. 2.
    Baumbach LL, Chamberlain IS, Ward PA, Farwell NJ, Caskey CT (1989) Molecular and clinical correlations of deletions leading to Duchenne and Becker muscular dystrophies. Neurology 39:465–474Google Scholar
  3. 3.
    Beggs AH, Koenig M, Boyce FM, Kunkel LM (1990) Detection of 98% of DMDBMD gene deletions by polymerase chain reaction. Hum Genet 86:45–48Google Scholar
  4. 4.
    Beggs AH, Hoffman EP, Synder JR, Arahata K, Specht L, Shapiro F, Angelini C, Sugita H, Kunkel LM (1991) Exploring the molecular basis for variability among patients with Becker muscular dystrophy: dystrophin gene and protein studies. Am J Hum Genet 49:54–67Google Scholar
  5. 5.
    Blonden LAJ, Dunnen JT den, Paassen HMB van, Wapemaar MC, Ginjaar HB, Bakker E, Pearson PL, Ommen GJB van (1989) High resolution deletion breakpoint mapping in the DMD gene by whole cosmid hybridisation. Nucleic Acids Res 17:5611–5621Google Scholar
  6. 6.
    Bushby KMD (1992) Genetic and clinical correlations of Xp21 muscular dystrophy. J Inherited Metab Dis 15:551–564Google Scholar
  7. 7.
    Bushby KMD, Gardner-Medwin D (1992) The clinical, genetic and dystrophin characteristics of Becker muscular dystrophy. I. Natural history. J Neurol 240:98–104Google Scholar
  8. 8.
    Campbell KP, Kahl SD (1989) Association of dystrophin and an integral membrane glycoprotein. Nature 338:259–262Google Scholar
  9. 9.
    Chelly J, Gilgenkrantz H, Lambert M, Hamard G, Chafey P, Recan D, Ginjaar IB, Fardeau M, Tome F, Kahn A, Kaplan JC (1991) The dystrophin transcripts in DMD and BMD patients with gene deletion. Angelini C, Danieli GA, Fontanari D (eds) Muscular dystrophy research: from molecular diagnosis toward therapy. (Excerpta Medica international congress set 934) Excerpta Medica, Amsterdam, pp 147–156Google Scholar
  10. 10.
    Cross RA, Stewart M, Kendrick-Jones J (1991) Structural predictions for the central domain of dytrophin. FEBS Lett 262:87–92Google Scholar
  11. 11.
    Cullen MJ, Walsh J, Nicholson LVB, Harris JB (1990) Ultrastructural localisation of dystrophin in human muscle by using gold immunolabelling. Proc R Soc Lond 240:197–210Google Scholar
  12. 12.
    Dunnen IT den, Grootscholten PM, Bakker E, Blonden LAJ, Ginjaar HB, Wagenaar MC, Passen HMB van, Broeckhaven C van, Pearson PL, Ommen GJB van (1989) Topography of the Duchenne muscular dystrophy (DMD) gene: FIGS and cDNA analysis of 194 cases reveals 115 deletion and 13 duplications. Am J Hum Genet 45:835–847Google Scholar
  13. 13.
    England SB, Nicholson LVB, Johnson MA, Forrest SM, Love DR, Zubrycka-Gaarn EE, Bulman DE, Harris JB, Davies KE (1990) Very mild muscular dystrophy associated with the deletion of 46% of dystrophin. Nature 342:180–182Google Scholar
  14. 14.
    Forrest SM, Cross GS, Speer A, Gardner-Medwin D, Burn J, Davies KE (1987) Preferential deletions of exons in Duchenne and Becker muscular dystrophy. Nature 359:638–640Google Scholar
  15. 15.
    Gilgenkrantz H, Chelly J, Lambert M, Recan D, Barbot JC, Ommen GJB van (1989) Analysis of molecular deletions with cDNA probes in patients with Duchenne and Becker muscular dystrophies. Genomics 5:574–580Google Scholar
  16. 16.
    Gillard EF, Chamberlain JS, Murphy EG, Duff CL, Smith B, Burghes AHM, Thompson MW, Sutherland J, Oss I, Bodry SE, Klamut HJ, Ray PN, Worton RG (1989) Molecular and phenotypic analysis of patients with deletions within the deletion rich region of the Duchenne muscular dystrophy (DMD) gene. Am J Hum Genet 45:507–520Google Scholar
  17. 17.
    Gospe SM, Lozaro RP, Lava NS, Grootscholten BS, Scott MD, Fischbeck KH (1989) Familial X-linked myalgia and cramps: a non-progressive myopathy associated with a deletion in the dystrophin gene. Neurology 39:1277–1280Google Scholar
  18. 18.
    Hodgson S, Hart K, Abbs S, Heckmatt J, Rodillo E, Bobrow M, Dubowitz V (1989) Correlation of clinical and deletion data in Duchenne and Becker muscular dystrophy. J Med Genet 26:682–693Google Scholar
  19. 19.
    Hoffman EP, Brown RH Jr, Kunkel LM (1987) Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 51:919–928Google Scholar
  20. 20.
    Hoffman EP, Fischbeck KH, Brown RH Jr, Johnson M, Medori R, Loike JD, Harris JB, Waterston R, Brooke M, Specht L, Kupsky W, Chamberlain J, Caskey T, Shapiro F, Kunkel LM (1988) Characterisation of dystrophin in muscle biopsy specimens from patients with Duchenne's or Becker's muscular dystrophy. N Engl J Med 318:1363–1368Google Scholar
  21. 21.
    Hoffman EP, Kunkel LP, Angelini C, Clarke A, Johnson M, Harris JB (1989) Improved diagnosis of Becker muscular dystrophy by dystrophin testing. Neurology 39:1011–1017Google Scholar
  22. 22.
    Koenig M, Kunkel LM (1990) Detailed analysis of the repeat domains of dystrophin reveals four potential hinge segments that may confer flexibility. J Biol Chem 265:4560–4566Google Scholar
  23. 23.
    Koenig M, Hoffman EP, Bertelson CJ, Monaco AP, Feener C, Kunkel LM (1987) Complete cloning of the Duchenne Muscular Dystrophy (DMD) cDNA and preliminary genomic organisation of the DMD gene in normal and affected individuals. Cell 50:509–517Google Scholar
  24. 24.
    Koenig M, Monaco AP, Kunkel LM (1988) The complete sequence of dystrophin predicts a rod-shaped cytoskeletal protein. Cell 53:219–228Google Scholar
  25. 25.
    Koenig M, Beggs AH, Mayer M, Scherpf S, Heindrich K, Bettecken T, Meng G, Muller CR, Lindlof M, Kaariainen H, De la Chapelle A, Kiuru A, Savontaus M-L, Gilgencrantz H, Recan D, Chelly J, Kaplan J-C, Covone AE, Archidiacono N, Romeo G, Liechti-Gallati S, Schneider V, Braga S, Moser H, Darras BT, Murhpy P, Rrancke U, Chen JD, Morgan G, Denton M, Greenberg CR, Wrongemann K, Blonden LAJ, Paassen HMB van, Ommen GJB van, Kunkel LM (1989) The molecular basis for Duchenne versus Becker dystrophy: correlation of severity with type of deletion. Am J Hum Genet 45:498–506Google Scholar
  26. 26.
    Lidov HGW, Byers TJ, Watkins SC, Kunkel LM (1990) Localisation of dystrophin to post-synaptic regions of central nervous system cortical neurons. Nature 348:725–728Google Scholar
  27. 27.
    Liechti-Gallati S, Koenig M, Kunkel LM, Frez D, Bolthauser E, Schneider V, Braza S, Moser H (1989) Molecular deletion patterns in Duchenne and Becker type muscular dystrophy. Hum Genet 81:343–348Google Scholar
  28. 28.
    Love DR, England SB, Speer A, Marsden RF, Bloomfield JF, Roche AL, Cross GS, Mountford RC, Smith TJ, Davies KE (1991) Sequences of junction fragments in the deletion-prone region of the dystrophin gene. Genomics 10:57–67Google Scholar
  29. 29.
    Medori R, Brooke MH, Waterston RH (1989) Genetic abnormalities in Duchenne and Becker dystrophies: clinical correlations. Neurology 39:461–465Google Scholar
  30. 30.
    Medori R, Brooke MH, Waterston RH (1989) Two dissimilar brothers with Becker's dystrophy have an idential genetic defect. Neurology 39:1493–1496Google Scholar
  31. 31.
    Monaco AP, Bertelson CJ, Liechti-Gallati S, Moser H, Kunkel LM (1988) An explanation for the phenotypic difference between patients bearing partial deletions of the DMD locus. Genomics 2:90–95Google Scholar
  32. 32.
    Nicholson LVB, Davison K, Falkous G, Harwood C, O'Donnell E, Slater CR, Harris JB (1989) Dystrophin in skeletal muscle. I. Western blot analysis using a monoclonal antibody. J Neurol Sci 94:125–136Google Scholar
  33. 33.
    Nicholson LVB, Johnson MA, Gardner-Medwin D, Bhattacharya SS, Harris JB (1990) Heterogeneity of dystrophin expression in patients with Duchenne and Becker muscular dystrophy. Acta Neuropathol 80:239–250Google Scholar
  34. 34.
    Nicholson LVB, Johnson MA, Davison K, O'Donnell E, Falkous G, Barron M, Harris JB (1992) Dystrophin or a “related protein” in Duchenne muscular dystrophy? Acta Neurol Scan 86:8–14Google Scholar
  35. 35.
    Norman AM, Thomas NJT, Kingston HM, Harper P (1990) Becker muscular dystrophy: correlation of deletion type with clinical severity. J Med Genet 27:236–239Google Scholar
  36. 36.
    Passos-Bueno MR, Rapport D, Love D, Flint T, Bortolini ER, Zatz M, Davies KE (1990) Screening of deletions in the dystrophin gene with the cDNA probes Cf23a, Cf56a and Cf15a. J Med Genet 27:145–150Google Scholar
  37. 37.
    Rappaport D, Passos-Bueno MR, Brandao L (1991) Apparent association of mental retardation and specific patterns of deletions screened with probes cf56a and cf23a in Duchenne muscular dystrophy. Am J Med Genet 39:437–441Google Scholar

Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • K. M. D. Bushby
    • 1
  • D. Gardner-Medwin
    • 2
  • L. V. B. Nicholson
    • 1
  • M. A. Johnson
    • 3
  • I. D. Haggerty
    • 1
  • N. J. Cleghorn
    • 1
  • J. B. Harris
    • 3
  • S. S. Bhattacharyal
    • 1
  1. 1.Department of Human GeneticsNewcastle upon TyneUK
  2. 2.Children's DepartmentNewcastle General HospitalNewcastle upon TyneUK
  3. 3.Muscular Dystrophy Group LaboratoriesNewcastle General HospitalNewcastle upon TyneUK

Personalised recommendations