Abstract
This report is the second part of a trilogy from a multidisciplinary study which was undertaken to record the relationships between clinical severity and dystrophin gene and protein expression. The aim in part 2 was to correlate the effect of gene deletions on protein expression in individual patients with well defined clinical phenotypes. Among the DMD patients, most of the deletions/duplications disrupted the open reading frame, but three patients had in frame deletions. Some of the intermediate D/BMD patients had mutations which were frameshifting while others were in frame. All of the deletions/duplications in the BMD patients maintained the open reading frame and 25/26 deletions in typical BMD group 5 started with exon 45. The deletion of single exon 44 was the most common mutation in patients from groups 1 to 3. Dystrophin was detected in sections and blots from 58% of the DMD patients with a size that was compatible with synthesis from mRNA in which the reading frame had been restored. Certain deletions were particularly associated with the occurrence of limited dystrophin synthesis in DMD patients. For example, 9/11 DMD patients missing single exons had some detectable dystrophin labelling compared with 10/24 who had deletions affecting more than one exon. All patients missing single exon 44 or 45 had some dystrophin. Deletions starting or finishing with exons 3 or 51 (8/9) cases were usually associated with dystrophin synthesis whereas those starting or finishing with exons 46 or 52 (11/11) were not. Formal IQ assessments (verbal, performance, and full scores) were available for 47 patients. Mean IQ score among the DMD patients was 83 and no clear relationship was found between gene mutations and IQ. The mutations in patients with a particularly severe deficit of verbal IQ were spread throughout the gene.
Full text
PDF







Images in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Acsadi G., Dickson G., Love D. R., Jani A., Walsh F. S., Gurusinghe A., Wolff J. A., Davies K. E. Human dystrophin expression in mdx mice after intramuscular injection of DNA constructs. Nature. 1991 Aug 29;352(6338):815–818. doi: 10.1038/352815a0. [DOI] [PubMed] [Google Scholar]
- Appleton R. E., Bushby K., Gardner-Medwin D., Welch J., Kelly P. J. Head circumference and intellectual performance of patients with Duchenne muscular dystrophy. Dev Med Child Neurol. 1991 Oct;33(10):884–890. doi: 10.1111/j.1469-8749.1991.tb14797.x. [DOI] [PubMed] [Google Scholar]
- Barnea E., Zuk D., Simantov R., Nudel U., Yaffe D. Specificity of expression of the muscle and brain dystrophin gene promoters in muscle and brain cells. Neuron. 1990 Dec;5(6):881–888. doi: 10.1016/0896-6273(90)90348-j. [DOI] [PubMed] [Google Scholar]
- Baumbach L. L., Chamberlain J. S., Ward P. A., Farwell N. J., Caskey C. T. Molecular and clinical correlations of deletions leading to Duchenne and Becker muscular dystrophies. Neurology. 1989 Apr;39(4):465–474. doi: 10.1212/wnl.39.4.465. [DOI] [PubMed] [Google Scholar]
- Beggs A. H., Hoffman E. P., Kunkel L. M. Additional dystrophin fragment in Becker muscular dystrophy may result from proteolytic cleavage at deletion junctions. Am J Med Genet. 1992 Oct 1;44(3):378–381. doi: 10.1002/ajmg.1320440322. [DOI] [PubMed] [Google Scholar]
- Beggs A. H., Hoffman E. P., Snyder J. R., Arahata K., Specht L., Shapiro F., Angelini C., Sugita H., Kunkel L. M. Exploring the molecular basis for variability among patients with Becker muscular dystrophy: dystrophin gene and protein studies. Am J Hum Genet. 1991 Jul;49(1):54–67. [PMC free article] [PubMed] [Google Scholar]
- Blonden L. A., den Dunnen J. T., van Paassen H. M., Wapenaar M. C., Grootscholten P. M., Ginjaar H. B., Bakker E., Pearson P. L., van Ommen G. J. High resolution deletion breakpoint mapping in the DMD gene by whole cosmid hybridization. Nucleic Acids Res. 1989 Jul 25;17(14):5611–5621. doi: 10.1093/nar/17.14.5611. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Boyce F. M., Beggs A. H., Feener C., Kunkel L. M. Dystrophin is transcribed in brain from a distant upstream promoter. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1276–1280. doi: 10.1073/pnas.88.4.1276. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Brooke M. H., Fenichel G. M., Griggs R. C., Mendell J. R., Moxley R., Miller J. P., Province M. A. Clinical investigation in Duchenne dystrophy: 2. Determination of the "power" of therapeutic trials based on the natural history. Muscle Nerve. 1983 Feb;6(2):91–103. doi: 10.1002/mus.880060204. [DOI] [PubMed] [Google Scholar]
- Bulman D. E., Murphy E. G., Zubrzycka-Gaarn E. E., Worton R. G., Ray P. N. Differentiation of Duchenne and Becker muscular dystrophy phenotypes with amino- and carboxy-terminal antisera specific for dystrophin. Am J Hum Genet. 1991 Feb;48(2):295–304. [PMC free article] [PubMed] [Google Scholar]
- Bushby K. M., Gardner-Medwin D., Nicholson L. V., Johnson M. A., Haggerty I. D., Cleghorn N. J., Harris J. B., Bhattacharya S. S. The clinical, genetic and dystrophin characteristics of Becker muscular dystrophy. II. Correlation of phenotype with genetic and protein abnormalities. J Neurol. 1993 Feb;240(2):105–112. doi: 10.1007/BF00858726. [DOI] [PubMed] [Google Scholar]
- Bushby K. M., Gardner-Medwin D. The clinical, genetic and dystrophin characteristics of Becker muscular dystrophy. I. Natural history. J Neurol. 1993 Feb;240(2):98–104. doi: 10.1007/BF00858725. [DOI] [PubMed] [Google Scholar]
- Chelly J., Gilgenkrantz H., Lambert M., Hamard G., Chafey P., Récan D., Katz P., de la Chapelle A., Koenig M., Ginjaar I. B. Effect of dystrophin gene deletions on mRNA levels and processing in Duchenne and Becker muscular dystrophies. Cell. 1990 Dec 21;63(6):1239–1248. doi: 10.1016/0092-8674(90)90419-f. [DOI] [PubMed] [Google Scholar]
- Chelly J., Hamard G., Koulakoff A., Kaplan J. C., Kahn A., Berwald-Netter Y. Dystrophin gene transcribed from different promoters in neuronal and glial cells. Nature. 1990 Mar 1;344(6261):64–65. doi: 10.1038/344064a0. [DOI] [PubMed] [Google Scholar]
- Den Dunnen J. T., Grootscholten P. M., Bakker E., Blonden L. A., Ginjaar H. B., Wapenaar M. C., van Paassen H. M., van Broeckhoven C., Pearson P. L., van Ommen G. J. Topography of the Duchenne muscular dystrophy (DMD) gene: FIGE and cDNA analysis of 194 cases reveals 115 deletions and 13 duplications. Am J Hum Genet. 1989 Dec;45(6):835–847. [PMC free article] [PubMed] [Google Scholar]
- Dickson G., Love D. R., Davies K. E., Wells K. E., Piper T. A., Walsh F. S. Human dystrophin gene transfer: production and expression of a functional recombinant DNA-based gene. Hum Genet. 1991 Nov;88(1):53–58. doi: 10.1007/BF00204929. [DOI] [PubMed] [Google Scholar]
- Dunckley M. G., Love D. R., Davies K. E., Walsh F. S., Morris G. E., Dickson G. Retroviral-mediated transfer of a dystrophin minigene into mdx mouse myoblasts in vitro. FEBS Lett. 1992 Jan 20;296(2):128–134. doi: 10.1016/0014-5793(92)80363-l. [DOI] [PubMed] [Google Scholar]
- England S. B., Nicholson L. V., Johnson M. A., Forrest S. M., Love D. R., Zubrzycka-Gaarn E. E., Bulman D. E., Harris J. B., Davies K. E. Very mild muscular dystrophy associated with the deletion of 46% of dystrophin. Nature. 1990 Jan 11;343(6254):180–182. doi: 10.1038/343180a0. [DOI] [PubMed] [Google Scholar]
- Gangopadhyay S. B., Sherratt T. G., Heckmatt J. Z., Dubowitz V., Miller G., Shokeir M., Ray P. N., Strong P. N., Worton R. G. Dystrophin in frameshift deletion patients with Becker muscular dystrophy. Am J Hum Genet. 1992 Sep;51(3):562–570. [PMC free article] [PubMed] [Google Scholar]
- Hodgson S. V., Abbs S., Clark S., Manzur A., Heckmatt J. Z., Dubowitz V., Bobrow M. Correlation of clinical and deletion data in Duchenne and Becker muscular dystrophy, with special reference to mental ability. Neuromuscul Disord. 1992;2(4):269–276. doi: 10.1016/0960-8966(92)90059-f. [DOI] [PubMed] [Google Scholar]
- Hodgson S., Hart K., Abbs S., Heckmatt J., Rodillo E., Bobrow M., Dubowitz V. Correlation of clinical and deletion data in Duchenne and Becker muscular dystrophy. J Med Genet. 1989 Nov;26(11):682–693. doi: 10.1136/jmg.26.11.682. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hoffman E. P., Brown R. H., Jr, Kunkel L. M. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell. 1987 Dec 24;51(6):919–928. doi: 10.1016/0092-8674(87)90579-4. [DOI] [PubMed] [Google Scholar]
- Hoffman E. P., Fischbeck K. H., Brown R. H., Johnson M., Medori R., Loike J. D., Harris J. B., Waterston R., Brooke M., Specht L. Characterization of dystrophin in muscle-biopsy specimens from patients with Duchenne's or Becker's muscular dystrophy. N Engl J Med. 1988 May 26;318(21):1363–1368. doi: 10.1056/NEJM198805263182104. [DOI] [PubMed] [Google Scholar]
- Hoffman E. P., Kunkel L. M., Angelini C., Clarke A., Johnson M., Harris J. B. Improved diagnosis of Becker muscular dystrophy by dystrophin testing. Neurology. 1989 Aug;39(8):1011–1017. doi: 10.1212/wnl.39.8.1011. [DOI] [PubMed] [Google Scholar]
- Hoffman E. P., Kunkel L. M. Dystrophin abnormalities in Duchenne/Becker muscular dystrophy. Neuron. 1989 Jan;2(1):1019–1029. doi: 10.1016/0896-6273(89)90226-2. [DOI] [PubMed] [Google Scholar]
- Hoffman E. P., Morgan J. E., Watkins S. C., Partridge T. A. Somatic reversion/suppression of the mouse mdx phenotype in vivo. J Neurol Sci. 1990 Oct;99(1):9–25. doi: 10.1016/0022-510x(90)90195-s. [DOI] [PubMed] [Google Scholar]
- Kaplan L. C., Osborne P., Elias E. The diagnosis of muscular dystrophy in patients referred for language delay. J Child Psychol Psychiatry. 1986 Jul;27(4):545–549. doi: 10.1111/j.1469-7610.1986.tb00641.x. [DOI] [PubMed] [Google Scholar]
- Karagan N. J., Richman L. C., Sorensen J. P. Analysis of verbal disability in Duchenne muscular dystrophy. J Nerv Ment Dis. 1980 Jul;168(7):419–423. doi: 10.1097/00005053-198007000-00005. [DOI] [PubMed] [Google Scholar]
- Koenig M., Beggs A. H., Moyer M., Scherpf S., Heindrich K., Bettecken T., Meng G., Müller C. R., Lindlöf M., Kaariainen H. The molecular basis for Duchenne versus Becker muscular dystrophy: correlation of severity with type of deletion. Am J Hum Genet. 1989 Oct;45(4):498–506. [PMC free article] [PubMed] [Google Scholar]
- Koenig M., Monaco A. P., Kunkel L. M. The complete sequence of dystrophin predicts a rod-shaped cytoskeletal protein. Cell. 1988 Apr 22;53(2):219–228. doi: 10.1016/0092-8674(88)90383-2. [DOI] [PubMed] [Google Scholar]
- Lederfein D., Levy Z., Augier N., Mornet D., Morris G., Fuchs O., Yaffe D., Nudel U. A 71-kilodalton protein is a major product of the Duchenne muscular dystrophy gene in brain and other nonmuscle tissues. Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5346–5350. doi: 10.1073/pnas.89.12.5346. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Leibowitz D., Dubowitz V. Intellect and behaviour in Duchenne muscular dystrophy. Dev Med Child Neurol. 1981 Oct;23(5):577–590. doi: 10.1111/j.1469-8749.1981.tb02039.x. [DOI] [PubMed] [Google Scholar]
- Love D. R., England S. B., Speer A., Marsden R. F., Bloomfield J. F., Roche A. L., Cross G. S., Mountford R. C., Smith T. J., Davies K. E. Sequences of junction fragments in the deletion-prone region of the dystrophin gene. Genomics. 1991 May;10(1):57–67. doi: 10.1016/0888-7543(91)90484-v. [DOI] [PubMed] [Google Scholar]
- Love D. R., Flint T. J., Genet S. A., Middleton-Price H. R., Davies K. E. Becker muscular dystrophy patient with a large intragenic dystrophin deletion: implications for functional minigenes and gene therapy. J Med Genet. 1991 Dec;28(12):860–864. doi: 10.1136/jmg.28.12.860. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Love D. R., Flint T. J., Genet S. A., Middleton-Price H. R., Davies K. E. Becker muscular dystrophy patient with a large intragenic dystrophin deletion: implications for functional minigenes and gene therapy. J Med Genet. 1991 Dec;28(12):860–864. doi: 10.1136/jmg.28.12.860. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Love D. R., Flint T. J., Genet S. A., Middleton-Price H. R., Davies K. E. Becker muscular dystrophy patient with a large intragenic dystrophin deletion: implications for functional minigenes and gene therapy. J Med Genet. 1991 Dec;28(12):860–864. doi: 10.1136/jmg.28.12.860. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Malhotra S. B., Hart K. A., Klamut H. J., Thomas N. S., Bodrug S. E., Burghes A. H., Bobrow M., Harper P. S., Thompson M. W., Ray P. N. Frame-shift deletions in patients with Duchenne and Becker muscular dystrophy. Science. 1988 Nov 4;242(4879):755–759. doi: 10.1126/science.3055295. [DOI] [PubMed] [Google Scholar]
- Medori R., Brooke M. H., Waterston R. H. Genetic abnormalities in Duchenne and Becker dystrophies: clinical correlations. Neurology. 1989 Apr;39(4):461–465. doi: 10.1212/wnl.39.4.461. [DOI] [PubMed] [Google Scholar]
- Monaco A. P., Bertelson C. J., Liechti-Gallati S., Moser H., Kunkel L. M. An explanation for the phenotypic differences between patients bearing partial deletions of the DMD locus. Genomics. 1988 Jan;2(1):90–95. doi: 10.1016/0888-7543(88)90113-9. [DOI] [PubMed] [Google Scholar]
- Nicholson L. V., Bushby K. M., Johnson M. A., den Dunnen J. T., Ginjaar I. B., van Ommen G. J. Predicted and observed sizes of dystrophin in some patients with gene deletions that disrupt the open reading frame. J Med Genet. 1992 Dec;29(12):892–896. doi: 10.1136/jmg.29.12.892. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nicholson L. V., Johnson M. A., Bushby K. M., Gardner-Medwin D. Functional significance of dystrophin positive fibres in Duchenne muscular dystrophy. Arch Dis Child. 1993 May;68(5):632–636. doi: 10.1136/adc.68.5.632. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nicholson L. V., Johnson M. A., Bushby K. M., Gardner-Medwin D. Functional significance of dystrophin positive fibres in Duchenne muscular dystrophy. Arch Dis Child. 1993 May;68(5):632–636. doi: 10.1136/adc.68.5.632. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nicholson L. V., Johnson M. A., Gardner-Medwin D., Bhattacharya S., Harris J. B. Heterogeneity of dystrophin expression in patients with Duchenne and Becker muscular dystrophy. Acta Neuropathol. 1990;80(3):239–250. doi: 10.1007/BF00294640. [DOI] [PubMed] [Google Scholar]
- Norman A. M., Thomas N. S., Kingston H. M., Harper P. S. Becker muscular dystrophy: correlation of deletion type with clinical severity. J Med Genet. 1990 Apr;27(4):236–239. doi: 10.1136/jmg.27.4.236. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nudel U., Zuk D., Einat P., Zeelon E., Levy Z., Neuman S., Yaffe D. Duchenne muscular dystrophy gene product is not identical in muscle and brain. Nature. 1989 Jan 5;337(6202):76–78. doi: 10.1038/337076a0. [DOI] [PubMed] [Google Scholar]
- Pizzuti A., Pieretti M., Fenwick R. G., Gibbs R. A., Caskey C. T. A transposon-like element in the deletion-prone region of the dystrophin gene. Genomics. 1992 Jul;13(3):594–600. doi: 10.1016/0888-7543(92)90129-g. [DOI] [PubMed] [Google Scholar]
- Rapaport D., Passos-Bueno M. R., Brandão L., Love D., Vainzof M., Zatz M. Apparent association of mental retardation and specific patterns of deletions screened with probes cf56a and cf23a in Duchenne muscular dystrophy. Am J Med Genet. 1991 Jun 15;39(4):437–441. doi: 10.1002/ajmg.1320390414. [DOI] [PubMed] [Google Scholar]
- Rapaport D., Passos-Bueno M. R., Takata R. I., Campiotto S., Eggers S., Vainzof M., Makover A., Nudel U., Yaffe D., Zatz M. A deletion including the brain promoter of the Duchenne muscular dystrophy gene is not associated with mental retardation. Neuromuscul Disord. 1992;2(2):117–120. doi: 10.1016/0960-8966(92)90043-6. [DOI] [PubMed] [Google Scholar]
- Roberts R. G., Barby T. F., Manners E., Bobrow M., Bentley D. R. Direct detection of dystrophin gene rearrangements by analysis of dystrophin mRNA in peripheral blood lymphocytes. Am J Hum Genet. 1991 Aug;49(2):298–310. [PMC free article] [PubMed] [Google Scholar]
- SEASHORE H. G. Differences between verbal and performance IQs on the Wechsler Intelligence Scale for Children. J Consult Psychol. 1951 Feb;15(1):62–67. doi: 10.1037/h0060790. [DOI] [PubMed] [Google Scholar]
- SEASHORE H., WESMAN A., DOPPELT J. The standardization of the Wechsler intelligence scale for children. J Consult Psychol. 1950 Apr;14(2):99–110. doi: 10.1037/h0056307. [DOI] [PubMed] [Google Scholar]
- Slater C. R., Nicholson L. V. Is dystrophin labelling always discontinuous in Becker muscular dystrophy? J Neurol Sci. 1991 Feb;101(2):187–192. doi: 10.1016/0022-510x(91)90044-8. [DOI] [PubMed] [Google Scholar]
- Vainzof M., Passos-Bueno M. R., Rapaport D., Pavanello R. C., Zatz M., Bulman D. E. Additional dystrophin fragment in Becker muscular dystrophy patients: correlation with the pattern of DNA deletion. Am J Med Genet. 1992 Oct 1;44(3):382–384. doi: 10.1002/ajmg.1320440323. [DOI] [PubMed] [Google Scholar]
- Vainzof M., Passos-Bueno M. R., Rapaport D., Pavanello R. C., Zatz M., Bulman D. E. Additional dystrophin fragment in Becker muscular dystrophy patients: correlation with the pattern of DNA deletion. Am J Med Genet. 1992 Oct 1;44(3):382–384. doi: 10.1002/ajmg.1320440323. [DOI] [PubMed] [Google Scholar]
- Voit T., Stuettgen P., Cremer M., Goebel H. H. Dystrophin as a diagnostic marker in Duchenne and Becker muscular dystrophy. Correlation of immunofluorescence and western blot. Neuropediatrics. 1991 Aug;22(3):152–162. doi: 10.1055/s-2008-1071434. [DOI] [PubMed] [Google Scholar]
- Wells D. J., Wells K. E., Walsh F. S., Davies K. E., Goldspink G., Love D. R., Chan-Thomas P., Dunckley M. G., Piper T., Dickson G. Human dystrophin expression corrects the myopathic phenotype in transgenic mdx mice. Hum Mol Genet. 1992 Apr;1(1):35–40. doi: 10.1093/hmg/1.1.35. [DOI] [PubMed] [Google Scholar]
- den Dunnen J. T., Casula L., Makover A., Bakker B., Yaffe D., Nudel U., van Ommen G. J. Mapping of dystrophin brain promoter: a deletion of this region is compatible with normal intellect. Neuromuscul Disord. 1991;1(5):327–331. doi: 10.1016/0960-8966(91)90118-c. [DOI] [PubMed] [Google Scholar]