Skip to main content

PMC Search Update

PMC Beta search will replace the current PMC search the week of September 7, 2025. Try out PMC Beta search now and give us your feedback. Learn more

NCBI home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1988 Nov;43(5):620–629.

Intragenic deletions in 21 Duchenne muscular dystrophy (DMD)/Becker muscular dystrophy (BMD) families studied with the dystrophin cDNA: location of breakpoints on HindIII and BglII exon-containing fragment maps, meiotic and mitotic origin of the mutations.

B T Darras 1, P Blattner 1, J F Harper 1, A J Spiro 1, S Alter 1, U Francke 1
PMCID: PMC1715543  PMID: 2903663

Abstract

Following the strategy outlined in an accompanying paper, we studied 32 X-linked muscular dystrophy families (29 Duchenne [DMD] and three Becker [BMD] type) for abnormalities of HindIII and BglII fragments detected by the entire dystrophin cDNA. Twenty-one different single-intragenic deletions, and no duplications, were identified. The deletion endpoints were precisely mapped on the published HindIII fragment map. Detailed analysis of overlapping deletions led to clarification of the fragment order for some previously unsettled regions of the HindIII map and to the construction of a partial map of exon-containing BglII fragments. For the regions involved in deletions, the corresponding HindIII and BglIII fragments could be identified. Noncontiguous comigrating fragments were detected in two regions by careful analysis of the patterns in deletion patients. Four of the 21 deletions generated novel restriction fragments that facilitated detection of female carriers in these families. Twelve of the deletions had a breakpoint in one of the two large introns known to be the sites of breakpoint clusters. By combining deletions and RFLP analyses, we unequivocally identified the gamete that first carried the mutation in 13 families: eight oocytes and five sperm. Germ-line mosaicism previously detected in one male was confirmed by cDNA studies. In two additional families gonadal mosaicism was found in females. As evidence is accumulating for frequent mitotic origin of these deletion mutations, this phenomenon has to be considered when postulating mutational mechanisms and in genetic counseling of DMD/BMD families.

Full text

PDF
620

Images in this article

624Figure 1
on p.624
625Figure 2
on p.625

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Antonarakis S. E., Waber P. G., Kittur S. D., Patel A. S., Kazazian H. H., Jr, Mellis M. A., Counts R. B., Stamatoyannopoulos G., Bowie E. J., Fass D. N. Hemophilia A. Detection of molecular defects and of carriers by DNA analysis. N Engl J Med. 1985 Oct 3;313(14):842–848. doi: 10.1056/NEJM198510033131402. [DOI] [PubMed] [Google Scholar]
  2. Bakker E., Van Broeckhoven C., Bonten E. J., van de Vooren M. J., Veenema H., Van Hul W., Van Ommen G. J., Vandenberghe A., Pearson P. L. Germline mosaicism and Duchenne muscular dystrophy mutations. Nature. 1987 Oct 8;329(6139):554–556. doi: 10.1038/329554a0. [DOI] [PubMed] [Google Scholar]
  3. Ballabio A., Parenti G., Carrozzo R., Sebastio G., Andria G., Buckle V., Fraser N., Craig I., Rocchi M., Romeo G. Isolation and characterization of a steroid sulfatase cDNA clone: genomic deletions in patients with X-chromosome-linked ichthyosis. Proc Natl Acad Sci U S A. 1987 Jul;84(13):4519–4523. doi: 10.1073/pnas.84.13.4519. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bartlett R. J., Pericak-Vance M. A., Koh J., Yamaoka L. H., Chen J. C., Hung W. Y., Speer M. C., Wapenaar M. C., Van Ommen G. J., Bakker E. Duchenne muscular dystrophy: high frequency of deletions. Neurology. 1988 Jan;38(1):1–4. doi: 10.1212/wnl.38.1.1. [DOI] [PubMed] [Google Scholar]
  5. Bonifas J. M., Morley B. J., Oakey R. E., Kan Y. W., Epstein E. H., Jr Cloning of a cDNA for steroid sulfatase: frequent occurrence of gene deletions in patients with recessive X chromosome-linked ichthyosis. Proc Natl Acad Sci U S A. 1987 Dec;84(24):9248–9251. doi: 10.1073/pnas.84.24.9248. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cross G. S., Speer A., Rosenthal A., Forrest S. M., Smith T. J., Edwards Y., Flint T., Hill D., Davies K. E. Deletions of fetal and adult muscle cDNA in Duchenne and Becker muscular dystrophy patients. EMBO J. 1987 Nov;6(11):3277–3283. doi: 10.1002/j.1460-2075.1987.tb02646.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Darras B. T., Francke U. A partial deletion of the muscular dystrophy gene transmitted twice by an unaffected male. Nature. 1987 Oct 8;329(6139):556–558. doi: 10.1038/329556a0. [DOI] [PubMed] [Google Scholar]
  8. Darras B. T., Harper J. F., Francke U. Prenatal diagnosis and detection of carriers with DNA probes in Duchenne's muscular dystrophy. N Engl J Med. 1987 Apr 16;316(16):985–992. doi: 10.1056/NEJM198704163161604. [DOI] [PubMed] [Google Scholar]
  9. Darras B. T., Koenig M., Kunkel L. M., Francke U. Direct method for prenatal diagnosis and carrier detection in Duchenne/Becker muscular dystrophy using the entire dystrophin cDNA. Am J Med Genet. 1988 Mar;29(3):713–726. doi: 10.1002/ajmg.1320290341. [DOI] [PubMed] [Google Scholar]
  10. Forrest S. M., Cross G. S., Flint T., Speer A., Robson K. J., Davies K. E. Further studies of gene deletions that cause Duchenne and Becker muscular dystrophies. Genomics. 1988 Feb;2(2):109–114. doi: 10.1016/0888-7543(88)90091-2. [DOI] [PubMed] [Google Scholar]
  11. Forrest S. M., Cross G. S., Speer A., Gardner-Medwin D., Burn J., Davies K. E. Preferential deletion of exons in Duchenne and Becker muscular dystrophies. Nature. 1987 Oct 15;329(6140):638–640. doi: 10.1038/329638a0. [DOI] [PubMed] [Google Scholar]
  12. Forrest S. M., Smith T. J., Cross G. S., Read A. P., Thomas N. S., Mountford R. C., Harper P. S., Geirsson R. T., Davies K. E. Effective strategy for prenatal prediction of Duchenne and Becker muscular dystrophy. Lancet. 1987 Dec 5;2(8571):1294–1297. doi: 10.1016/s0140-6736(87)91192-5. [DOI] [PubMed] [Google Scholar]
  13. Fox J. E., Rosenberg L. E. Toward a molecular understanding of ornithine transcarbamylase deficiency. Adv Neurol. 1988;48:71–81. [PubMed] [Google Scholar]
  14. Francke U., Harper J. F., Darras B. T., Cowan J. M., McCabe E. R., Kohlschütter A., Seltzer W. K., Saito F., Goto J., Harpey J. P. Congenital adrenal hypoplasia, myopathy, and glycerol kinase deficiency: molecular genetic evidence for deletions. Am J Hum Genet. 1987 Mar;40(3):212–227. [PMC free article] [PubMed] [Google Scholar]
  15. Gillard E. F., Affara N. A., Yates J. R., Goudie D. R., Lambert J., Aitken D. A., Ferguson-Smith M. A. Deletion of a DNA sequence in eight of nine families with X-linked ichthyosis (steroid sulphatase deficiency). Nucleic Acids Res. 1987 May 26;15(10):3977–3985. doi: 10.1093/nar/15.10.3977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gitschier J., Wood W. I., Tuddenham E. G., Shuman M. A., Goralka T. M., Chen E. Y., Lawn R. M. Detection and sequence of mutations in the factor VIII gene of haemophiliacs. 1985 May 30-Jun 5Nature. 315(6018):427–430. doi: 10.1038/315427a0. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. Karel E. R., te Meerman G. J., Ten Kate L. P. On the power to detect differences between male and female mutation rates for Duchenne muscular dystrophy, using classical segregation analysis and restriction fragment length polymorphisms. Am J Hum Genet. 1986 Jun;38(6):827–840. [PMC free article] [PubMed] [Google Scholar]
  19. Koenig M., Hoffman E. P., Bertelson C. J., Monaco A. P., Feener C., Kunkel L. M. Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals. Cell. 1987 Jul 31;50(3):509–517. doi: 10.1016/0092-8674(87)90504-6. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. Koh J., Bartlett R. J., Pericak-Vance M. A., Speer M. C., Yamaoka L. H., Phillips K., Hung W. Y., Ray P. N., Worton R. G., Gilbert J. R. Inherited deletion at Duchenne dystrophy locus in normal male. Lancet. 1987 Nov 14;2(8568):1154–1155. doi: 10.1016/s0140-6736(87)91590-x. [DOI] [PubMed] [Google Scholar]
  22. Lanman J. T., Jr, Pericak-Vance M. A., Bartlett R. J., Chen J. C., Yamaoka L., Koh J., Speer M. C., Hung W. Y., Roses A. D. Familial inheritance of a DXS164 deletion mutation from a heterozygous female. Am J Hum Genet. 1987 Aug;41(2):138–144. [PMC free article] [PubMed] [Google Scholar]
  23. Monaco A. P., Bertelson C. J., Colletti-Feener C., Kunkel L. M. Localization and cloning of Xp21 deletion breakpoints involved in muscular dystrophy. Hum Genet. 1987 Mar;75(3):221–227. doi: 10.1007/BF00281063. [DOI] [PubMed] [Google Scholar]
  24. 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]
  25. Moser H. Duchenne muscular dystrophy: pathogenetic aspects and genetic prevention. Hum Genet. 1984;66(1):17–40. doi: 10.1007/BF00275183. [DOI] [PubMed] [Google Scholar]
  26. Müller C. R., Grimm T. Estimation of the male to female ratio of mutation rates from the segregation of X-chromosomal DNA haplotypes in Duchenne muscular dystrophy families. Hum Genet. 1986 Oct;74(2):181–183. doi: 10.1007/BF00282088. [DOI] [PubMed] [Google Scholar]
  27. Robertson M. Muscular dystrophy: mapping the disease phenotype. Nature. 1987 Jun 4;327(6121):372–373. doi: 10.1038/327372a0. [DOI] [PubMed] [Google Scholar]
  28. Roncuzzi L., Ferlini A., Pirozzi A., Romeo G. Origin of new mutations in Duchenne muscular dystrophy. Hum Genet. 1986 Dec;74(4):456–460. doi: 10.1007/BF00280507. [DOI] [PubMed] [Google Scholar]
  29. Smith T. J., Forrest S. M., Cross G. S., Davies K. E. Duchenne and Becker muscular dystrophy mutations: analysis using 2.6 kb of muscle cDNA from the 5' end of the gene. Nucleic Acids Res. 1987 Dec 10;15(23):9761–9769. doi: 10.1093/nar/15.23.9761. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Wapenaar M. C., Kievits T., Hart K. A., Abbs S., Blonden L. A., den Dunnen J. T., Grootscholten P. M., Bakker E., Verellen-Dumoulin C., Bobrow M. A deletion hot spot in the Duchenne muscular dystrophy gene. Genomics. 1988 Feb;2(2):101–108. doi: 10.1016/0888-7543(88)90090-0. [DOI] [PubMed] [Google Scholar]
  31. Wood S., McGillivray B. C. Germinal mosaicism in Duchenne muscular dystrophy. Hum Genet. 1988 Mar;78(3):282–284. doi: 10.1007/BF00291677. [DOI] [PubMed] [Google Scholar]
  32. Yang T. P., Patel P. I., Chinault A. C., Stout J. T., Jackson L. G., Hildebrand B. M., Caskey C. T. Molecular evidence for new mutation at the hprt locus in Lesch-Nyhan patients. Nature. 1984 Aug 2;310(5976):412–414. doi: 10.1038/310412a0. [DOI] [PubMed] [Google Scholar]
  33. Yen P. H., Allen E., Marsh B., Mohandas T., Wang N., Taggart R. T., Shapiro L. J. Cloning and expression of steroid sulfatase cDNA and the frequent occurrence of deletions in STS deficiency: implications for X-Y interchange. Cell. 1987 May 22;49(4):443–454. doi: 10.1016/0092-8674(87)90447-8. [DOI] [PubMed] [Google Scholar]
  34. Youssoufian H., Antonarakis S. E., Aronis S., Tsiftis G., Phillips D. G., Kazazian H. H., Jr Characterization of five partial deletions of the factor VIII gene. Proc Natl Acad Sci U S A. 1987 Jun;84(11):3772–3776. doi: 10.1073/pnas.84.11.3772. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. den Dunnen J. T., Bakker E., Breteler E. G., Pearson P. L., van Ommen G. J. Direct detection of more than 50% of the Duchenne muscular dystrophy mutations by field inversion gels. Nature. 1987 Oct 15;329(6140):640–642. doi: 10.1038/329640a0. [DOI] [PubMed] [Google Scholar]
  36. van Ommen G. J., Bertelson C., Ginjaar H. B., den Dunnen J. T., Bakker E., Chelly J., Matton M., van Essen A. J., Bartley J., Kunkel L. M. Long-range genomic map of the Duchenne muscular dystrophy (DMD) gene: isolation and use of J66 (DXS268), a distal intragenic marker. Genomics. 1987 Dec;1(4):329–336. doi: 10.1016/0888-7543(87)90032-2. [DOI] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES