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. 1994 Jan;31(1):33–36. doi: 10.1136/jmg.31.1.33

French myotonic dystrophy families show expansion of a CTG repeat in complete linkage disequilibrium with an intragenic 1 kb insertion.

C Lavedan 1, H Hofmann-Radvanyi 1, C Boileau 1, C Bonaïti-Pellié 1, D Savoy 1, P Shelbourne 1, C Duros 1, J P Rabes 1, I Dehaupas 1, S Luce 1, et al.
PMCID: PMC1049595  PMID: 8151634

Abstract

The molecular basis of myotonic dystrophy (DM) has been characterised. All DM mutations characterised to date appear as an unstable elongation of a fragment containing a tandem repeat of a CTG motif, which can be visualised in both EcoRI and BamHI digests. It has been shown that the fragment is polymorphic in the normal population. Another 1 kb insertion/deletion polymorphism located near the unstable CTG repeat region has been identified. The 1 kb insertion allele is present in all DM patients. These different polymorphic systems can be distinguished using cDNA25 and BamHI, because this enzyme cuts between the site of the 1 kb insertion and the CTG repeat. We thus haplotyped DM patients from 72 French families and clearly showed that all chromosomes (100%) with the DM mutation carried the 1 kb insertion as well. In addition to this association, we detected significant linkage disequilibrium between the DM locus and D19S63 for which allelic frequencies were different from other European populations. Our results in the French DM population are thus in agreement with the hypothesis that the CTG expansion occurred on one or a few ancestral chromosomes carrying the large 1 kb insertion allele.

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Selected References

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

  1. Aslanidis C., Jansen G., Amemiya C., Shutler G., Mahadevan M., Tsilfidis C., Chen C., Alleman J., Wormskamp N. G., Vooijs M. Cloning of the essential myotonic dystrophy region and mapping of the putative defect. Nature. 1992 Feb 6;355(6360):548–551. doi: 10.1038/355548a0. [DOI] [PubMed] [Google Scholar]
  2. Brook J. D., Harley H. G., Rundle S. A., Walsh K. V., Shaw D. J. RFLP for a DNA clone which maps to 19q13.2-19qter (D19S63). Nucleic Acids Res. 1990 Feb 25;18(4):1085–1085. [PMC free article] [PubMed] [Google Scholar]
  3. Brook J. D., McCurrach M. E., Harley H. G., Buckler A. J., Church D., Aburatani H., Hunter K., Stanton V. P., Thirion J. P., Hudson T. Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3' end of a transcript encoding a protein kinase family member. Cell. 1992 Feb 21;68(4):799–808. doi: 10.1016/0092-8674(92)90154-5. [DOI] [PubMed] [Google Scholar]
  4. Buxton J., Shelbourne P., Davies J., Jones C., Van Tongeren T., Aslanidis C., de Jong P., Jansen G., Anvret M., Riley B. Detection of an unstable fragment of DNA specific to individuals with myotonic dystrophy. Nature. 1992 Feb 6;355(6360):547–548. doi: 10.1038/355547a0. [DOI] [PubMed] [Google Scholar]
  5. Cobo A., Grinberg D., Balcells S., Vilageliu L., Gonzàlez-Duarte R., Baiget M. Linkage disequilibrium detected between myotonic dystrophy and the anonymous marker D19S63 in the Spanish population. Hum Genet. 1992 May;89(3):287–291. doi: 10.1007/BF00220541. [DOI] [PubMed] [Google Scholar]
  6. Fu Y. H., Pizzuti A., Fenwick R. G., Jr, King J., Rajnarayan S., Dunne P. W., Dubel J., Nasser G. A., Ashizawa T., de Jong P. An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science. 1992 Mar 6;255(5049):1256–1258. doi: 10.1126/science.1546326. [DOI] [PubMed] [Google Scholar]
  7. Griggs R. C., Wood D. S. Criteria for establishing the validity of genetic recombination in myotonic dystrophy. Neurology. 1989 Mar;39(3):420–421. doi: 10.1212/wnl.39.3.420. [DOI] [PubMed] [Google Scholar]
  8. Harley H. G., Brook J. D., Floyd J., Rundle S. A., Crow S., Walsh K. V., Thibault M. C., Harper P. S., Shaw D. J. Detection of linkage disequilibrium between the myotonic dystrophy locus and a new polymorphic DNA marker. Am J Hum Genet. 1991 Jul;49(1):68–75. [PMC free article] [PubMed] [Google Scholar]
  9. Harley H. G., Brook J. D., Rundle S. A., Crow S., Reardon W., Buckler A. J., Harper P. S., Housman D. E., Shaw D. J. Expansion of an unstable DNA region and phenotypic variation in myotonic dystrophy. Nature. 1992 Feb 6;355(6360):545–546. doi: 10.1038/355545a0. [DOI] [PubMed] [Google Scholar]
  10. Harley H. G., Rundle S. A., Reardon W., Myring J., Crow S., Brook J. D., Harper P. S., Shaw D. J. Unstable DNA sequence in myotonic dystrophy. Lancet. 1992 May 9;339(8802):1125–1128. doi: 10.1016/0140-6736(92)90729-m. [DOI] [PubMed] [Google Scholar]
  11. Henry I., Uzan G., Weil D., Nicolas H., Kaplan J. C., Marguerie C., Kahn A., Junien C. The genes coding for A alpha-, B beta-, and gamma-chains of fibrinogen map to 4q2. Am J Hum Genet. 1984 Jul;36(4):760–768. [PMC free article] [PubMed] [Google Scholar]
  12. Höweler C. J., Busch H. F., Geraedts J. P., Niermeijer M. F., Staal A. Anticipation in myotonic dystrophy: fact or fiction? Brain. 1989 Jun;112(Pt 3):779–797. doi: 10.1093/brain/112.3.779. [DOI] [PubMed] [Google Scholar]
  13. Imbert G., Kretz C., Johnson K., Mandel J. L. Origin of the expansion mutation in myotonic dystrophy. Nat Genet. 1993 May;4(1):72–76. doi: 10.1038/ng0593-72. [DOI] [PubMed] [Google Scholar]
  14. Johnson K., Shelbourne P., Davies J., Buxton J., Nimmo E., Siciliano M. J., Bachinski L. L., Anvret M., Harley H., Rundle S. A new polymorphic probe which defines the region of chromosome 19 containing the myotonic dystrophy locus. Am J Hum Genet. 1990 Jun;46(6):1073–1081. [PMC free article] [PubMed] [Google Scholar]
  15. Lavedan C., Hofmann-Radvanyi H., Rabes J. P., Roume J., Junien C. Different sex-dependent constraints in CTG length variation as explanation for congenital myotonic dystrophy. Lancet. 1993 Jan 23;341(8839):237–237. doi: 10.1016/0140-6736(93)90097-z. [DOI] [PubMed] [Google Scholar]
  16. Lavedan C., Hofmann-Radvanyi H., Shelbourne P., Rabes J. P., Duros C., Savoy D., Dehaupas I., Luce S., Johnson K., Junien C. Myotonic dystrophy: size- and sex-dependent dynamics of CTG meiotic instability, and somatic mosaicism. Am J Hum Genet. 1993 May;52(5):875–883. [PMC free article] [PubMed] [Google Scholar]
  17. MacKenzie A. E., MacLeod H. L., Hunter A. G., Korneluk R. G. Linkage analysis of the apolipoprotein C2 gene and myotonic dystrophy on human chromosome 19 reveals linkage disequilibrium in a French-Canadian population. Am J Hum Genet. 1989 Jan;44(1):140–147. [PMC free article] [PubMed] [Google Scholar]
  18. Mahadevan M., Tsilfidis C., Sabourin L., Shutler G., Amemiya C., Jansen G., Neville C., Narang M., Barceló J., O'Hoy K. Myotonic dystrophy mutation: an unstable CTG repeat in the 3' untranslated region of the gene. Science. 1992 Mar 6;255(5049):1253–1255. doi: 10.1126/science.1546325. [DOI] [PubMed] [Google Scholar]
  19. Morton N. E., Macpherson J. N. Population genetics of the fragile-X syndrome: multiallelic model for the FMR1 locus. Proc Natl Acad Sci U S A. 1992 May 1;89(9):4215–4217. doi: 10.1073/pnas.89.9.4215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Mulley J. C., Staples A., Donnelly A., Gedeon A. K., Hecht B. K., Nicholson G. A., Haan E. A., Sutherland G. R. Explanation for exclusive maternal origin for congenital form of myotonic dystrophy. Lancet. 1993 Jan 23;341(8839):236–237. doi: 10.1016/0140-6736(93)90096-y. [DOI] [PubMed] [Google Scholar]
  21. Nokelainen P., Alanen-Kurki L., Winqvist R., Falck B., Somer H., Leisti J., Johnson K., Savontaus M. L., Peltonen L. Linkage disequilibrium detected between dystrophia myotonica and APOC2 locus in the Finnish population. Hum Genet. 1990 Oct;85(5):541–545. doi: 10.1007/BF00194234. [DOI] [PubMed] [Google Scholar]
  22. Richards R. I., Holman K., Friend K., Kremer E., Hillen D., Staples A., Brown W. T., Goonewardena P., Tarleton J., Schwartz C. Evidence of founder chromosomes in fragile X syndrome. Nat Genet. 1992 Jul;1(4):257–260. doi: 10.1038/ng0792-257. [DOI] [PubMed] [Google Scholar]
  23. Shelbourne P., Winqvist R., Kunert E., Davies J., Leisti J., Thiele H., Bachmann H., Buxton J., Williamson B., Johnson K. Unstable DNA may be responsible for the incomplete penetrance of the myotonic dystrophy phenotype. Hum Mol Genet. 1992 Oct;1(7):467–473. doi: 10.1093/hmg/1.7.467. [DOI] [PubMed] [Google Scholar]
  24. Tsilfidis C., MacKenzie A. E., Mettler G., Barceló J., Korneluk R. G. Correlation between CTG trinucleotide repeat length and frequency of severe congenital myotonic dystrophy. Nat Genet. 1992 Jun;1(3):192–195. doi: 10.1038/ng0692-192. [DOI] [PubMed] [Google Scholar]
  25. Tsilfidis C., MacKenzie A. E., Shutler G., Leblond S., Bailly J., Johnson K., Williamson R., Siegel-Bartelt J., Korneluk R. G., Shelbourne P. D19S51 is closely linked with and maps distal to the myotonic dystrophy locus on 19q. Am J Hum Genet. 1991 Nov;49(5):961–965. [PMC free article] [PubMed] [Google Scholar]
  26. Verkerk A. J., Pieretti M., Sutcliffe J. S., Fu Y. H., Kuhl D. P., Pizzuti A., Reiner O., Richards S., Victoria M. F., Zhang F. P. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell. 1991 May 31;65(5):905–914. doi: 10.1016/0092-8674(91)90397-h. [DOI] [PubMed] [Google Scholar]
  27. Yamagata H., Miki T., Ogihara T., Nakagawa M., Higuchi I., Osame M., Shelbourne P., Davies J., Johnson K. Expansion of unstable DNA region in Japanese myotonic dystrophy patients. Lancet. 1992 Mar 14;339(8794):692–692. doi: 10.1016/0140-6736(92)90862-w. [DOI] [PubMed] [Google Scholar]

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