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Effect of the myotonic dystrophy (DM) mutation on mRNA levels of the DM gene

Nature Genetics volume 4, pages 233–238 (1993)Cite this article

Abstract

Myotonic dystrophy (DM) results from the amplification of an unstable CTG repeat in the 3′ untranslated region of a transcript encoding a putative serine/threonine kinase. We have analysed the amplification of the repeat and the steady state levels of the DM kinase (DMK) mRNA in tissues and cell lines from normal and congenital DM individuals. Southern blot analysis of DNA samples from a severely affected neonate shows somatic heterogeneity of the repeat in all tissues studied. RNA analyses on these tissues show a marked increase in DMK steady state mRNA levels. We demonstrate that the mutant DMK allele is expressed regardless of the number of CTG repeats and that the increase in DMK mRNA levels is due to elevated mutant mRNA levels. We postulate that elevated DMK levels explains the dominant inheritance pattern of DM.

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References

  1. Vanier, T.M. Dystrophia Myotonia in Childhood. Br. Med. J. 2, 1285–1288 (1960).

    Article  Google Scholar 

  2. Harper, P.S. . in Myotonic Dystrophy 2nd edn (Saunders, Philadelphia, 1989).

    Google Scholar 

  3. Sarnat, H.B. & Silbert, S.W., Maturational Arrest of Fetal Muscle in Neonatal Myotonic Dystrophy. Arch. Neurol. 33, 466–474 (1976).

    Article  CAS  PubMed  Google Scholar 

  4. Soussi-Yanicostas, N. et al. Distinct contractile protein profile in congenital myotonic dystrophy and X-linked myotubular myopathy. Neuromusc Dis 1, 103–111 (1992).

    Article  Google Scholar 

  5. Aslanidis, C. et al. Cloning of the essential myotonic dystrophy region and mapping of the putative defect. Nature 355, 548–551 (1992).

    Article  CAS  PubMed  Google Scholar 

  6. Mahadevan, M. et al. Myotonic dystrophy mutation: an unstable CTG repeat in the 3′ untranslated region of the gene. Science 255, 1253–1255 (1992).

    Article  CAS  PubMed  Google Scholar 

  7. Brook, J.D. et al. Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTQ) repeat at the 3′ end of a transcript encoding a protein kinase family member. Cell 68, 799–808 (1992).

    Article  CAS  PubMed  Google Scholar 

  8. Buxton, J. et al. Detection of an unstable fragment of DNA specific to individuals with myotonic dystrophy. Nature 355, 547–548 (1992).

    Article  CAS  PubMed  Google Scholar 

  9. Fu, Y.H. et al. An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science 255, 1256–1258 (1992).

    Article  CAS  PubMed  Google Scholar 

  10. Jansen, G. et al. Characterization of the myotonic dystrophy region predicts multiple protein isoform-encoding mRNAs. Nature Genet. 1, 261–266 (1992).

    Article  CAS  PubMed  Google Scholar 

  11. Harley, H.G. et al. Expansion of an unstable DNA region and phenotypic variation in myotonic dystrophy. Nature 355, 545–546 (1992).

    Article  CAS  PubMed  Google Scholar 

  12. Tsilfidis, C., MacKenzie, A.E., Mettler, G., Barcelo, J. & Korneluk, R.G. Correlation between CTG trinucleotide repeat length and frequency of severe congenital myotonic dystrophy. Nature Genet. 1, 192–195 (1992).

    Article  CAS  PubMed  Google Scholar 

  13. Barcelo, J.M., Mahadevan, M.S., Tsilfidis, C., MacKenzie, A.E. & Korneluk, R.G. Intergenerational stability of the myotonic dystrophy protomutation. Hum. molec. Genet. (in the press)

  14. Caskey, C.T., Pizzuti, A., Fu, Y.-H., Fenwick, R.G. & Nelson, D.L. Triplet repeat mutations in human disease. Science 256, 784–788 (1992).

    Article  CAS  PubMed  Google Scholar 

  15. Richards, R.I. & Sutherland, G.R. Dynamic mutations: A new class of mutations causing human disease. Cell 70, 709–712 (1992).

    Article  CAS  PubMed  Google Scholar 

  16. Howeler, C.J., Busch, H.F.M., Geraedts, J.P.M., Niermeijer, M.F. & Staal, A. Anticipation in myotonic dystrophy: fact or fiction? Brain 112, 779–797 (1989).

    Article  PubMed  Google Scholar 

  17. Fu, Y.-H. et al. Variation of the CGG repeat at the fragile X site results in genetic instability: Resolution of the Sherman paradox. Cell 67, 1047–1058 (1991).

    Article  CAS  PubMed  Google Scholar 

  18. Annemieke, J.M. et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65, 905–914 (1991).

    Article  Google Scholar 

  19. Pieretti, M. et al. Absence of expression of the FMR-1 gene in fragile X syndrome. Cell 66, 817–822 (1991).

    Article  CAS  PubMed  Google Scholar 

  20. Bell, M.V. et al. Physical mapping across the fragile X: Hypermethylation and clinical expression of the fragile X syndrome. Cell 64, 861–866 (1991).

    Article  CAS  PubMed  Google Scholar 

  21. Sutcliffe, J.S. et al. DNA methylation represses FMR-1 transcription in fragile X syndrome. Hum. molec. Genet. 1, 397–400 (1992).

    Article  CAS  PubMed  Google Scholar 

  22. La Spada, A.R., Wilson, E.M., Lubahn, D.B., Harding, A.E. & Fischbeck, K.H. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352, 77–79 (1991).

    Article  CAS  PubMed  Google Scholar 

  23. The Huntington's disease collaborative research group. Cell 72, 971–983 (1993).

    Article  Google Scholar 

  24. McAllister, R.M., Melnyk, J., Finkelstein, J.Z., Adams, E.C. Jr., & Gardner, M.B. Cultivation in vitro of cells derived from a human rhabdomyosarcoma. Cancer 24, 520–526 (1969).

    Article  CAS  PubMed  Google Scholar 

  25. Gililand, G., Perrin, S., Blanchard, K. & Bunn, H.F. Analysis of cytokine mRNA and DNA: detection and quantitation by competitive polymerase chain reaction. Proc. natn. Acad. Sci. U.S.A. 87, 2725–2729 (1990).

    Article  Google Scholar 

  26. Fu, Y.-H. et al. Decreased expression of myotonin-protein kinase messenger RNA and protein in adult form of myotonic dystrophy. Science 260, 235–238 (1993).

    Article  CAS  PubMed  Google Scholar 

  27. Zucker, M. & Stiegler, P. Optimal computer folding of large RNA sequences using thermodynamics and auxiliary information. Nucl. Acids Res. 9, 133–148 (1981).

    Article  Google Scholar 

  28. Mullner, E.W. & Kuhn, L.C. A stem-loop in the 3′ untranslated region mediates iron-dependent regulation of transferrin receptor mRNA stability in the cytoplasm. Cell 53, 815–825 (1988).

    Article  CAS  PubMed  Google Scholar 

  29. Mullner, E.W., Neupert, B. & Kuhn, L.C. A specific mRNA binding factor regulates the iron- dependent stability of cytoplasmic transferrin receptor mRNA. Cell 58, 373–382 (1989).

    Article  CAS  PubMed  Google Scholar 

  30. Peltz, S.W., Brewer, G., Bernstein, P., Hart, P.A. & Ross, J. Regulation of mRNA turnover in eukaryotic cells. Crit. Rev. Euk. Gene Exp. 1, 99–126 (1991).

    CAS  Google Scholar 

  31. Bernstein, P.L., Herrick, D.J., Prokipcak, R.D. & Ross, J. Control of c-myc mRNA half-life in vitro by a protein capable of binding to a coding stability determinant. Genes Dev. 6, 642–654 (1992).

    Article  CAS  PubMed  Google Scholar 

  32. Dix, D.J., Lin, P.-N., Kimata, Y. & Theil, E.C. The iron regulatory region of ferritin mRNA is also a positive control elememt for iron-independent translation. Biochemistry 31, 2818–2822 (1992).

    Article  CAS  PubMed  Google Scholar 

  33. Kaspar, R.L., Kakegawa, T., Cranston, H. & White, M.W. A regulatory cis element and a specific binding factor involved in the mitogenic control of murine ribosomal protein L32 translation. J. biol. Chem. 267, 508–514 (1992).

    CAS  PubMed  Google Scholar 

  34. Sengupta, D.N., Berkhout, B., Gatignol, A., Zhou, A. & Silverman, R.H. Direct evidence for translational regulation by leader RNA and Tat protein of human immunodeficiency virus type 1. Proc. natn. Acad. Sci. U.S.A. 87, 7492–7496 (1990).

    Article  CAS  Google Scholar 

  35. McCormack, S.J., Thomis, D.C. & Samuel, C.E. Mechanism of interferon action: Identification of a RNA binding domain within the N-terminal region of the human RNA-dependent P1/elF-2 alpha protein kinase. Virology 188, 47–56 (1992).

    Article  CAS  PubMed  Google Scholar 

  36. Wisdom, R. & Lee, W. Translation of c-myc mRNA is required for its post-transcriptional regulation during myogenesis. J. biol. Chem. 265, 19015–19021 (1990).

    CAS  PubMed  Google Scholar 

  37. Taylor, S.S., Buechler, J.A. & Yonemoto, W. cAMP-dependent protein kinase: framework for a diverse family of regulatory enzymes. An. Rev. Biochem. 59, 971–1005 (1990).

    Article  CAS  Google Scholar 

  38. Farkas-Bargeton, E. et al. Immaturity of muscle fibers in the congenital form of myotonic dystrophy. J. neurol. Sci. 83, 145–159 (1988).

    Article  CAS  PubMed  Google Scholar 

  39. Li, L., Heller-Harrison, R., Czech, M. & Olson, E. Cyclic AMP-dependent protein kinase inhibits the activity of myogenic helix-loop-helix proteins. Molec. cell. Biol. 12, 4478–4485 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Li, L. et al. FGF inactivates myogenic helix-loop-helix proteins through phosphorylation of a conserved protein kinase C site in their DNA-binding domain. Cell 71, 1181–1194 (1992).

    Article  CAS  PubMed  Google Scholar 

  41. Piechaczyk, M. et al. Post-transcriptional regulation of glyceraldehyde-3-phosphate-dehydrogenase gene expression in rat tissues. Nucl. Acids Res. 12, 6951–6963 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Puissant, C. & Houdebine, L.-M. An improvement of the single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Biotechniques 8, 148–149 (1990).

    CAS  PubMed  Google Scholar 

  43. Birnboim, H.C. Rapid extraction of high molecular weight RNA from cultured cells and granulocytes for Northern analysis. Nucl. Acids Res. 16, 1487–1497 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sambrook, J., Fritsch, E.F. & Maniatis, T. Molecular Cloning: A Laboratory Manual 2nd edn (Cold Spring Harbor, New York 1989).

    Google Scholar 

  45. Sabourin, L.A. & Hawley, R.G. Suppression of programmed death and G1 arrest in B-cell hybridomas by interleukin-6 is not accompanied by altered expression of immediate early response genes. J. cell. Physiol. 145, 564–574 (1990).

    Article  CAS  PubMed  Google Scholar 

  46. Dretzen, G., Bellard, M., Sassone-Corsi, P. & Chambon, P. A reliable method for the recovery of DNA fragments from agarose and acrylamide gels. Anal. Biochem. 112, 295–298 (1981).

    Article  CAS  PubMed  Google Scholar 

  47. Feinberg, A.P. & Vogelstein, B. A technique for radiolabelling DNA restriction endonuclease fragments to high specific activity. Anal. Biochem. 132, 6–13 (1983).

    Article  CAS  PubMed  Google Scholar 

  48. Mahadevan, M. et al. Structure and genomic sequence of the myotonic dystrophy (DM kinase) gene. Hum. molec. Genet. (in the press).

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Author information

Authors and Affiliations

  1. Department of Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, K1H 8M5, Canada

    Luc A. Sabouri, Mani S. Mahadevan, Monica Narang & Robert G. Korneluk

  2. Division of Genetics, Childrens Hospital of Eastern Ontario, Ottawa, Ontario, K1H 8L1, Canada

    Linda C. Surh & Robert G. Korneluk

  3. St-Joseph's Health Centre, University of Western Ontario, London, Ontario, NGA 6V2, Canada

    David S.C. Lee

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Sabouri, L., Mahadevan, M., Narang, M. et al. Effect of the myotonic dystrophy (DM) mutation on mRNA levels of the DM gene. Nat Genet 4, 233–238 (1993). https://doi.org/10.1038/ng0793-233

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