Journal home
Advance online publication
Current issue
Archive
Press releases
Free Association (blog)
Supplements
Focuses
Guide to authors
Online submissionOnline submission
For referees
Free online issue
Contact the journal
Subscribe
Advertising
work@npg
Reprints and permissions
About this site
For librarians
 
NPG Resources
Nature
Nature Biotechnology
Nature Cell Biology
Nature Medicine
Nature Methods
Nature Reviews Cancer
Nature Reviews Genetics
Nature Reviews Molecular Cell Biology
news@nature.com
Nature Conferences
RNAi Gateway
NPG Subject areas
Biotechnology
Cancer
Chemistry
Clinical Medicine
Dentistry
Development
Drug Discovery
Earth Sciences
Evolution & Ecology
Genetics
Immunology
Materials Science
Medical Research
Microbiology
Molecular Cell Biology
Neuroscience
Pharmacology
Physics
Browse all publications
Article
Nature Genetics  13, 325 - 335 (1996)
doi:10.1038/ng0796-325

Mice lacking the myotonic dystrophy protein kinase develop a late onset progressive myopathy

Sita Reddy1, 5, Daniel B. J. Smith2, Mark M. Rich2, John M. Leferovich2, Patricia Reilly1, Brigid M. Davis1, Khoa Tran1, Helen Rayburn1, Roderick Bronson3, Didier Cros4, Rita J. Balice-Gordon2 & David Housman1

  1Center for Cancer Research, M.I.T. Cambridge, Massachusetts 02138, USA

  2Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6074, USA

  3Department of Pathology, Tufts University Schools of Medicine and Veterinary Medicine, Boston, Massachusetts 02111, USA

  4Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts 02214, USA

  5Institute for Genetic Medicine, Department of Neuroscience, University of Southern California, HMR 602, 2011 Zonal Avenue, Los Angeles, California 90033, USA

Myotonic dystrophy (DM) is an autosomal dominant disorder resulting from the expansion of a CTG repeat in the 3' untranslated region of a putative protein kinase (DMPK). To elucidate the role of DMPK in DM pathogenesis we have developed DMPK deficient (DMPK-/-) mice. DMPK-/- mice develop a late-onset, progressive skeletal myopathy that shares some pathological features with DM. Muscles from mature mice show variation in fibre size, increased fibre degeneration and fibrosis. Adult DMPK-/- mice show ultrastructural changes in muscle and a 50% decrease in force generation compared to young mice. Our results indicate that DMPK may be necessary for the maintenance of skeletal muscle structure and function and suggest that a decrease in DMPK levels may contribute to DM pathology.

REFERENCES
  1. Harper, P.S. in Myotonic Dystrophy. 2nd. ed. (W.B. Saunders, 1989).
  2. Howeler, C.J., Busch, H.F., Geraedts, J.P., Niermeijer, M.F. & Staal, A. Anticipation in myotonic dystrophy: Fact or fiction?. Brain 112, 779−797 (1989). | PubMed  | ISI |
  3. O'Brien, T., Harper, P.S. Course, prognosis and complications of childhood-onset myotonic dystrophy. Dev. Med. Child. Neurol. 26, 62−67 (1984). | PubMed  | ChemPort |
  4. Brook, J.D. et al. 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 68, 799−808 (1992). | Article | PubMed  | ISI | ChemPort |
  5. Fu, Y.-H. et al. An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science 255, 1256−1258 (1992). | PubMed  | ISI | ChemPort |
  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). | PubMed  | ISI | ChemPort |
  7. Harley, H. et al. Size of the unstable CTG repeat sequence in relation to phenotype and parental transmission in myotonic dystrophy. Am. J. Hum. Genet. 52, 1164−1174 (1993). | PubMed  | ISI | ChemPort |
  8. La Spada, A.R., Wilson, E.M., Lubahn, D.B., Harding, A.E. & Fishbeck, K.H. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352, 77−79 (1991). | Article | PubMed  | ISI | ChemPort |
  9. Verkerk, A.J.M.H. et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a fragile X breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65, 905−914 (1991). | PubMed  | ISI | ChemPort |
  10. The Huntington's Disease Research Group. A novel gene encoding a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosome. Cell 72, 971−983 (1993). | PubMed  | ISI |
  11. Knight, S.J. et al. Trinucleotide repeat amplification and hypermethylation of a CpG island in FRAXE mental retardation. Cell 74, 127−134 (1993). | Article | PubMed  | ISI | ChemPort |
  12. Orr, H.T. et al. Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nature Genet. 4, 221−226 (1993). | Article | PubMed  | ISI | ChemPort |
  13. Burke, J.R. et al. The Haw River syndrome: dentatorubropallidoluysian atrophy (DRPLA) in an African-American family. Nature Genet. 7, 521−524 (1994). | Article | PubMed  | ISI | ChemPort |
  14. Koide, R. et al. Unstable expansion of CAG repeat in hereditary dentatorubralpallidoluysian atrophy (DRPLA). Nature Genet. 6 1994). | PubMed  | ChemPort |
  15. Nancarrow, J.K. et al. Implications of FRA 16A structure for the mechanism of chromosomal fragile site genesis. Science 264, 1938−1941 (1994). | PubMed  | ISI | ChemPort |
  16. Pieretti, M. et al. Absence of expression of the FMR-1 gene in fragile X syndrome. Cell 66, 817−822 (1991). | Article | PubMed  | ISI | ChemPort |
  17. Feng, Y. et al. Translational supression by trinucleotide repeat at FMR1. Science 268, 731−734 (1995). | PubMed  | ISI | ChemPort |
  18. Housman, D. Gain of glutamines, gain of function. Nature Genet. 10, 3−4 (1995). | Article | PubMed  | ISI | ChemPort |
  19. Fu, Y.-H. et al. Decreased expression of myotonin-protein kinase messenger RNA and protein in adult form of myotonic dystrophy. Science 260, 235−237 (1993). | PubMed  | ISI | ChemPort |
  20. Sabouri, L.A. et al. Effect of the myotonic dystrophy (DM) mutation on mRNA levels of the DM gene. Nature Genet. 4, 233−238 (1993). | Article | PubMed  | ISI | ChemPort |
  21. Carango, P., Noble, J.E., Marks, H.G. & Funanage, V.L. Absence of myotonic dystrophy protein kinase (DMPK) mRNA as a result of a triplet repeat expansion in myotonic dystrophy. Genomics 18, 340−348 (1993). | Article | PubMed  | ISI | ChemPort |
  22. Hofmann-Radvanyi, H. et al. Myotonic dystrophy: Absence of CTG enlarged transcript in congenital forms and low expression of the normal allele. Hum. Mol. Genet. 2, 1263−1267 (1993). | PubMed  | ChemPort |
  23. Novelli, G. et al. Failure in detecting mRNA transcripts from the mutated allele in myotonic dystrophy muscle. Biochem. Med. Metabol. Biol. 50, 85−92 (1993). | Article | ISI | ChemPort |
  24. Koga, R. et al. Decreased myotonin-protein kinase in skeletal and cardiac muscles in myotonic dystrophy. Biochem. Biophys. Res. Commun. 202, 577−585 (1994). | Article | PubMed  | ISI | ChemPort |
  25. Krahe, R. et al. Effect of myotonic dystrophy trinucleotide repeat expansion on DMPK transcription and processing. Genomics 28 (1995). | Article | PubMed  | ChemPort |
  26. Wang, J. et al. Myotonic dystrophy: evidence for a possible dominant-negative RNA mutation. Hum. Mol. Gen. 4, 599−606 (1995). | PubMed  | ISI | ChemPort |
  27. Maeda, M. et al. Identification, tissue-specific expression, and subcellular localization of the 80 and 71 kDa forms of myotonic dystrophy kinase protein. J. Biol. Chem. 270, 20246−20249 (1995). | Article | PubMed  | ISI | ChemPort |
  28. Jansen, G. et al. Characterization of the myotonic dystrophy region predicts multiple protein isoform-encoding mRNAs. Nature Genet. 1, 261−266 (1992). | Article | PubMed  | ISI | ChemPort |
  29. Mahadevan, M.S. et al. Structure and genomic sequence of the myotonic dystrophy (DM kinase). Gene 2, 299−304 (1993). | ChemPort |
  30. Kamps, M.R., Taylor, S.S. & Sefton, B.M. Direct evidence that oncogenic tyrosine kinases and cyclic AMP-dependent protein kinases have homologous ATP binding sites. Nature 310, 589−592 (1984). | PubMed  | ISI | ChemPort |
  31. Hanks, S.K., Quinn, A.M. & Hunter, T. The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science 241, 42−52 (1988). | PubMed  | ISI | ChemPort |
  32. Sacco, P., Jones, D.A., Dick, J.R.T. & Vrbova, G. Contractile properties and susceptibility to exercise induced damage of normal and mdx tibialis anterior muscle. Clin. Sci. 82, 227−336 (1992). | PubMed  | ISI | ChemPort |
  33. Burke, R.E. Physiology of Motor Units in Myology 2nd. ed. (eds. Andrew G. Engel & Clara Franzini-Armstrong) 1, 464−484 (McGraw-Hill Inc., New York 1994).
  34. Bailce-Gordon, R.J. & Lichtman, J.W. In vivo visualization of the growth of pre and postsynaptic elements of mouse neuromuscular junctions. J. Neurosci. 10, 894−908 (1990). | PubMed  | ChemPort |
  35. Wernig, A. & Herrera, A.A. Sprouting and remodelling at the nerve-muscle junction. Prog. Neurobiol. 7, 251−291 (1986). | Article |
  36. Morgan-Hughes, J.A. Mitochondrial diseases in Myology 2nd. ed. (eds. Andrew G. Engel and Clara Franzini-Armstrong) 1610−1660 (McGraw-Hill Inc., New York 1994).
  37. Moss, F.P. & Leblond, C.P. Satellite cells as a source of nuclei in muscles of growing rats. Anat Rec. 170, 421−436 (1970). | ISI |
  38. Campion, D.R. The muscle satellite cell: A review. Int. Rev. Cytol. 87, 225−251 (1984). | PubMed  | ISI | ChemPort |
  39. Grounds, M.D., Garrett, K., Lai, M.C., Wright, W.E. & Beilharz, M.W. Identification of skeletal muscle precursor cells in vivo by use of MyoD and myogenin probes. Cell Tissue Res. 267, 99−104 (1992). | PubMed  | ISI | ChemPort |
  40. Koishi, K., Zhang, M., McLennan, I.S. & Haris, A.J. MyoD protein accumalates in satellite cells and is neurally regulated in regenerating myotubes and skeletal muscle fibers. Developmental Dynamics 202, 244−254 (1995). | PubMed  | ISI | ChemPort |
  41. Beilharz, M.W., Lareu, R.R., Garrett, K.L., Grounds, M.D. & Fletcher, S. Quantitation of muscle precursor cell activity in skeletal muscle by northern analysis of MyoD and Myogenin expression: Application to dystrophic (mdx) mouse model. Mol. and Cell. Neurosciences 3, 326−331 (1992). | ChemPort |
  42. Gambke, B. & Rubinstein, N.A. A monoclonal antibody to embryonic myosin heavy chain of rat skeletal muscle. J. Biol. Chem. 259, 12092−12100 (1984). | PubMed  | ChemPort |
  43. Bancroft, J.D. & Stevens, A. Theory and Practice of Histological Techniques. (1990).
  44. Casanova, G. & Jerusalem, F. Myopathology of myotonic dystrophy. A morphometric study. Acta Neuropathol 45, 231 (1979). | PubMed  | ChemPort |
  45. Anderson, J.E., Ovalle, W.K. & Bressler, B.H., Electron Microscopic and Autoradiographic Characterization of Hindlimb Muscle Regeneration in mdx Mouse. Anat. Rec. 219, 243−257 (1987). | PubMed  | ISI | ChemPort |
  46. Carnwath, J.W. & Shotton, D.M. Muscular dystrophy in the mdx mouse: Histopathology of the soleus and extensor digitorum longus muscles. J. Neurol. Sci. 80, 39−54 (1987). | Article | PubMed  | ISI | ChemPort |
  47. Fitzsimons, R.B. & Hoh, J.F.Y. Embryonic and foetal myosins in human skeletal muscle: the presence of foetal myosins in Duchenne muscular dystrophy and infantile spinal muscular atrophy. J. Neurol. Sci. 52, 367−384 (1981). | Article | PubMed  | ISI | ChemPort |
  48. Karsch-Mizrachi, I., Travis, M., Blau, H. & Leinwald, L.A. Expression and DNA sequence of a human embryonic skeletal muscle myosin heavy chain gene. Nuc. Acids. Res. 17, 6167−6179 (1989). | ChemPort |
  49. McComas, A.J., Campbell, M.J. & Sica, R.E.P. Electrophysiological study of dystrophica myotonica. J. Neurol. Neurosurg. Psychiat. 34, 132−139 (1971). | PubMed  | ISI | ChemPort |
  50. Belanger, A.Y. & McComas, A.J. Contractile properties of muscles in myotonic dystrphy. J. Neuro Neurosurg. Psychiat. 46, 625−631 (1983). | ISI | ChemPort |
  51. Taylor, R.G., Abresch, R.T., Lieberman, J.S., Fowler, W.MN. & Entrikin, R.K. In vivo quantification of muscle contractility in humans: healthy subjects and patients with myotonic muscular dystrophy. Arch. Phys. Med. Rehabil. 73, 233−236 (1992). | Article | PubMed  | ISI | ChemPort |
  52. Salvatori, S., Biral, D., Furlan, S. & O., M. Identification and localization of the myotonic dystrophy gene product in skeletal and cardiac muscles. Biochem. Biophys. Res. Commun. 203, 1365−1370 (1994). | Article | PubMed  | ISI | ChemPort |
  53. Dunne, P.W., Ma, L., Casey, D.L., Harati, Y. & Epstein, H.F. Localization of myotonic dystrophy protein kinase in skeletal muscle and its alteration with disease. Cell Motility and the Cytoskeleton 33 1995).
  54. Timchenko, L. et al. Full-length myotonin protein kinase (72 KDa) displays serine kinase activity. Proc. Natl. Acad. Sci. USA 92, 5366−5370 (1995). | PubMed  | ChemPort |
  55. Petrof, B.J., Shrager, J.B., Stedman, H.H., Kelly, A.M. & Sweeny, H.L. Dystrophin protects the sarcolemma from stresses developed during muscle contraction. Proc. Natl. Acad. Sci. USA 90, 3710−3714 (1993). | PubMed  | ChemPort |
  56. Dubowitz, V., Muscle Biopsy 2nd. ed. (W.B. Saunders, 1985).
  57. Aleu, F.P. & Afifi, A.K. Ultrastructure of muscle in myotonic dystrophy. Am. J. Pathol. 45, 221−231. (1964). | PubMed  | ISI | ChemPort |
  58. Johnson, A.G. Alteration of the Z lines and I-band myofilaments in human skeletal muscle. Arch Neuropathol (Berlin) 12, 218−226 (1969). | ChemPort |
  59. Johnson, A.G. & Woolf, A.L. Abnormal sarcolemmal nuclei encountered in several cases of dystrophica myotonica. Acta neuropath. (Berl.) 12, 183−188 (1969). | ChemPort |
  60. Fardeau, M. Ultrastructural lesions in progressive muscular dystrophies. A critical study of their specificity. In: J.N. Walton, N. Canal and G. Scarlata eds: Muscle Diseases, Amsterdam. Experta Medica, 98−108 (1970).
  61. Schotland, D.L. An electron microscopic investigation of myotonic dystrophy. J. Neuropath. & Exper. Neurol. 29, 241−253 (1970). | ChemPort |
  62. Bulfield, G., Siller, W.G., Wright, P.A. & Moore, K.J. X-chromosome-linked muscular dystrophy (mdx) in the mouse. Proc. Natl. Acad. Sci. USA 81, 1189−1192 (1984). | PubMed  | ChemPort |
  63. Rastinjad, F. & Blau, H. Genetic complementation reveals a novel regulatory role for 3' untranslated region in growth and differentiation. Cell 72, 903−917 (1993). | PubMed  |
  64. Wang, Y.-H., Amirhaeri, S., Kang, S., Wells, R.D. & Griffith, J.D. Preferential nucleosome assembly at DNA triplet repeats from the myotonic dystrophy gene. Science 265, 1709−1712 (1994). | PubMed  | ISI | ChemPort |
  65. Wang, Y.-H. & Griffith, J. Expanded CTG triplet blocks from the myotonic dystrophy gene create the strongest known natural nucleosome positioning elements. Genomics 25, 570−573 (1995). | Article | PubMed  | ISI | ChemPort |
  66. Boucher, C.A. et al. A novel homeodomain encoding gene is associated with a large CpG island interrupted by the myotonic dystrophy unstable (CTG)n repeat. Hum. Mol. Genet. 4, 1919−1925 (1995). | PubMed  | ISI | ChemPort |
  67. Shaw, D.J. et al. Genomic organization and transcriptional units at the myotonic dystrophy locus. Genomics 18, 673−679 (1993). | PubMed  | ISI | ChemPort |
  68. Tybulewicz, V.L.J., Crawford, C.E., Jackson, P.K., Bronson, R.T. & Mulligan, R.C. Neonatal lethality and lymhopenia in mice with a homozygous disruption of the c-abl proto-oncogene. Cell 65, 1153−1163 (1991). | Article | PubMed  | ISI | ChemPort |
  69. Mansour, S.L., Thomas, K.R. & Capecchi, M.R. Disruption of the proto-oncogene int-2 in mouse embryo-derived stem-cells: a general strategy for targeting mutations to nonselectable genes. Nature 336, 348−352 (1988). | Article | PubMed  | ISI | ChemPort |
  70. Laird, R.W. et al. Simplified mammalian DNA isolation procedure. Nucl. Acids Res. 19, 4293 (1991). | PubMed  | ISI | ChemPort |
  71. Hogan, B., Constantini, F. & Lacy, E. Manipulating the Mouse Embryo: A Laboratory Manual. (Cold Spring Harbor Laboratory Press, 1986).
  72. Davis, R.L., Weintraub, H. & Lassar, A.B. Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell 51, 987−1000 (1987). | Article | PubMed  | ISI | ChemPort |
  73. Braun, T.G. et al. Differential expression of myogenic determination genes in muscle cells: possible autoactivation by the Myf gene products. EMBO J. 8, 3617−3625 (1989). | PubMed  | ISI | ChemPort |
  74. Braun, T., Buschhausen-Denker, G., Bober, E., Tannich, E. & Arnold, H.-H. A novel human muscle factor related to but distinct from MyoD1 induces myogenic conversion in 10T1/2 fibroblasts. EMBO. J. 8, 701−709 (1989). | PubMed  | ISI | ChemPort |
  75. Rhodes, S.J. & Konieczny, S.F. Identification of MRF4: a new member of the muscle regulatory factor gene family. Genes Dev. 3, 2050−2061 (1989). | PubMed  | ISI | ChemPort |
  76. Shackleford, G.M. & Varmus, H.E. Expression of the proto-oncogene int1 is restricted to post meiotic male germ cells and the neural tube of midgestational embryos. Cell 50, 89−95 (1987). | Article | PubMed  | ISI | ChemPort |
  77. Close, K. Dynamic properties of mammalian skeletal muscle. Phys. Rev. 52, 129−197 (1972). | ISI |
  78. Schiaffino, S., Gorza, L., Dones, I., Cornelio, F. & Sartore, S. Fetal myosin immunoreactivity in human dystrophic muscle. Muscle Nerve 9, 51−58 | PubMed  | ChemPort |
 Top
 Top
Abstract
Previous | Next
Table of contents
Download PDFDownload PDF
Send to a friendSend to a friend
Save this linkSave this link

Open Innovation Challenges

  • Optimizing Sub-cellular Localization Tags

    • Deadline: Jan 31 2010
    • Reward: $20,000 USD

    The Seeker is looking for methods to optimize sub-cellular localization tags for protein expression....

  • Single-cell Analysis Platform

    • Deadline: Dec 02 2009
    • Reward: $5,000 USD

    This Challenge is looking for novel approaches to analyzing changes at a single-cell level. This is...

naturejobs

References
Export citation
Export references
natureproducts

Search buyers guide:

 
ADVERTISEMENT
 
Nature Genetics
ISSN: 1061-4036
EISSN: 1546-1718
Journal home | Advance online publication | Current issue | Archive | Press releases | Supplements | Focuses | For authors | Online submission | Permissions | For referees | Free online issue | About the journal | Contact the journal | Subscribe | Advertising | work@npg | naturereprints | About this site | For librarians
Nature Publishing Group, publisher of Nature, and other science journals and reference works©1996 Nature Publishing Group | Privacy policy