Journal of Molecular Neuroscience

, Volume 34, Issue 3, pp 241–248

Animal Models for Genetic Neuromuscular Diseases

  • Mariz Vainzof
  • Danielle Ayub-Guerrieri
  • Paula C. G. Onofre
  • Poliana C. M. Martins
  • Vanessa F. Lopes
  • Dinorah Zilberztajn
  • Lucas S. Maia
  • Karen Sell
  • Lydia U. Yamamoto
Article

Abstract

The neuromuscular disorders are a heterogeneous group of genetic diseases, caused by mutations in genes coding sarcolemmal, sarcomeric, and citosolic muscle proteins. Deficiencies or loss of function of these proteins leads to variable degree of progressive loss of motor ability. Several animal models, manifesting phenotypes observed in neuromuscular diseases, have been identified in nature or generated in laboratory. These models generally present physiological alterations observed in human patients and can be used as important tools for genetic, clinic, and histopathological studies. The mdx mouse is the most widely used animal model for Duchenne muscular dystrophy (DMD). Although it is a good genetic and biochemical model, presenting total deficiency of the protein dystrophin in the muscle, this mouse is not useful for clinical trials because of its very mild phenotype. The canine golden retriever MD model represents a more clinically similar model of DMD due to its larger size and significant muscle weakness. Autosomal recessive limb-girdle MD forms models include the SJL/J mice, which develop a spontaneous myopathy resulting from a mutation in the Dysferlin gene, being a model for LGMD2B. For the human sarcoglycanopahties (SG), the BIO14.6 hamster is the spontaneous animal model for δ-SG deficiency, whereas some canine models with deficiency of SG proteins have also been identified. More recently, using the homologous recombination technique in embryonic stem cell, several mouse models have been developed with null mutations in each one of the four SG genes. All sarcoglycan-null animals display a progressive muscular dystrophy of variable severity and share the property of a significant secondary reduction in the expression of the other members of the sarcoglycan subcomplex and other components of the Dystrophin-glycoprotein complex. Mouse models for congenital MD include the dy/dy (dystrophia-muscularis) mouse and the allelic mutant dy2J/dy2J mouse, both presenting significant reduction of α2-laminin in the muscle and a severe phenotype. The myodystrophy mouse (Largemyd) harbors a mutation in the glycosyltransferase Large, which leads to altered glycosylation of α-DG, and also a severe phenotype. Other informative models for muscle proteins include the knockout mouse for myostatin, which demonstrated that this protein is a negative regulator of muscle growth. Additionally, the stress syndrome in pigs, caused by mutations in the porcine RYR1 gene, helped to localize the gene causing malignant hypertermia and Central Core myopathy in humans. The study of animal models for genetic diseases, in spite of the existence of differences in some phenotypes, can provide important clues to the understanding of the pathogenesis of these disorders and are also very valuable for testing strategies for therapeutic approaches.

Keywords

Animal models Neuromuscular disease Proteins defects Muscle proteins 

References

  1. Allamand, V., & Campbell, K. P. (2000). Animal models for muscular dystrophy: Valuable tools for the development of therapies. Human Molecular Genetics, 9, 2459–2467.PubMedCrossRefGoogle Scholar
  2. Araki, E., Nakamura, K., Nakao, K., Kameya, S., Kobayashi, O., Nonaka, I., et al. (1997). Targeted disruption of exon 52 in the mouse dystrophin gene induced muscle degeneration similar to that observed in Duchenne muscular dystrophy. Biochemical And Biophysical Research Communications, 238, 492–497.PubMedCrossRefGoogle Scholar
  3. Barresi, R., Michele, D. E., Kanagawa, M., Harper, H. A., Dovico, S. A., Satz, J. S., et al. (2004). LARGE can functionally bypass alpha- dystroglycan glycosylation defects in distinct congenital muscular dystrophies. Natural Medicines, 10, 696–703.CrossRefGoogle Scholar
  4. Bittner, R. E., Anderson, L. V., Burkhardt, E., Bashir, R., Vafiadaki, E., Ivanova, S., et al. (1999). Dysferlin deletion in SJL mice (SJL-Dysf) defines a natural model for limb girdle muscular dystrophy 2B. Nature Genetics, 23, 141–142.PubMedCrossRefGoogle Scholar
  5. Bogdanovich, S., Krag, T. O., Barton, E. R., Morris, L. D., Whittemore, L. A., Ahima, R. S., et al. (2002). Functional improvement of dystrophic muscle by myostatin blockade. Nature, 420, 418–421.PubMedCrossRefGoogle Scholar
  6. Brandom, B. W. (2006). Genetics of Malignant Hyperthermia. The Scientific World Journal, 6, 1722–1730.Google Scholar
  7. Browning, C. A., Grewal, P. K., Moore, C. J., & Hewitt, J. E. (2005). A rapid PCR method for genotyping the Largemyd mouse, a model of glycosylation-deficient congenital muscular dystrophy. Neuromuscular Disorders, 15, 331–335.PubMedCrossRefGoogle Scholar
  8. Bulfield, G., Siller, W. G., Wight, P. A. L., & Moore, K. J. (1984). X-Chromosome-linked muscular dystrophy (mdx) in the mouse. Proceedings of the National Academy of Sciences of the United States of America, 81, 1189–1192.PubMedCrossRefGoogle Scholar
  9. Collins, C. A., & Morgan, J. E. (2003). Duchenne's muscular dystrophy: animal models used to investigate pathogenesis and develop therapeutic strategies. International Journal of Experimental Pathology, 84, 165–172.PubMedCrossRefGoogle Scholar
  10. Cooper, B. J., Winand, N. J., Stedman, H., Valentine, B. A., Hoffman, E. P., Kunkel, L. M., et al. (1988). The homologue of the Duchenne locus is defective in X-linked muscular dystrophy of dogs. Nature, 334, 154–156.PubMedCrossRefGoogle Scholar
  11. Cote, P. D., Moukhles, H., Lindenbaum, M., & Carbonetto, S. (1999). Chimaeric mice deficient in dystroglycans develop muscular dystrophy and have disrupted myoneural synapses. Nature Genetics, 23, 338–342.PubMedCrossRefGoogle Scholar
  12. Dangain, J., & Vrbova, G. (1984). Muscle development in (mdx) mutant mice. Muscle & Nerve, 7, 700–704.CrossRefGoogle Scholar
  13. Durbeej, M., & Campbell, K. P. (2002). Muscular dystrophies involving the dystrophin-glycoprotein complex: an overview of current mouse models. Current Opinion in Genetics & Development, 12, 349–361.CrossRefGoogle Scholar
  14. Ervasti, E., & Campbell, K. P. (1993). A role for the dystrophin-glycoprotein complex as a transmembrane linker between laminin and actin. Journal of Cell Biology, 122, 809–823.PubMedCrossRefGoogle Scholar
  15. Fujii, J., Otsu, K., Zorzato, F., Leon, S., de Khanna, V. K., Weiler, J. E., et al. (1991). Identification of a mutation in porcine ryanodine receptor associated with malignant hyperthermia. Science, 253, 448–451.PubMedCrossRefGoogle Scholar
  16. Grewal, P. K., Holzffeind, P. J., Bittner, R. E., & Hewitt, J. E. (2001). Mutant glycosyltranferase and altered glycosylation of a-dystroglican in the myodystrophy mouse. Nature Genetics, 28, 151–154.PubMedCrossRefGoogle Scholar
  17. Gussoni, E., Soneoka, Y., Strickland, C. D., Buzney, E. A., Khan, M. K., Flint, A. F., et al. (1999). Dystrophin expression in the mdx mouse restored by stem cell transplantation. Nature, 401, 390–394.PubMedGoogle Scholar
  18. Hoffman, E. P., Brown Jr, R. H., & Kunkel, L. M. (1987). Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell, 51, 919–928.PubMedCrossRefGoogle Scholar
  19. Hoffman, E. P., Morgan, J. E., Watkins, S. C., & Partridge, T. A. (1990). Somatic reversion/suppression of the mouse mdx phenotype in vivo. Journal of The Neurological Sciences, 99, 9–25.PubMedCrossRefGoogle Scholar
  20. Holt, K. H., Crosbie, R. H., Venzke, D. P., & Campbell, K. P. (2000). Biosynthesis of dystroglycan: processing of a precursor propeptide. FEBS Letters, 468, 79–83.PubMedCrossRefGoogle Scholar
  21. Mosher, D. S., Quignon, P., Bustamante, C. D., Sutter, N. B., Ellersh, C. S., Parker, H. G., et al. (2007). A mutation in the myostatin gene increases muscle mass and enhances racing performance in heterozygote dogs. PLoS Genetics, 3, 779–786.CrossRefGoogle Scholar
  22. Muntoni, F., Brockington, M., Torelli, S., & Brown, S. C. (2004). Defective glycosylation in congenital muscular dystrophies. Current Opinion in Neurology, 17, 205–209.PubMedCrossRefGoogle Scholar
  23. Ohlendieck, K., & Campbell, K. P. (1991). Dystrophin-associated proteins are greatly reduced in skeletal muscle from mdx mice. Journal of Cell Biology, 115, 1685–1694.PubMedCrossRefGoogle Scholar
  24. Patel, K., & Amthor, H. (2005). The function of Myostatin and strategies of Myostatin blockade-new hope for therapies aimed at promoting growth of skeletal muscle. Neuromuscular Disorders, 15, 117–126.PubMedCrossRefGoogle Scholar
  25. Shelton, D. G., & Engvall, E. (2005). Canine and feline models of human inherited muscle diseases. Neuromuscular Diseases, 15, 127–138.CrossRefGoogle Scholar
  26. Sicinski, P., Geng, Y., Ryder-Cook, A. S., Barnard, E. A., Darlison, M. G., & Barnard, P. J. (1989). The molecular basis of muscular dystrophy in the mdx mouse. A point mutation. Science, 244, 1578–1580.PubMedCrossRefGoogle Scholar
  27. Straub, V., & Campbell, K. P. (1997). Muscular dystrophies and the dystrophin-glycoprotein complex. Current Opinion in Neurology, 10, 168–175.PubMedCrossRefGoogle Scholar
  28. Straub, V., Duclos, F., Venzke, D. P., Lee, J. C., Cutshall, S., Leveille, C. J., et al. (1998). Molecular pathogenesis of muscle degeneration in the delta-sarcoglycan-deficient hamster. American Journal of Pathology, 153, 1623–1630.PubMedGoogle Scholar
  29. Sunada, Y., Bernier, S. M., Utani, A., Yamada, Y., & Campbell, K. P. (1995). Identification of a novel mutant transcript of laminin α2 chain gene responsible for muscular dystrophy and dysmyelination in dy2J mice. Human Molecular Genetics, 4, 1055–1061.PubMedCrossRefGoogle Scholar
  30. Tome, F. M., Evangelista, T., Leclerc, A., Sunada, Y., Manole, E., Estournet, B., et al. (1994). Congenital muscular dystrophy with merosin deficiency. Comptes Rendus De l'AcadeÂmie Des Sciences III, 317, 351–357.Google Scholar
  31. Vainzof, M., Zatz, M. (2007). Muscular dystrophies and protein mutations. In: Uversky VN and Fink AL (Eds) Protein misfolding, aggregation, and conformational diseases. Part B: Molecular mechanisms of conformational diseases. In: Zouhair Atassi (Ed.) Series protein reviews, vol. 6, Springer, USA, pp 391–403.Google Scholar
  32. Valentine, B. A., Winand, N. J., Pradhan, D., Moise, N. S., de Lahunta, A., Kornegay, J. N., et al. (1992). Canine X-linked muscular dystrophy as an animal model of Duchenne muscular dystrophy: a review. American Journal of Medical Genetics, 42, 352–356.PubMedCrossRefGoogle Scholar
  33. Vilquin, J-T., vignier, N., Tremblay, J. P., Engvall, E., Schwartz, K., & Fiszman, M. (2000). Identification of homozygous and heterozygous dy2j mice by PCR. Neuromuscular Disorders, 10, 59–62.PubMedCrossRefGoogle Scholar
  34. Williamson, R. A., Henry, M. D., Daniels, K. J., Hrstka, R. F., Lee, J. C., Sunada, Y., et al. (1997). Dystroglycan is essential for early embryonic development: disruption of Reichert's membrane in Dag1-null mice. Human Molecular Genetics, 6, 831–841.PubMedCrossRefGoogle Scholar
  35. Xu, H., Wu, X-R., Wewer, U. M., & Engvall, E. (1994). Murine muscular dystrophy caused by a mutation in the laminin a2 (Lama2) gene. Nature Genetics, 8, 297–301.PubMedCrossRefGoogle Scholar
  36. Yang, T., Riehl, J., Esteve, E., Matthael, K. I., Goth, S., Allen, P. D., et al. (2006). Pharmacologic and Funcional characterization of malignant hyperthermia in the R163C RYR1 knock-in mouse. Anestesiology, 105, 1164–1175.CrossRefGoogle Scholar
  37. Yoshida, M., & Ozawa, E. (1990). Glycoprotein complex anchoring dystrophin to sarcolemma. Journal of Biochemistry, 108, 748–752.PubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  • Mariz Vainzof
    • 1
    • 2
  • Danielle Ayub-Guerrieri
    • 1
  • Paula C. G. Onofre
    • 1
  • Poliana C. M. Martins
    • 1
  • Vanessa F. Lopes
    • 1
  • Dinorah Zilberztajn
    • 1
  • Lucas S. Maia
    • 1
  • Karen Sell
    • 1
  • Lydia U. Yamamoto
    • 1
  1. 1.Human Genome Research Center, Dept of Genetics and Evolutionary BiologyUniversity of Sao PauloSao PauloBrasil
  2. 2.Human Genome Research Center, IBUSP, R. do Matão106 Cidade UniversitáriaSao PauloBrazil

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