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The mouse dystonia musculorum gene is a neural isoform of bullous pemphigoid antigen 1

Nature Genetics volume 10, pages 301–306 (1995)Cite this article

Abstract

Dystonia musculorum (dt) is a hereditary neurodegenerative disease in mice that leads to a sensory ataxia. We describe cloning of a candidate dt gene, dystonin, that is predominantly expressed in the dorsal root ganglia and other sites of neurodegeneration in dt mice. Dystonin encodes an N–terminal actin binding domain and a C–terminal portion comprised of the hemidesmosomal protein, bullous pemphigoid antigen 1 (bpagl). dt and bpag1 are part of the same transcription unit which is partially deleted in a transgenic strain of mice, Tg4, that harbours an insertional mutation at the dt locus, and in mice that carry a spontaneous dt mutation, dtAlb. We also demonstrate abnormal dystonin transcripts in a second dt mutant, dt24J. We conclude that mutations in the dystonin gene are the primary genetic lesion in dt mice.

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References

  1. Duchen, L.W., Falconer, D.S. & Strich, S.J., A hereditary neuropathy of mice affecting mainly sensory pathways. J. Physiol. 165, 7–9 (1963).

    Google Scholar 

  2. Duchen, L.W. & Strich, S.J. Clinical and pathological studies of an hereditary neuropathy in mice. Brain 87, 367–378 (1964).

    Article  CAS  Google Scholar 

  3. Duchen, L.W. Dystonia musculorum — an inherited disease of the nervous system in the mouse. Adv. Neurol. 14, 353–365 (1976).

    CAS  PubMed  Google Scholar 

  4. Hanker, J.S. & Peach, R. Histochemical and ultrastructural studies of primary sensory neurons in mice with dystonia musculorum. I. Acetylcholinesteraseand lysosomal hydrolases. Neuropath. app. Neurobiol. 2, 79–97 (1976).

    Article  Google Scholar 

  5. Janota, I. Ultrastructural studies of an hereditary sensory neuropathy in mice (dystonia musculorum). Brain 95, 529–536 (1972).

    Article  CAS  Google Scholar 

  6. Sotelo, C. & Guenet, J.L. Pathologic changes in the CMS of dystonia musculorum mutant mouse: an animal model for human spinocerebellar ataxia. Neuroscience 27, 403–424 (1988).

    Article  CAS  Google Scholar 

  7. AI-Ali, S.Y. & Al-Zuhar, A.G.H. Fine structural study of the spinal cord and spinal ganglia in mice afflicted with a hereditary sensory neuropathy, dystonia musculorum. J. submicr. Cytol. Pathol. 21, 737–748 (1989).

    Google Scholar 

  8. Messer, A. & Strominger, N.L. An allele of the mouse mutant dystonia musculorum exhibits lesions in red nucleus and striatum. Neuroscience 5, 543–549 (1980).

    Article  CAS  Google Scholar 

  9. Kothary, R. et al. A transgene containing lacZ inserted into the dystonia locus is expressed in neural tube. Nature 335, 435–437 (1988).

    Article  CAS  Google Scholar 

  10. Brown, A. et al. The genomic structure of an insertional mutation in the Dystonia musculorum locus. Genomics 20, 371–376 (1994).

    Article  CAS  Google Scholar 

  11. Roberds, L. GRAIL seeks out genes buried in DMA sequence. Science 254, 805 (1991).

    Article  Google Scholar 

  12. Frohman, A.M., Dush, M.K. & Martin, G.R. Rapid amplification of full-length cDNAs from rare transcripts: amplification using a single gene-specific oligonucleotide primer. Proc. Natn. Acad. Sci. U.S.A. 85, 8998–9002 (1988).

    Article  CAS  Google Scholar 

  13. Loh, E.Y., Elliott, J.F., Cwirla, S., Lanier, L.L. & Davis, M.M. Polymerasechain reaction with single-sided specificity: analysis of T-cell receptor δ-chain. Science 258, 955–964 (1989).

    Google Scholar 

  14. Koenig, M. et al. Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals. Cell 50, 509–517 (1987).

    Article  CAS  Google Scholar 

  15. Dubreuil, R.R., Byers, T.J., Stewart, C.T. & Kiehart, D.P. A β-spectrin isoform from Drosophila (beta H) is similar in size to vertebrate dystrophin. J. Cell Biol. 111, 1849–1858 (1990).

    Article  CAS  Google Scholar 

  16. Witke, W., Schleicher, M., Lottspeich, F. & Noegel, A. Studies on the transcription, translation, and structure of α-actinin in Dictyostelium discoideum. J. Cell Biol. 103, 969–975 (1986).

    Article  CAS  Google Scholar 

  17. Noegel, A., Witke, W. & Schleicher, M. Calcium-sensitive non-muscle α-actinin contains EF-hand structures and highly conserved regions. FEBS Lett. 221, 391–396 (1987).

    Article  CAS  Google Scholar 

  18. Vandekerckhove, J. & Vancompernolle, K. Structural relationships of actin binding proteins. Curr. Opin. Cell Biol. 4, 36–42 (1992).

    Article  CAS  Google Scholar 

  19. Frappier, T., Derancourt, J. & Pradel, L.-A. Actin and neurofilament binding domain of brain spectrin β-subunit. Eur. J. Biochem. 205, 85–91 (1992).

    Article  CAS  Google Scholar 

  20. Copeland, N.G. et al. Chromosomal localization of mouse bulbus pemphigoid antigens, BPAG1 and BPAG2: Identification of a new region of homology between mouse and human chromosomes. Genomics. 15, 180–181 (1993).

    Article  CAS  Google Scholar 

  21. Brown, A., Lemieux, N., Rossant, J. & Kothary, R. Human homolog of a mouse sequence from the dystonia musculorum locus is on chromosome 6p12. Mamm. Genome 5, 434–437 (1994).

    Article  CAS  Google Scholar 

  22. Stanley, J.R., Tanaka, T., Mueller, S., Klaus-Kovtun, V. & Roop, D. Isolation of cDNA for bullous pemphigoid antigen by use of patients' autoantibodies. J. Clin. Invest. 82, 1864–1870 (1988).

    Article  CAS  Google Scholar 

  23. Sawamura, D., Li, K.-H., Chu, M.-L. & Uitto, J., Antigen (BPAG1): Amino acid sequences deduced from cloned cDNAs predict biologically important peptide segments and protein domains. J. biol. Chem. 266, 17784–17790 (1991).

    CAS  PubMed  Google Scholar 

  24. Tamai, K. et al. The human 230-kD Bullous pemphigoid antigen gene (BPAG1). Exon-lntron organization and identification of regulatory tissue specific elements in the promoter region. J. Clin. Invest. 92, 814–822 (1993).

    Article  CAS  Google Scholar 

  25. Tamai, K., Li, K. & Uitto, J. Identification of a DNA-binding protein (Keratinocyte Transcriptional Protein-1) recognizing a keratinocyte-specific regulatory element in the 230-kDa Bullous pemphigoid antigen gene. J. biol. Chem. 289, 493–502 (1994).

    Google Scholar 

  26. Sawamura, D. et al. Mouse 230-kDa bullous pemphigoid antigen gene : structural and functional characterization of the 5′-flanking region and interspecies conservation of the deduced amino-terminal peptide sequence of the protein. J. invest. Dermatol. 103, 651–655 (1994).

    Article  CAS  Google Scholar 

  27. Kaneko, T. & LePage, G.A. Growth characteristics and drug responses of a murine lung carcinoma in vitro and in vivo. Cancer Res. 38, 2084–2090 (1978).

    CAS  PubMed  Google Scholar 

  28. Luna, E.J. & Hitt, A.L. Cytoskeleton-plasma membrane interactions. Science 258, 955–964 (1992).

    Article  CAS  Google Scholar 

  29. Palek, J. & Sahr, E. Mutations of the red blood cell membrane proteins: from clinical evaluation to detection of the underlying genetic defect. Blood 80, 308–330 (1992).

    CAS  PubMed  Google Scholar 

  30. Ann, A.H. & Kunkel, L.M. The structural and functional diversity of dystrophin. Nature Genet. 3, 283–291 (1993).

    Article  Google Scholar 

  31. Sealock, R. & Froehner, S.C. Dystrophin-associated proteins and synapse formation: Is α-dystroglycan the agrin receptor? Cell 77, 617–619 (1994).

    Article  CAS  Google Scholar 

  32. Gee, S.H., Montanaro, F., Lindenbaum, M.H., Carbonetto, S. Dystroglycan-α, a dystrophin-associated glycoprotein, is a functional agrin receptor. Cell 77, 675–686 (1994).

    Article  CAS  Google Scholar 

  33. Campanelli, J.T., Roberds, S.L., Campbell, K.P. & Scheller, R.H. A role for dystrophin-associated glycoproteins and utrophin in agrin-induced AChr clustering. Cell 77, 663–674 (1994).

    Article  CAS  Google Scholar 

  34. Hoffman, E.P., Brown, R.H. & Kunkel, L.M. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 51, 919–928 (1987).

    Article  CAS  Google Scholar 

  35. Mutasim, D.F. et al. A pool of bullous pemphigoid antigens isintracellularand associated with the basal cell cytoskeleton-hemidesmosome complex. J. Invest. Dermatol. 84, 47–53 (1985).

    Article  CAS  Google Scholar 

  36. Klatte, D.H., Kurpakus, M.A., Grelling, K.A. & Jones, J.C.R. Immunochemical characterization of three components of the hemidesmosome and their expression in cultured epithelial cells. J. Cell Biol. 109, 3377–3390 (1989).

    Article  CAS  Google Scholar 

  37. Guo, F. et al. Gene targeting of bpag1 abnormalities in mechanical strength and cell migration in stratified epithelia and neurologic degeneration. Cell 81, 233–243 (1995).

    Article  CAS  Google Scholar 

  38. Goldman, J.E. & Yen, S.H. Cytoskeletal protein abnormalities in neurodegenerative diseases. Ann. Neurol. 19, 209–223 (1986).

    Article  CAS  Google Scholar 

  39. Campbell, R.M. & Peterson, A.C. An intrinsic neuronal defect operates in dystonia musculorum: a study of dt/dt<>+/+ chimeras. Neuron 9, 693–703 (1992).

    Article  CAS  Google Scholar 

  40. Xu, Z., Cork, L.C., Griffin, J.W. & Cleveland, D.W. Increased expression of neurofilament subunit NF-L produces morphological alterations that resemble the pathology of human motor neuron disease. Cell 73, 23–34 (1993).

    Article  CAS  Google Scholar 

  41. Coté, F., Collard, J.F. & Julien, J.-P. Progressive neuropathy in transgenic mice expressing the human neurofilament heavy chain: a mouse model of amyotrophic lateral sclerosis. Cell 73, 35–46 (1993).

    Article  Google Scholar 

  42. Lee, M.K., Marszalek, J.R. & Cleveland, D.W. A mutant neurofilament subunit causes massive, selective motor neuron death: implications for the pathogenesis of human motor neuron disease. Neuron 13, 975–988 (1994).

    Article  CAS  Google Scholar 

  43. Hildebrand, C. Ultrastructural and light microscopic studies of the developing feline spinal cord white matter.II. Cell death and myelin sheath disintegration in the early postnatal period. Acta. Physiol. Scand. (suppl.). 364, 109–144 (1971).

    Article  CAS  Google Scholar 

  44. McLeod, J.G. An electrophysiological and pathological study of peripheral nerves in Friedreich's ataxia. J. neurol. Sci. 12, 333–349 (1971).

    Article  CAS  Google Scholar 

  45. Ouvrier, R.A., McLeod, J.G. & Conchin, T.E. Friedreich's ataxia. Early detection and progression of peripheral nerve abnormalities. J. neurol. Sci. 55, 137–145 (1982).

    Article  CAS  Google Scholar 

  46. McLeod, J.G. & Evans, W.A. Peripheral neuropathy in spinocerebellar degenerations. Muscle & Nerve 4, 51–61 (1981).

    Article  CAS  Google Scholar 

  47. Harding, A.E. The Hereditary Ataxias and Related Disorders (Churchill Livingston, New York, 1984).

  48. Koskinen, T. et al. Infantile onset spinocerebellar ataxia with sensory neuropathy: a new inherited disease. J. neurol. Sci. 121, 50–56 (1994).

    Article  CAS  Google Scholar 

  49. Koskinen, T., Sainio, K., Rapola, J., Pihko, H. & Paetau, A. Sensory neuropathy in infantile onset spinocerebellar ataxia (IOSCA). Muscle & Nerve 17, 509–515 (1994).

    Article  CAS  Google Scholar 

  50. Sawamura, D. et al. Bullous pemphigoid antigen: cDNA cloning and mapping of the gene to the short arm of human chromosome 6. Genomics 8, 722–726 (1990).

    Article  CAS  Google Scholar 

  51. Hanauer, A. et al. The Friedreich's ataxia gene is assigned to chromosome 9q13–q21 by mapping of tightly linked markers and shows linkage disequilibrium with D9S15. Am. J. Hum. Genet. 46, 133–137 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Orr, H.T. et al. Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nature Genet. 4, 221–226 (1993).

    Article  CAS  Google Scholar 

  53. Gispert, S. et al. Chromosomal assignment of the second locus for autosomal dominant cerebellar ataxia (SCA2) to chromosome 12q23–24.1. Nature Genet. 4, 295–299 (1993).

    Article  CAS  Google Scholar 

  54. Takiyama, Y. et al. The gene for Machado-Joseph disease maps to human chromosome 14q. Nature Genet. 4, 300–304 (1993).

    Article  CAS  Google Scholar 

  55. Ranum, L., Schut, L.J., Lundgren, J.K., Orr, H.T. & Livingston, D.M. Spinocerebellar ataxia type 5 in a family descended from the grandparents of President Lincoln maps to chromosome 11. Nature Genet. 8, 280–284 (1994).

    Article  CAS  Google Scholar 

  56. Muller, U., Graeber, M.B., Haberhausen, G. & Kohler, A. Molecular basis and diagnosis of neurogenetic disorders. J. neurol. Sci. 124, 119–140 (1994).

    Article  CAS  Google Scholar 

  57. Subramony, S.H. Degenerative ataxias. Curr. Opin. Neurol. 7, 316–322 (1994).

    Article  CAS  Google Scholar 

  58. Lopes, C.I., Andermann, E. & Rouleau, G.A. Evidence for the existence of a fourth dominantly inherited spinocerebellar ataxia locus. Genomics 21, 270–274 (1994).

    Article  Google Scholar 

  59. Hogan, B., Costantini, F. & Lacy, E. Manipulating the Mouse Embryo. A Laboratory Manual (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 1986).

    Google Scholar 

  60. Altschul, S.F., Gish, W., Miller, W., Myers, E.W. & Lipman, D.J. Basic local alignment search tool. J. molec. Biol. 215, 403–410 (1990).

    Article  CAS  Google Scholar 

  61. Sambrook, J., Fritsch, E.F. & Maniatis, T., Cloning: A Laboratory Manual. (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 1989).

    Google Scholar 

  62. Tso, J.Y., Sun, X.H., Kao, T.H., Reece, K.S. & Wu, R. Isolation and characterization of rat and human glyceraldehyde-3-phosphate dehydrogenase cDNAs: genomic complexity and molecular evolution of the gene. Nucl. Acids Res. 13, 2485–2502 (1985).

    Article  CAS  Google Scholar 

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Author notes

  1. Arthur Brown

    Present address: Neurobiology Laboratory, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, California, 92037, USA

Authors and Affiliations

  1. Institut du cancer de Montréal, Centre de Recherche L.-C. Simard, Montréal, Québec, H2L 4M1, Canada

    Arthur Brown, Gilbert Bernier, Martine Mathieu & Rashmi Kothary

  2. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, M5G 1X5, Canada

    Arthur Brown & Janet Rossant

  3. Department of Molecular and Medical Genetics, University of Toronto, Canada

    Arthur Brown & Janet Rossant

  4. Department of Medicine, University of Montréal, Canada

    Rashmi Kothary

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Brown, A., Bernier, G., Mathieu, M. et al. The mouse dystonia musculorum gene is a neural isoform of bullous pemphigoid antigen 1. Nat Genet 10, 301–306 (1995). https://doi.org/10.1038/ng0795-301

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