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Glycine receptor β–subunit gene mutation in spastic mouse associated with LINE–1 element insertion

Abstract

Congenital myoclonus is a widespread neurologic disorder characterized by hyperexcitability, muscular spasticity and myoclonus associated with marked reduction in neural glycine binding sites. The recessive mouse mutation spastic (spa) is a prototype of inherited myoclonus. Here we show that defects in the gene encoding the β–subunit of the glycine receptor (Glrb) underlie spa: Glrb maps to the same region of mouse chromosome 3 as spa, and Glrb mRNA is markedly reduced throughout brains of spa mice, most likely as a result of an insertional mutation of a 7.1 kilobase LINE–1 element within intron 6 of Glrb. These results provide evidence that Glrb is necessary for postsynaptic expression of glycine receptor complexes, and suggest Glrb as a candidate gene for inherited myoclonus in other species.

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References

  1. 1

    Betz, H. Structure and function of inhibitory glycine receptors. Quart. Rev. Biophys. 25, 381–394 (1992).

    CAS  Article  Google Scholar 

  2. 2

    Betz, H. Ligand-gated ion channels in the brain: the amino acid receptor family. Neuron 5, 383–392 (1990).

    CAS  Article  Google Scholar 

  3. 3

    Grenningloh, G. et al. The strychnine-binding subunit of the glycine receptor shows homology with nicotinic acetylcholine receptors. Nature 328, 215–220 (1987).

    CAS  Article  Google Scholar 

  4. 4

    Kuhse, J., Schmieden, V. & Betz, H. Identification and functional expression of a novel ligand binding subunit of the inhibitory glycine receptor. J. biol. Chem. 265, 22317–22320 (1990).

    CAS  PubMed  Google Scholar 

  5. 5

    Kuhse, J., Schmieden, V. & Betz, H. A single amino acid exchange alters the pharmacology of neonatal rat glycine receptor subunit. Neuron 5, 867–873 (1990).

    CAS  Article  Google Scholar 

  6. 6

    Grenningloh, G. et al. Cloning and expression of the 58 kd β subunit of the inhibitory glycine receptor. Neuron 4, 963–970 (1990).

    CAS  Article  Google Scholar 

  7. 7

    Schmieden, V., Kuhse, J. & Betz, H. Agonist pharmacology of neonatal and adult glycine receptor α subunits: identification of amino acid residues involved in taurine activation. EMBO J. 11, 2025–2032 (1992).

    CAS  Article  Google Scholar 

  8. 8

    Schmieden, V., Grenningloh, G., Schofield, P.R. & Betz, H. Functional expression in Xenopus oocytes of the strychnine binding 48 kd subunit of the glycine receptor. EMBO J. 3, 695–700 (1989).

    Article  Google Scholar 

  9. 9

    Sontheimer, H. et al. Functional chloride channels by mammalian cell expression of rat glycine receptor subunit. Neuron 2, 1491–1497 (1989).

    CAS  Article  Google Scholar 

  10. 10

    Pribilla, I., Takagi, T., Langosch, D., Bormann, J. & Betz, H. The atypical M2 segment of the β subunit confers picrotoxinin resistance to inhibitory glycine receptor channels. EMBO J. 11, 4305–4311 (1992).

    CAS  Article  Google Scholar 

  11. 11

    White, W.F. & Heller, A.H. Glycine receptor alteration in the mutant mouse spastic. Nature 298, 655–657 (1982).

    CAS  Article  Google Scholar 

  12. 12

    Gundlach, A.L. et al. Deficit of glycine/strychnine receptors in inherited myoclonus of Poll Hereford calves. Science 241, 1807–1810 (1988).

    CAS  Article  Google Scholar 

  13. 13

    Gundlach, A.L. Disorder of the inhibitory glycine receptor: inherited myoclonus in Poll Hereford calves. FASEB J. 4, 2761–2766 (1990).

    CAS  Article  Google Scholar 

  14. 14

    Gundlach, A.L., Kortz, G., Burazin, T.C.D., Madigan, J. & Higgins, R.J. Deficit of inhibitory glycine receptors in spinal cord from Peruvian Pasos: evidence for an equine form of inherited myoclonus. Brain Res. 628, 263–270 (1993).

    CAS  Article  Google Scholar 

  15. 15

    Shiang, R. et al. Mutations in the α1 subunit of the inhibitory glycine receptor cause the dominant neurologic disorder, hyperekplexia. Nature Genet. 5, 351–358 (1993).

    CAS  Article  Google Scholar 

  16. 16

    Ryan, S.G. et al. A missense mutation in the gene encoding the α1 subunit of the inhibitory glycine receptor causes the spasmodic mouse phenotype. Nature Genet. 7, 131–135 (1994).

    CAS  Article  Google Scholar 

  17. 17

    Heller, A.H. & Hallett, M. Electrophysiological studies with the spastic mutant mouse. Brain Res. 234, 299–308 (1982).

    CAS  Article  Google Scholar 

  18. 18

    Chai, C.K. Hereditary spasticity in mice. J. Hered. 52, 241–243 (1961).

    Article  Google Scholar 

  19. 19

    Chai, C.K., Roberts, E. & Sidman, R.L. Influence of aminooxyacetic acid, a gamma-aminobutyrate transaminase inhibitor, on hereditary spastic defect in the mouse. Proc. Soc. exp. Biol. Med. 109, 491–495 (1962).

    CAS  Article  Google Scholar 

  20. 20

    Meier, H. & Chai, C.K. spastic, an hereditary neurological mutation in the mouse characterized by vertebral arthropathy and leptomeningeal cyst formation. Exp. Med. Surg. 28, 24–38 (1970).

    CAS  PubMed  Google Scholar 

  21. 21

    Ziv, I., Blackburn, N., Rang, M. & Koreska, J. Muscle growth in normal and spastic mice. Dev. Med. child Neurol. 26, 94–99 (1984).

    CAS  Article  Google Scholar 

  22. 22

    Lane, P.W. Two new mutations in linkage group XVI of the house mouse, flaky tail and varitint-waddler-J. J. Hered. 63, 135–140 (1972).

    CAS  Article  Google Scholar 

  23. 23

    Eicher, E.M. & Lane, P.W. Assignment of LG XVI to chromosome 3 in the mouse. J. Hered. 71, 315–318 (1980).

    CAS  Article  Google Scholar 

  24. 24

    White, W.F. The glycine receptor in the mutant mouse spastic (spa): strychnine binding characteristics and pharmacology Brain Res. 329, 1–6 (1985).

    CAS  Article  Google Scholar 

  25. 25

    Becker, C.M., Hermans-Borgmeyer, I., Schmitt, B. & Betz, H. The glycine receptor deficiency of the mutant mouse spastic: evidence for normal glycine receptor structure and localization. J. Neurosci. 6, 1358–1364 (1986).

    CAS  Article  Google Scholar 

  26. 26

    Becker, C.M., Schmieden, V., Tarroni, P., Strasser, U. & Betz, H. Isoform-selective deficit of glycine receptors in the mouse mutant spastic. Neuron 8, 283–289 (1992).

    CAS  Article  Google Scholar 

  27. 27

    White, W.F. & Heller, A.H. Glycine and GABA uptake in the mutant mouse spastic. Soc. Neurosci. (Abstr.) 8, 575 (1982).

    Google Scholar 

  28. 28

    Biscoe, T.J., Fry, J.P., Martin, I.L. & Rickets, C. Binding of GABA and benzodiazepine receptor ligands in the spinal cord of the spastic mouse, (ab). J. Physiol. 317, 32–33 (1981).

    Google Scholar 

  29. 29

    Biscoe, T.J. & Fry, J.P. GABA and benzodiazepine receptor in neurologically mutant mice. in Actions and Interactions of GABA and Benzodiazepines, N.G. Bowery, Ed. 217–237 (Raven Press, New York, 1984).

    Google Scholar 

  30. 30

    Seldin, M.F. et al. Genetic analysis of autoimmune gld mice. I. Identification of a restriction fragment length polymorphism closely linked to the gld mutation within a conserved linkage group. J. exp. Med. 167, 688–693 (1988).

    CAS  Article  Google Scholar 

  31. 31

    Green, E.L. Linkage, recombination and mapping. in Genetics and Probability in Animal Breeding Experiments 77–113 (Macmillan, New York, 1981).

    Chapter  Google Scholar 

  32. 32

    Bishop, D.T. The information content of phase-known matings for ordering genetic loci. Genet. Epidemiol. 2, 349–361 (1985).

    CAS  Article  Google Scholar 

  33. 33

    Seldin, M.F., Prins, J-B., Rodrigues, N.R., Todd, J.A. & Meisler, M.H. Mouse chromosome 3. Mamm. Genome 4, S47–S57 (1993).

    CAS  Article  Google Scholar 

  34. 34

    El Mestikawy, S. et al. Characterization of an atypical member of the Na+/Cl- dependent transporter family: Chromosomal localization and distribution in GABAergic and glutamatergic neurons in the rat brain. J. Neurochem. 62, 445–455 (1994).

    CAS  Article  Google Scholar 

  35. 35

    Gregor, P. et al. Chromosomal localization of glutamate receptor genes: Relationships to familial amyotrophic lateral sclerosis and other neurologic disorders of mice and humans. Proc. natn. Acad. Sci. U.S.A. 90, 3053–3057 (1993).

    CAS  Article  Google Scholar 

  36. 36

    Moseley, W.S. & Seldin, M.F. Definition of mouse chromosome 1 and 3 gene linkage groups that are conserved on human chromosome 1: Evidence that a conserved linkage group spans the centromere of human chromosome 1. Genomics 5, 899–905 (1989).

    CAS  Article  Google Scholar 

  37. 37

    Malosio, M-L., Marqueze-Pouey, B., Kuhse, J. & Betz, H. Widespread expression of glycine receptor subunit mRNAs in the adult and developing rat brain. EMBO J. 10, 2401–2409 (1991).

    CAS  Article  Google Scholar 

  38. 38

    Betz, H. Glycine receptors: heterogeneous and widespread in the mammalian brain. Trends Neurosci. 14, 458–461 (1991).

    CAS  Article  Google Scholar 

  39. 39

    Sommer, B., Poustka, A., Spurr, N.K. & Seeburg, P.H. The murine GABAA receptor δ-subunit gene: structure and assignment to human chromosome 1. DNA Cell Biol. 9, 561–568 (1990).

    CAS  Article  Google Scholar 

  40. 40

    Kirkness, E.F., et al. Isolation, characterization, and localization of human genomic DNA encoding the β1 subunit of GABAA, receptor (GABRB1) Genomics 10, 985–995 (1991).

    CAS  Article  Google Scholar 

  41. 41

    Lasham, A., Vreugdenhil, E., Bateson, A.N., Barnard, E.A. & Darlison, M.G. Conserved organization of γ-aminobutyric acidA receptor genes: cloning and analysis of the chicken β4-subunit gene. J. Neurochem. 57, 352–355 (1991).

    CAS  Article  Google Scholar 

  42. 42

    Fanning, T.G. Size and structure of the highly repetitive BAM HI element in mice. Nuci. Acids Res. 11, 5073–5091 (1983).

    CAS  Article  Google Scholar 

  43. 43

    Loeb, D.D. et al. The sequence of a large L1 Md element reveals a tandemly repeated 5′ end and several features found in retrotransposons. Molec. cell. Biol. 6, 168–182 (1986).

    CAS  Article  Google Scholar 

  44. 44

    Kuhse, J., Laube, B., Magalei, D. & Betz, H. Assembly of the in hibitory glycine receptor: Identification of amino acid sequence motifs governing subunit stoichiometry. Neuron 11, 1049–1056 (1993).

    CAS  Article  Google Scholar 

  45. 45

    Hoch, W., Betz, H. & Becker, C.M. Primary cultures of mouse spinal cord express the neonatal isoform of the inhibitory glycine receptor. Neuron 3, 339–348 (1989).

    CAS  Article  Google Scholar 

  46. 46

    Eickbush, T.H. Transposing without ends: the non-LTR retrotransposable elements. New Biologist 4, 430–440 (1992).

    CAS  PubMed  Google Scholar 

  47. 47

    Kazazian, Jr H.H. et al. Hemophilia A resulting from de novo insertion of L1 sequences represents a novel mechanism for mutation in man. Nature 332, 164–166 (1988).

    CAS  Article  Google Scholar 

  48. 48

    Narita, N. et al. Insertion of a 5′ truncated L1 element into the 3′ end of exon 44 of the dystrophin gene resulted in skipping of the exon during splicing in a case of Duchenne muscular dystrophy. J. clin. Invest. 91, 1862–1867 (1993).

    CAS  Article  Google Scholar 

  49. 49

    Morse, B., Rotherg, P.G., South, V.J., Spandorfer, J.M. & Astrin, S.M. Insertional mutagenesis of the MYC locus by a LINE-1 sequence in a human breast carcinoma. Nature 333, 87–90 (1988).

    CAS  Article  Google Scholar 

  50. 50

    Steinmeyer, K. et al. Inactivation of muscle chloride channel by transposon Insertion in myotonic mice. Nature 354, 304–308 (1991).

    CAS  Article  Google Scholar 

  51. 51

    Adachi, M., Watanabe-Fukunaga, R. & Nagata, S. Aberrant transcription caused by the insertion of an early transposable element in an intron of the Fas antigen gene of Ipr mice. Proc. natn. Acad. Sci. U.S.A. 90, 1756–1760 (1993).

    CAS  Article  Google Scholar 

  52. 52

    Kobayashi, S., Hirano, T., Kakinuma, M. & Uede, T. Transcriptional repression and differential splicing of FAS mRNA by early transposon (ETn) insertion in autoimmune Ipr mice. Biochem. Biophys. res. Commun. 191, 617–624 (1993).

    CAS  Article  Google Scholar 

  53. 53

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

    Google Scholar 

  54. 54

    Giros, B., El Mestikawy, S., Bertrand, L. & Caron, M.G. Cloning and functional characterization of a cocaine-sensitive dopamine transporter. FEBS Lett. 295, 149–154 (1991).

    CAS  Article  Google Scholar 

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Kingsmore, S., Giros, B., Suh, D. et al. Glycine receptor β–subunit gene mutation in spastic mouse associated with LINE–1 element insertion. Nat Genet 7, 136–142 (1994). https://doi.org/10.1038/ng0694-136

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