Mammalian Genome

, Volume 18, Issue 11, pp 749–756 | Cite as

The mouse mutants recoil wobbler and nmf373 represent a series of Grm1 mutations

  • Andrew J. Sachs
  • Jamie K. Schwendinger
  • Andy W. Yang
  • Neena B. Haider
  • Arne M. Nystuen


The identification of novel mutant alleles is important for understanding critical functional domains of a protein and establishing genotype:phenotype correlations. The recoil wobbler (rcw) allelic series of spontaneous ataxic mutants and the ENU-induced mutant nmf373 genetically mapped to a shared region of chromosome 10. Their mutant phenotypes are strikingly similar; all have an ataxic phenotype that is recessive, early-onset, and is not associated with neurodegeneration. In this study we used complementation tests to show that these series of mutants are allelic to a knockout mutant of Grm1. Subsequently, a duplication of exon 4 and three missense mutations were identified in Grm1: I160T, E292D, and G337E. All mutations occurred within the ligand-binding region and changed conserved amino acids. In the rcw mutant, the Grm1 gene is expressed and the protein product is properly localized to the molecular layer of the cerebellar cortex. Grm1 is responsible for the generation of inositol 1,4,5-trisphosphate (IP3). The inositol second messenger system is the central mechanism for calcium release from intracellular stores in cerebellar Purkinje cells. Several of the genes involved in this pathway are mutated in mouse ataxic disorders. The novel rcw mutants represent a resource that will have utility for further studies of inositol second-messenger-system defects in neurogenetic disorders.



The DNA Sequencing Core at UNMC receives partial support from NIH grant No. P20 RR016469 from the INBRE Program of the National Center for Research Resources.


  1. Aiba A, Kano M, Chen C, Stanton ME, Fox GD, et al. (1994a) Deficient cerebellar long-term depression and impaired motor learning in mGluR1 mutant mice. Cell 79:377–388PubMedCrossRefGoogle Scholar
  2. Aiba A, Chen C, Herrup K, Rosenmund C, Stevens CF, et al. (1994b) Reduced hippocampal long-term potentiation and context-specific deficit in associative learning in mGluR1 mutant mice. Cell 79:365–375PubMedCrossRefGoogle Scholar
  3. Aramori I, Nakanishi S (1992) Signal transduction and pharmacological characteristics of a metabotropic glutamate receptor, mGlur1, in transfected CHO cells. Neuron 8:757–765PubMedCrossRefGoogle Scholar
  4. Berridge MJ, Dawson RM, Downes CP, Heslop JP, Irvine RF (1983) Changes in the levels of inositol phosphates after agonist-dependent hydrolysis of membrane phosphoinositides. Biochem J 212:473–482PubMedGoogle Scholar
  5. Berridge MJ, Bootman MD, Roderick HL (2003) Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol 4:517–529PubMedCrossRefGoogle Scholar
  6. Bordi F, Ugolini A (1999) Group I metabotropic glutamate receptors: implications for brain diseases. Prog Neurobiol 59:55–79PubMedCrossRefGoogle Scholar
  7. Brody SA, Conquet F, Geyer MA (2003) Disruption of prepulse inhibition in mice lacking mGluR1. Eur J Neurosci 18:3361–3366PubMedCrossRefGoogle Scholar
  8. Brzovic PS, Kayastha AM, Miles EW, Dunn MF (1992) Substitution of glutamic acid 109 by aspartic acid alters the substrate specificity and catalytic activity of the beta-subunit in the tryptophan synthase bienzyme complex from Salmonella typhimurium. Biochemistry 31:1180–1190PubMedCrossRefGoogle Scholar
  9. Chuang SC, Bianchi R, Kim D, Shin HS, Wong RK (2001) Group I metabotropic glutamate receptors elicit epileptiform discharges in the hippocampus through PLCbeta1 signaling. J Neurosci 21:6387–6394PubMedGoogle Scholar
  10. Clark AT, Goldowitz D, Takahashi JS, Vitaterna MH, Siepka SM, et al. (2004) Implementing large-scale ENU mutagenesis screens in North America. Genetica 122:51–64PubMedCrossRefGoogle Scholar
  11. Coesmans M, Smitt PA, Linden DJ, Shigemoto R, Hirano T, et al. (2003) Mechanisms underlying cerebellar motor deficits due to mGluR1 autoantibodies. Ann Neurol 53:325–336PubMedCrossRefGoogle Scholar
  12. Conquet F, Bashir ZI, Davies CH, Daniel H, Ferraguti F, et al. (1994) Motor deficit and impairment of synaptic plasticity in mice lacking mGluR1. Nature 372:237–243PubMedCrossRefGoogle Scholar
  13. Conti V, Aghaie A, Cilli M, Martin N, Caridi G, et al. (2006) crv4, a mouse model for human ataxia associated with kyphoscoliosis caused by an mRNA splicing mutation of the metabotropic glutamate receptor 1 (Grm1). Int J Mol Med 18:593–600PubMedGoogle Scholar
  14. Cook SA, Bronson RT, Davisson MT (2006) Recoil wobbler, rcw, a new neurological mutation in the proximal region of mouse chromosome 10. Mouse Mutant Resource website, The Jackson Laboratory, Bar Harbor ME. Accessed 1 August 2007
  15. De Vry J, Horvath E, Schreiber R (2001) Neuroprotective and behavioral effects of the selective metabotropic glutamate mGlu(1) receptor antagonist BAY 36–7620. Eur J Pharmacol 428:203–214PubMedCrossRefGoogle Scholar
  16. Dolmetsch RE, Xu K, Lewis RS (1998) Calcium oscillations increase the efficiency and specificity of gene expression. Nature 392:933–936PubMedCrossRefGoogle Scholar
  17. Hardingham GE, Chawla S, Johnson CM, Bading H (1997) Distinct functions of nuclear and cytoplasmic calcium in the control of gene expression. Nature 385:260–265PubMedCrossRefGoogle Scholar
  18. Jensen AA, Sheppard PO, O’Hara PJ, Krogsgaard-Larsen P, Brauner-Osborne H (2000) The role of Arg(78) in the metabotropic glutamate receptor mGlu(1) for agonist binding and selectivity. Eur J Pharmacol 397:247–253PubMedCrossRefGoogle Scholar
  19. Jiao Y, Yan J, Zhao Y, Donahue LR, Beamer WG, et al. (2005) Carbonic anhydrase-related protein VIII deficiency is associated with a distinctive lifelong gait disorder in waddles mice. Genetics 171:1239–1246PubMedCrossRefGoogle Scholar
  20. Kano M, Hashimoto K, Kurihara H, Watanabe M, Inoue Y, et al. (1997) Persistent multiple climbing fiber innervation of cerebellar Purkinje cells in mice lacking mGluR1. Neuron 18:71–79PubMedCrossRefGoogle Scholar
  21. Kim D, Jun KS, Lee SB, Kang NG, Min DS, et al. (1997) Phospholipase C isozymes selectively couple to specific neurotransmitter receptors. Nature 389:290–293PubMedCrossRefGoogle Scholar
  22. Kunishima N, Shimada Y, Tsuji Y, Sato T, Yamamoto M, et al. (2000) Structural basis of glutamate recognition by a dimeric metabotropic glutamate receptor. Nature 407:971–977PubMedCrossRefGoogle Scholar
  23. Lee AC, Wong RK, Chuang SC, Shin HS, Bianchi R (2002) Role of synaptic metabotropic glutamate receptors in epileptiform discharges in hippocampal slices. J Neurophysiol 88:1625–1633PubMedGoogle Scholar
  24. Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A, et al. (2007) Genome-wide atlas of gene expression in the adult mouse brain. Nature 445:168–176PubMedCrossRefGoogle Scholar
  25. Levenes C, Daniel H, Jaillard D, Conquet F, Crepel F (1997) Incomplete regression of multiple climbing fibre innervation of cerebellar Purkinje cells in mGLuR1 mutant mice. Neuroreport 8:571–574PubMedCrossRefGoogle Scholar
  26. Li W, Llopis J, Whitney M, Zlokarnik G, Tsien RY (1998) Cell-permeant caged InsP3 ester shows that Ca2+ spike frequency can optimize gene expression. Nature 392:936–941PubMedCrossRefGoogle Scholar
  27. Masu M, Tanabe Y, Tsuchida K, Shigemoto R, Nakanishi S (1991) Sequence and expression of a metabotropic glutamate receptor. Nature 349:760–765PubMedCrossRefGoogle Scholar
  28. Matsumoto M, Nakagawa T, Inoue T, Nagata E, Tanaka K, et al. (1996) Ataxia and epileptic seizures in mice lacking type 1 inositol 1,4,5-trisphosphate receptor. Nature 379:168–171PubMedCrossRefGoogle Scholar
  29. Nicotera P, Orrenius S (1998) The role of calcium in apoptosis. Cell Calcium 23:173–180PubMedCrossRefGoogle Scholar
  30. Nystuen A, Legare ME, Shultz LD, Frankel WN (2001) A null mutation in inositol polyphosphate 4-phosphatase type I causes selective neuronal loss in weeble mutant mice. Neuron 32:203–212PubMedCrossRefGoogle Scholar
  31. Nystuen AM, Schwendinger JK, Sachs AJ, Yang AW, Haider NB (2007) A null mutation in VAMP1/synaptobrevin is associated with neurological defects and prewean mortality in the lethal-wasting mouse mutant. Neurogenetics 8:1–10PubMedCrossRefGoogle Scholar
  32. Offermanns S, Hashimoto K, Watanabe M, Sun W, Kurihara H, et al. (1997) Impaired motor coordination and persistent multiple climbing fiber innervation of cerebellar Purkinje cells in mice lacking Galphaq. Proc Natl Acad Sci U S A 94:14089–14094PubMedCrossRefGoogle Scholar
  33. Pollock PM, Cohen-Solal K, Sood R, Namkoong J, Martino JJ, et al. (2003). Melanoma mouse model implicates metabotropic glutamate signaling in melanocytic neoplasia. Nat Genet 34:108–112PubMedCrossRefGoogle Scholar
  34. Ray K, Hauschild BC (2000) Cys-140 is critical for metabotropic glutamate receptor-1 dimerization. J Biol Chem 275:34245–34251PubMedCrossRefGoogle Scholar
  35. Sato T, Shimada Y, Nagasawa N, Nakanishi S, Jingami H (2003) Amino acid mutagenesis of the ligand binding site and the dimer interface of the metabotropic glutamate receptor 1. Identification of crucial residues for setting the activated state. J Biol Chem 278:4314–4321PubMedCrossRefGoogle Scholar
  36. Schanne FA, Kane AB, Young EE, Farber JL (1979) Calcium dependence of toxic cell death: a final common pathway. Science 206:700–702PubMedCrossRefGoogle Scholar
  37. Shannon HE, Peters SC, Kingston AE (2005) Anticonvulsant effects of LY456236, a selective mGlu1 receptor antagonist. Neuropharmacology 49(Suppl 1):188–195PubMedCrossRefGoogle Scholar
  38. Sillevis Smitt P, Kinoshita A, De Leeuw B, Moll W, Coesmans M, et al. (2000) Paraneoplastic cerebellar ataxia due to autoantibodies against a glutamate receptor. N Engl J Med 342:21–27PubMedCrossRefGoogle Scholar
  39. Street VA, Bosma MM, Demas VP, Regan MR, Lin DD, et al. (1997) The type 1 inositol 1,4,5-trisphosphate receptor gene is altered in the opisthotonos mouse. J Neurosci 17:635–645PubMedGoogle Scholar
  40. Tanaka J, Nakagawa S, Kushiya E, Yamasaki M, Fukaya M, et al. (2000) Gq protein alpha subunits Galphaq and Galpha11 are localized at postsynaptic extra-junctional membrane of cerebellar Purkinje cells and hippocampal pyramidal cells. Eur J Neurosci 12:781–792PubMedCrossRefGoogle Scholar
  41. Tse FW, Tse A, Hille B, Horstmann H, Almers W (1997) Local Ca2+ release from internal stores controls exocytosis in pituitary gonadotrophs. Neuron 18:121–132PubMedCrossRefGoogle Scholar
  42. Tsuchiya D, Kunishima N, Kamiya N, Jingami H, Morikawa K (2002) Structural views of the ligand-binding cores of a metabotropic glutamate receptor complexed with an antagonist and both glutamate and Gd3+. Proc Natl Acad Sci U S A 99:2660–2665PubMedCrossRefGoogle Scholar
  43. VonDerLinden D, Ma X, Sandberg EM, Gernert K, Bernstein KE, et al. (2002) Mutation of glutamic acid residue 1046 abolishes Jak2 tyrosine kinase activity. Mol Cell Biochem 241:87–94PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Andrew J. Sachs
    • 1
  • Jamie K. Schwendinger
    • 1
  • Andy W. Yang
    • 1
  • Neena B. Haider
    • 1
    • 2
  • Arne M. Nystuen
    • 1
    • 3
  1. 1.Department of Genetics, Cell Biology and AnatomyUniversity of Nebraska Medical CenterOmahaUSA
  2. 2.Department of OphthalmologyUniversity of Nebraska Medical CenterOmahaUSA
  3. 3.6010 Durham Research CenterUniversity of Nebraska Medical CenterOmahaUSA

Personalised recommendations