Skip to main content

Advertisement

SpringerLink
Log in

Phenotypic heterogeneity in the stargazin allelic series

  • Published:
Mammalian Genome Aims and scope Submit manuscript

Abstract

The stargazer mutant mouse is characterized by its ataxic gait, head tossing, and absence seizures. The mutation was identified in the gamma2 subunit gene of the high voltage-dependent calcium channel, Cacng2. Subsequently, two allelic variants of stargazer have arisen, waggler and stargazer 3J. In this study, we have compared these new alleles to the original stargazer allele. All three mutations affect the Cacng2 mRNA levels as they all arise from disruptions within the introns of this gene. Our results show that the mutations cause reduced Cacng2 mRNA and protein levels. Stargazer and waggler mice have the least amount of mRNA and undetectable protein, whereas stargazer 3J appears to be the mildest allele, both in terms of the phenotype and protein expression. Electroencephalographic (EEG) analysis confirmed that stargazer has frequent spike-wave discharges (SWDs); the average duration of each discharge burst is 5 seconds and recurs every minute. The waggler allele causes a greater variation in SWD activity depending on the individual mouse, and the stargazer 3J mouse has no SWDs. The preliminary characterization of this heterogeneous allelic series provides a basis to explore more biochemical and physiological parameters relating to the role of the Cacng2 product in calcium channel activity, AMPA receptor localization, and cerebellar disturbances.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. S Bao L Chen X Qiao B Knusel RF Thompson (1998) ArticleTitleImpaired eye-blink conditioning in waggler, a mutant mouse with cerebellar BDNF deficiency. Learn Mem 5 355–364 Occurrence Handle1:STN:280:DyaK1Mzot1WlsQ%3D%3D Occurrence Handle10454360

    CAS  PubMed  Google Scholar 

  2. RS Chafetz WK Nahm JL Noebels (1995) ArticleTitleAberrant expression of neuropeptide Y in hippocampal mossy fibers in the absence of local cell injury following the onset of spike-wave synchronization. Brain Res Mol Brain Res 31 111–121 Occurrence Handle10.1016/0169-328X(95)00041-P Occurrence Handle1:CAS:528:DyaK2MXmt1yiurk%3D Occurrence Handle7476019

    Article  CAS  PubMed  Google Scholar 

  3. L Chen DM Chetkovich RS Petralia NT Sweeney Y Kawasaki et al. (2000) ArticleTitleStargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms. Nature 408 936–943 Occurrence Handle10.1038/35046031 Occurrence Handle1:STN:280:DC%2BD3M%2Fpt1Crug%3D%3D Occurrence Handle11140673

    Article  CAS  PubMed  Google Scholar 

  4. PJ Chu HM Robertson PM Best (2001) ArticleTitleCalcium channel gamma subunits provide insights into the evolution of this gene family. Gene 280 37–48 Occurrence Handle10.1016/S0378-1119(01)00738-7 Occurrence Handle1:CAS:528:DC%2BD3MXovFCrtb0%3D Occurrence Handle11738816

    Article  CAS  PubMed  Google Scholar 

  5. V Crunelli N Leresche (2002) ArticleTitleChildhood absence epilepsy: genes, channels, neurons and networks. Nat Rev Neurosci 3 371–382 Occurrence Handle10.1038/nrn811 Occurrence Handle1:CAS:528:DC%2BD38XjsFynurc%3D Occurrence Handle11988776

    Article  CAS  PubMed  Google Scholar 

  6. E DiPasquale KD Keegan JL Noebels (1997) ArticleTitleIncreased excitability and inward rectification in layer V cortical pyramidal neurons in the epileptic mutant mouse Stargazer. J Neurophysiol 77 621–631 Occurrence Handle1:STN:280:ByiB3MfjvFw%3D Occurrence Handle9065835

    CAS  PubMed  Google Scholar 

  7. K Hashimoto M Fukaya X Qiao K Sakimura M Watanabe et al. (1999) ArticleTitleImpairment of AMPA receptor function in cerebellar granule cells of ataxic mutant mouse stargazer. J Neurosci 19 6027–6036 Occurrence Handle1:CAS:528:DyaK1MXksVykur8%3D Occurrence Handle10407040

    CAS  PubMed  Google Scholar 

  8. DA Hosford FH Lin DL Kraemer Z Cao Y Wang et al. (1995) ArticleTitleNeural network of structures in which GABAB receptors regulate absence seizures in the lethargic (lh/lh) mouse model. J Neurosci 15 7367–7376 Occurrence Handle1:CAS:528:DyaK2MXptlOms7w%3D Occurrence Handle7472490

    CAS  PubMed  Google Scholar 

  9. MG Kang CC Chen R Felix VA Letts WN Frankel et al. (2001) ArticleTitleBiochemical and biophysical evidence for gamma 2 subunit association with neuronal voltage-activated Ca2+ channels. J Biol Chem 276 32917–32924 Occurrence Handle10.1074/jbc.M100787200 Occurrence Handle1:CAS:528:DC%2BD3MXmvFCmtLs%3D Occurrence Handle11441000

    Article  CAS  PubMed  Google Scholar 

  10. N Klugbauer S Dai V Specht L Lacinova E Marais et al. (2000) ArticleTitleA family of gamma-like calcium channel subunits. FEBS Lett 470 189–197 Occurrence Handle1:CAS:528:DC%2BD3cXhvV2ksro%3D Occurrence Handle10734232

    CAS  PubMed  Google Scholar 

  11. VA Letts R Felix GH Biddlecome J Arikkath CL Mahaffey et al. (1998) ArticleTitleThe mouse stargazer gene encodes a neuronal Ca2+-channel gamma subunit. Nat Genet 19 340–347 Occurrence Handle1:CAS:528:DyaK1cXlt1Cju7c%3D Occurrence Handle9697694

    CAS  PubMed  Google Scholar 

  12. DA McCormick D Contreras (2001) ArticleTitleOn the cellular and network bases of epileptic seizures. Annu Rev Physiol 63 815–846 Occurrence Handle10.1146/annurev.physiol.63.1.815 Occurrence Handle1:CAS:528:DC%2BD3MXjtFKmurs%3D Occurrence Handle11181977

    Article  CAS  PubMed  Google Scholar 

  13. JL Noebels X Qiao RT Bronson C Spencer MT Davisson (1990) ArticleTitleStargazer: a new neurological mutant on Chromosome 15 in the mouse with prolonged cortical seizures. Epilepsy Res 7 129–135 Occurrence Handle10.1016/0920-1211(90)90098-G Occurrence Handle1:STN:280:By6C2cnlt1Q%3D Occurrence Handle2289471

    Article  CAS  PubMed  Google Scholar 

  14. X Qiao F Hefti B Knusel JL Noebels (1996) ArticleTitleSelective failure of brain-derived neurotrophic factor mRNA expression in the cerebellum of stargazer, a mutant mouse with ataxia. J Neurosci 16 640–648 Occurrence Handle1:CAS:528:DyaK28XksFKltA%3D%3D Occurrence Handle8551348

    CAS  PubMed  Google Scholar 

  15. X Qiao L Chen H Gao S Bao F Hefti (1998) ArticleTitleCerebellar brain-derived neurotrophic factor-TrkB defect associated with impairment of eyeblink conditioning in Stargazer mutant mice. J Neurosci 18 6990–6999 Occurrence Handle1:CAS:528:DyaK1cXls1Ojsb4%3D Occurrence Handle9712667

    CAS  PubMed  Google Scholar 

  16. CA Richardson B Leitch (2002) ArticleTitleCerebellar Golgi, Purkinje, and basket cells have reduced gamma-aminobutyric acid immunoreactivity in stargazer mutant mice. J Comp Neurol 453 85–99 Occurrence Handle10.1002/cne.10406 Occurrence Handle12357434

    Article  PubMed  Google Scholar 

  17. AH Sharp JL Black 3rd SJ Dubel S Sundarraj JP Shen et al. (2001) ArticleTitleBiochemical and anatomical evidence for specialized voltage-dependent calcium channel gamma isoform expression in the epileptic and ataxic mouse, stargazer. Neuroscience 105 599–617 Occurrence Handle10.1016/S0306-4522(01)00220-2 Occurrence Handle1:CAS:528:DC%2BD3MXmtV2hs7o%3D Occurrence Handle11516827

    Article  CAS  PubMed  Google Scholar 

  18. OC Snead (1995) ArticleTitleBasic mechanisms of generalized absence seizures Ann Neurol 37 146–157 Occurrence Handle7847856

    PubMed  Google Scholar 

  19. HO Sweet (1993) ArticleTitleWaggler and stargazer are allelic. Mouse Genome 91 312–313

    Google Scholar 

  20. HO Sweet RT Bronson S Cook C Spencer MT Davisson (1991) ArticleTitleResearch News. 1. Waggler (wag). Mouse Genome 89 552

    Google Scholar 

  21. CL Thompson MH Tehrani EM Barnes FA Stephenson (1998) ArticleTitleDecreased expression of GABAA receptor alpha6 and beta3 subunits in stargazer mutant mice: a possible role for brain-derived neurotrophic factor in the regulation of cerebellar GABAA receptor expression? Brain Res Mol Brain Res 60 282–290 Occurrence Handle10.1016/S0169-328X(98)00205-8 Occurrence Handle1:CAS:528:DyaK1cXmtFWnt74%3D Occurrence Handle9757064

    Article  CAS  PubMed  Google Scholar 

  22. Y Zhang M Mori DL Burgess JL Noebels (2002) ArticleTitleMutations in high-voltage-activated calcium channel genes stimulate low-voltage-activated currents in mouse thalamic relay neurons. J Neurosci 22 6362–6371 Occurrence Handle1:CAS:528:DC%2BD38XlvFKns7g%3D Occurrence Handle12151514

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Drs. Susan Ackerman and Muriel Davisson for critical reviews of this manuscript. This work was supported by a grant from the NIH NS32801 to Verity A. Letts. Myoung-Goo. Kang was partly funded by an Epilepsy Foundation Predoctoral Fellowship, and Kevin P. Campbell is an Investigator of the Howard Hughes Medical Institute.

Author information

Authors and Affiliations

  1. The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA

    Verity A. Letts, Connie L. Mahaffey, Barbara Beyer, Heather Tenbrink & Wayne N. Frankel

  2. The Howard Hughes Medical Institute, Department of Physiology and Biophysics, Department of Neurology, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA

    Myoung-Goo Kang & Kevin P. Campbell

Authors
  1. Verity A. Letts
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Myoung-Goo Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Connie L. Mahaffey
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Barbara Beyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Heather Tenbrink
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kevin P. Campbell
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wayne N. Frankel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Verity A. Letts.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Letts, V.A., Kang, MG., Mahaffey, C.L. et al. Phenotypic heterogeneity in the stargazin allelic series . Mamm Genome 14, 506–513 (2003). https://doi.org/10.1007/s00335-003-2268-x

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00335-003-2268-x

Keywords

Search

Navigation