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Animal model - Cerebellar ataxia, seizures, premature death, and cardiac abnormalities in mice with targeted disruption of the Cacna2d2 gene

  1. Author:
    Ivanov, S. V.
    Ward, J. M.
    Tessarollo, L.
    McAreavey, D.
    Sachdev, V.
    Fananapazir, L.
    Banks, M. K.
    Morris, N.
    Djurickovic, D.
    vor-Henneman, D. E.
    Wei, M. H.
    Alvord, G. W.
    Gao, B. N.
    Richardson, J. A.
    Minna, J. D.
    Rogawski, M. A.
    Lerman, M. I.

  2. Author Address

    NCI, Basic Res Program, Frederick, MD 21702 USA. NCI, Lab Anim Sci Program, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA. NCI, Immunobiol Lab, Ctr Canc Res, Frederick, MD 21702 USA. NCI, Vet & Tumor Pathol Sect, Ctr Canc Res, Frederick, MD 21702 USA. NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. NCI, Neural Dev Sect, Comp & Stat Serv, Ctr Canc Res, Frederick, MD 21702 USA. NHLBI, Ctr Clin, NIH, Bethesda, MD 20892 USA. NHLBI, Clin Electrophysiol & Inherited Heart Dis Sect, Cardiol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Epilepsy Res Sect, Div Intramural Res, NIH, Bethesda, MD 20892 USA. Univ Texas, SW Med Ctr, Hamon Ctr Therapeut Oncol Res, Dallas, TX USA. Univ Texas, SW Med Ctr, Dept Pathol, Dallas, TX USA Ivanov, SV, NCI, Basic Res Program, Bldg 560,POB B, Frederick, MD 21702 USA
    1. Year: 2004
    2. Date: SEP
  2. Journal: American Journal of Pathology
    1. 165
    2. 3
    3. Pages: 1007-1018
  4. Type of Article: Article
  1. Abstract:

    CACNA2D2 is a putative tumor suppressor gene located in the human chromosome 3p21.3 region that shows frequent allelic imbalances in lung, breast, and other cancers. The alpha2delta-2 protein encoded by the gene is a regulatory subunit of voltage-dependent calcium channels and is expressed in brain, heart, and other tissues. Here we report that mice homozygous for targeted disruption of the Cacna2d2 gene exhibit growth retardation, reduced life span, ataxic gait with apoptosis of cerebellar granule cells followed by Purkinje cell depletion, enhanced susceptibility to seizures, and cardiac abnormalities. The Cacna2d2(tm1NCIF) null phenotype has much in common with that of Cacna1a mutants, such as cerebellar neuro-degeneration associated with ataxia, seizures, and premature death. A tendency to bradycardia and limited response of null mutants to isoflurane implicate alpha2delta-2 in sympathetic regulation of cardiac function. in summary, our findings provide genetic evidence that the alpha2delta-2 subunit serves in vivo as a component of P/Q-type calcium channels, is indispensable for the central nervous system function, and may be involved in hereditary cerebellar ataxias and epileptic disorders in humans

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External Sources

  1. View record in Web of Science®
  2. WOS: 000223732000029

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