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

Sergey V. Ivanov, Jerrold M. Ward, Lino Tessarollo, Dorothea McAreavey, Vandana Sachdev, Lameh Fananapazir, Melissa K. Banks, Nicole Morris, Draginja Djurickovic, Deborah E. Devor-Henneman, Ming Hui Wei, Gregory W. Alvord, Boning Gao, James A. Richardson, John D. Minna, Michael A Rogawski, Michael I. Lerman

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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 α2δ-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 Cacna2d2tm1NCIF 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 isoffarane implicate α2δ-2 in sympathetic regulation of cardiac function. In summary, our findings provide genetic evidence that the α2δ-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.

Original languageEnglish (US)
Pages (from-to)1007-1018
Number of pages12
JournalAmerican Journal of Pathology
Volume165
Issue number3
StatePublished - Sep 2004
Externally publishedYes

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ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Ivanov, S. V., Ward, J. M., Tessarollo, L., McAreavey, D., Sachdev, V., Fananapazir, L., Banks, M. K., Morris, N., Djurickovic, D., Devor-Henneman, D. E., Wei, M. H., Alvord, G. W., Gao, B., Richardson, J. A., Minna, J. D., Rogawski, M. A., & Lerman, M. I. (2004). Cerebellar ataxia, seizures, premature death, and cardiac abnormalities in mice with targeted disruption of the Cacna2d2 gene. American Journal of Pathology, 165(3), 1007-1018.