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(American Journal of Pathology. 2004;165:1007-1018.)
© 2004 American Society for Investigative Pathology

Animal Model

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^** and Michael I. Lerman

From the Basic Research Program,^* the Laboratory Animal Sciences Program, Science Applications International Corporation-Frederick, Inc., National Cancer Institute at Frederick, Frederick, Maryland; the Laboratory of Immunobiology, Veterinary and Tumor Pathology Section, the Mouse Cancer Genetics Program, Neural Development Section, Computer and Statistical Services, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland; the Clinical Center,^¶ Clinical Electrophysiology and Inherited Heart Diseases Section,|| Cardiology Branch, National Heart, Lung, and Blood Institute, Epilepsy Research Section,^** Division of Intramural Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland; and the Hamon Center for Therapeutic Oncology Research and the Department of Pathology,^¶¶ University of Texas, Southwestern Medical Center, Dallas, Texas

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