1. Cerebellar Ataxia, Seizures, Premature Death, and Cardiac Abnormalities in Mice with Targeted Disruption of the Cacna2d2 Gene
- Author
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John D. Minna, Draginja Djurickovic, Gregory W. Alvord, Jerrold M. Ward, Michael I. Lerman, Nicole L. Morris, Dorothea McAreavey, Michael A. Rogawski, Ming Hui Wei, Deborah E. Devor-Henneman, Boning Gao, Vandana Sachdev, James A. Richardson, Melissa K. Banks, Lameh Fananapazir, Sergey Ivanov, and Lino Tessarollo
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Ataxia ,Tumor suppressor gene ,Cerebellar Ataxia ,Heart Diseases ,Purkinje cell ,Mutant ,Blood Pressure ,Biology ,Motor Activity ,Pathology and Forensic Medicine ,Epilepsy ,Electrocardiography ,Mice ,Mice, Neurologic Mutants ,Purkinje Cells ,Seizures ,medicine ,Animals ,Genes, Tumor Suppressor ,Growth Disorders ,Mice, Knockout ,Cerebellar ataxia ,Voltage-dependent calcium channel ,Homozygote ,Gene targeting ,medicine.disease ,Mice, Inbred C57BL ,Disease Models, Animal ,medicine.anatomical_structure ,Gene Targeting ,Cancer research ,Female ,Animal Model ,Calcium Channels ,medicine.symptom ,Gene Deletion - 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.
- Published
- 2004