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Cerebellar Ataxia, Seizures, Premature Death, and Cardiac Abnormalities in Mice with Targeted Disruption of the Cacna2d2 Gene
- Publication Year :
- 2004
- Publisher :
- American Society for Investigative Pathology, 2004.
-
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.
- 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
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....3b3712963dd6b8513c1ad27897ad4403