Cerebellar ataxia, seizures, premature death, and cardiac abnormalities in mice with targeted disruption of the Cacna2d2 gene.
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.
Ivanov
Sergey V
SV
Basic Research Program, Science Applications International Corporation-Frederick, Inc., National Cancer Institute at Frederick, Frederick, Maryland, USA. ivanov@mail.ncifcrf.gov.
Ward
Jerrold M
JM
Tessarollo
Lino
L
McAreavey
Dorothea
D
Sachdev
Vandana
V
Fananapazir
Lameh
L
Banks
Melissa K
MK
Morris
Nicole
N
Djurickovic
Draginja
D
Devor-Henneman
Deborah E
DE
Wei
Ming-Hui
MH
Alvord
Gregory W
GW
Gao
Boning
B
Richardson
James A
JA
Minna
John D
JD
Rogawski
Michael A
MA
Lerman
Michael I
MI
D000818:Animals; D001794:Blood Pressure; D015220:Calcium Channels / Q000235:genetics / Q000502:physiology*; D002524:Cerebellar Ataxia / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D004195:Disease Models, Animal; D004562:Electrocardiography; D005260:Female; D017353:Gene Deletion; D018390:Gene Targeting; D016147:Genes, Tumor Suppressor; D006130:Growth Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006331:Heart Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006720:Homozygote; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D009043:Motor Activity; D011689:Purkinje Cells / Q000378:metabolism / Q000473:pathology; D012640:Seizures / Q000235:genetics / Q000401:mortality / Q000473:pathology*
C486058:Cacna2d2 protein, mouse; D015220:Calcium Channels