Animal model - Cerebellar ataxia, seizures, premature death, and cardiac abnormalities in mice with targeted disruption of the Cacna2d2 gene
Animal model - Cerebellar ataxia, seizures, premature death, and cardiac abnormalities in mice with targeted disruption of the Cacna2d2 gene
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DOI：
10.1016/s0002-9440(10)63362-7
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发表时间：
2004-09-01
影响因子：
6
通讯作者：
Lerman, MI
中科院分区：
文献类型：
--
作者：
Ivanov, SV;Ward, JM;Lerman, MI
CACNA2D2 是一种假定的肿瘤抑制基因，位于人类染色体 3p21.3 区域，在肺癌、乳腺癌和其他癌症中表现出频繁的等位基因失衡。该基因编码的 alpha2delta-2 蛋白是电压依赖性钙通道的调节亚基，在大脑、心脏和其他组织中表达。在这里，我们报道了 Cacna2d2 基因靶向破坏的纯合子小鼠表现出生长迟缓、寿命缩短、步态共济失调（伴有小脑颗粒细胞凋亡，随后浦肯野细胞耗竭）、癫痫易感性增强和心脏异常。 Cacna2d2(tm1NCIF) 无效表型与 Cacna1a 突变体有很多共同点，例如与共济失调、癫痫发作和过早死亡相关的小脑神经变性。无效突变体对异氟醚的心动过缓倾向和有限反应表明 alpha2delta-2 参与心脏功能的交感调节。总之，我们的研究结果提供了遗传证据，表明α2δ-2亚基在体内作为P/Q型钙通道的组成部分，对于中枢神经系统功能是不可或缺的，并且可能与人类遗传性小脑共济失调和癫痫病有关。
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.