Bett Glenna Cl, Lis Agnieszka, Wersinger Scott R, Baizer Joan S, Duffey Michael E, Rasmusson Randall L
Department of Gynecology and Obstetrics, Center for Cellular and Systems Electrophysiology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY ; Department of Physiology and Biophysics, Center for Cellular and Systems Electrophysiology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY.
Department of Physiology and Biophysics, Center for Cellular and Systems Electrophysiology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY.
N Am J Med Sci (Boston). 2012 Jul 25;5(3):135-140. doi: 10.7156/najms.2012.053135.
Timothy Syndrome (TS) arises from a point mutation in the human voltage-gated L-type Ca channel (Cav1.2). TS is associated with cardiac arrhythmias and sudden cardiac death, as well as congenital heart disease, impaired cognitive function, and autism spectrum disorders. TS results from a de novo gain-of-function mutation which affects the voltage dependent component of Cav1.2 inactivation. We created a knock-in TS mouse. No homozygous TS mice survived, but heterozygous TS2-NEO mice (with the mutation and the neocassette in situ) had a normal outward appearance and survived to reproductive age. Previously, we have demonstrated that these mice exhibit the triad of Autistic traits. In this paper we document other aspects of these mice including Cav1.2 isoform expression levels, normal physical strength, brain anatomy and a marked propensity towards self-injurious scratching. Gross brain anatomy was not markedly different in TS2-NEO mice compared to control littermates, and no missing structures were noted. The lack of obvious changes in brain structure is consistent with theTS2-NEO mice may provide a significant tool in understanding the role of calcium channel inactivation in both cardiac function and brain development.
Timothy综合征（TS）源于人类电压门控L型钙通道（Cav1.2）的一个点突变。TS与心律失常和心源性猝死相关，还与先天性心脏病、认知功能受损以及自闭症谱系障碍有关。TS由一种新生的功能获得性突变导致，该突变影响Cav1.2失活的电压依赖性成分。我们构建了一种敲入TS小鼠。没有纯合TS小鼠存活下来，但杂合TS2-NEO小鼠（带有突变和原位新盒）外观正常并存活至生殖年龄。此前，我们已证明这些小鼠表现出自闭症特征三联征。在本文中，我们记录了这些小鼠的其他方面，包括Cav1.2亚型表达水平、正常体力、脑解剖结构以及明显的自伤性抓挠倾向。与对照同窝小鼠相比，TS2-NEO小鼠的大体脑解剖结构没有明显差异，也未发现结构缺失。脑结构缺乏明显变化与TS2-NEO小鼠可能为理解钙通道失活在心脏功能和脑发育中的作用提供重要工具这一观点一致。
