An autism-causing calcium channel variant functions with selective autophagy to alter axon targeting and behavior.,PLOS Genetics

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An autism-causing calcium channel variant functions with selective autophagy to alter axon targeting and behavior.
PLOS Genetics ( IF 4.0 ) Pub Date : 2019-12-05 , DOI: 10.1371/journal.pgen.1008488
Tyler Buddell ₁ , Vladislav Friedman ₁ , Cody J Drozd ₁ , Christopher C Quinn ₁

Affiliation

Common and rare variants of the CACNA1C voltage-gated calcium channel gene have been associated with autism and other neurodevelopmental disorders including schizophrenia, bipolar disorder and ADHD. However, little is known about how CACNA1C variants affect cellular processes to alter neurodevelopment. The Timothy syndrome mutation is a rare de novo gain-of-function variant in CACNA1C that causes autism with high penetrance, providing a powerful avenue into investigating the role of CACNA1C variants in neurodevelopmental disorders. Here, we use egl-19, the C. elegans homolog of CACNA1C, to investigate the role of voltage-gated calcium channels in autism. We show that an egl-19(gof) mutation that is equivalent to the Timothy syndrome mutation can alter axon targeting and affect behavior in C. elegans. We find that wildtype egl-19 negatively regulates axon termination. The egl-19(gof) mutation represses axon termination to cause axon targeting defects that lead to the misplacement of electrical synapses and alterations in habituation to light touch. Moreover, genetic interactions indicate that the egl-19(gof) mutation functions with genes that promote selective autophagy to cause defects in axon termination and behavior. These results reveal a novel genetic mechanism whereby a de novo mutation in CACNA1C can drive alterations in circuit formation and behavior.

中文翻译：

导致自闭症的钙离子通道变异体具有选择性自噬功能，可改变轴突的靶向性和行为。

CACNA1C电压门控钙通道基因的常见和罕见变体已与自闭症和其他神经发育障碍（包括精神分裂症，双相情感障碍和ADHD）相关。然而，关于CACNA1C变体如何影响细胞过程以改变神经发育的知之甚少。提摩西综合征突变是CACNA1C中罕见的从头获得功能变异，可导致自闭症的高外显率，为研究CACNA1C变异在神经发育障碍中的作用提供了强有力的途径。在这里，我们使用egl-19（CACNA1C的秀丽隐杆线虫同源物）来研究电压门控钙通道在自闭症中的作用。我们显示，相当于Timothy综合征突变的egl-19（gof）突变可以改变轴突靶向性并影响秀丽隐杆线虫的行为。我们发现野生型egl-19负调节轴突终止。egl-19（gof）突变可抑制轴突终止，从而导致轴突靶向缺陷，从而导致电突触的错位和习惯于轻触的变化。此外，遗传相互作用表明egl-19（gof）突变与促进选择性自噬从而导致轴突终止和行为缺陷的基因共同起作用。这些结果揭示了一种新的遗传机制，由此CACNA1C中的从头突变可以驱动电路形成和行为的改变。遗传相互作用表明egl-19（gof）突变与促进选择性自噬导致轴突终止和行为缺陷的基因共同起作用。这些结果揭示了一种新颖的遗传机制，由此CACNA1C中的从头突变可以驱动电路形成和行为的改变。遗传相互作用表明egl-19（gof）突变与促进选择性自噬导致轴突终止和行为缺陷的基因共同起作用。这些结果揭示了一种新的遗传机制，由此CACNA1C中的从头突变可以驱动电路形成和行为的改变。

更新日期：2019-12-06

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