An autism-associated calcium channel variant causes defects in neuronal polarity in the ALM neuron of C. elegans.
An autism-associated calcium channel variant causes defects in neuronal polarity in the ALM neuron of C. elegans.
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DOI：
10.17912/micropub.biology.000378
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发表时间：
2021-04-01
影响因子：
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通讯作者：
Quinn CC
中科院分区：
文献类型：
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作者：
Buddell T;Quinn CC
CACNA 1C电压门控钙通道基因的变体与自闭症和其他神经发育障碍有关，包括双相情感障碍，精神分裂症和ADHD。Timothy综合征突变是CACNA 1C中一种罕见的从头获得性功能变体，可导致自闭症伴高自闭症，为研究CACNA 1C变体在神经发育障碍中的作用提供了强有力的途径。在我们以前的工作中，我们证明了一个egl-19（gof）突变，它相当于CACNA 1C中的Timothy综合征突变，可以破坏C中PLM轴突的终止。优美的在这里，我们报告了一种新的表型的egl-19（gof）突变，从而导致从ALM细胞体的异位过程的增长。我们还扩展了我们以前的结果表明，egl-19（GOF）突变导致轴突终止缺陷不仅在PLM轴突，但也在ALM轴突。这些结果表明Timothy综合征突变可以破坏轴突发育的多个步骤。进一步探索神经元极性和轴突终止这些扰动的分子机制的工作将使我们更好地了解CACNA 1C的变体如何导致自闭症的轴突缺陷。
Variants of the CACNA1C voltage-gated calcium channel gene have been associated with autism and other neurodevelopmental disorders including bipolar disorder, schizophrenia, and ADHD. 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. In our previous work, we demonstrated that an egl-19(gof) mutation, which is equivalent to the Timothy syndrome mutation in CACNA1C, can disrupt termination of the PLM axon in C. elegans. Here, we report a novel phenotype for the egl-19(gof) mutation, whereby it causes the growth of an ectopic process from the ALM cell body. We also extend our previous results to show that the egl-19(gof) mutation causes axon termination defects not only in the PLM axon, but also in the ALM axon. These results suggest that the Timothy syndrome mutation can disrupt multiple steps of axon development. Further work exploring the molecular mechanisms that underlie these perturbations in neuronal polarity and axon termination will give us better understanding of how variants in CACNA1C contribute to the axonal defects that underlie autism.