Buddell Tyler, Quinn Christopher C
University of Wisconsin, Milwaukee, WI USA.
MicroPubl Biol. 2021 Apr 1;2021. doi: 10.17912/micropub.biology.000378.
Variants of the 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 gain-of-function variant in that causes autism with high penetrance, providing a powerful avenue into investigating the role of variants in neurodevelopmental disorders. In our previous work, we demonstrated that an mutation, which is equivalent to the Timothy syndrome mutation in can disrupt termination of the PLM axon in . Here, we report a novel phenotype for the 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 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 contribute to the axonal defects that underlie autism.
电压门控钙通道基因的变异与自闭症及其他神经发育障碍有关，包括双相情感障碍、精神分裂症和注意力缺陷多动障碍。蒂莫西综合征突变是一种罕见的功能获得性变异，它会导致自闭症的高外显率，为研究变异在神经发育障碍中的作用提供了有力途径。在我们之前的工作中，我们证明了一种突变，它在功能上等同于蒂莫西综合征突变，可破坏秀丽隐杆线虫中PLM轴突的终止。在此，我们报告了该突变的一种新表型，即它会导致从ALM细胞体长出异位突起。我们还扩展了之前的结果，以表明该突变不仅会导致PLM轴突的轴突终止缺陷，还会导致ALM轴突的轴突终止缺陷。这些结果表明，蒂莫西综合征突变可破坏轴突发育的多个步骤。进一步探索这些神经元极性和轴突终止扰动背后分子机制的工作，将使我们更好地理解该基因中的变异如何导致自闭症背后的轴突缺陷。
