Investigation of how axon development is disrupted by the autism-causing Timothy syndrome mutation.

自闭症是一种高度可遗传的神经发育障碍，与 许多基因中的变种。然而，自闭症的生物学基础仍然很差。 明白了。为了深入了解导致自闭症的机制，我们将重点放在 Timothy综合征突变，CACNA1C电压门控钙突变 通道(VGCC)。蒂莫西综合症突变会导致高外显性自闭症， 为研究其背后的分子机制提供了一个强有力的途径 自闭症。我们的初步数据表明，Timothy综合征突变破坏了轴突 靶向线虫，为理解VGCC变异体的作用提供了一个模型 患有自闭症。在目标1中，我们将研究VGCC如何调节轴突靶向，以及VGCC如何 Timothy综合征突变改变这一过程，影响轴突连接和 行为。在目标2中，我们将研究Timothy综合征突变是如何改变的 自噬以及这一过程中的变化如何影响轴突靶向。在《目标3》中，我们将 确定VGCC中的其他错义突变是否会改变轴突靶向。这些 研究将为自闭症的生物学基础提供洞察力，并将确定 自闭症相关基因之间的相互作用可能被用来预测和 诊断自闭症。此外，CACNA1C基因也与 精神分裂症、双相情感障碍、重度抑郁症和注意缺陷多动 无序，这表明我们的结果可能更广泛地适用于其他 神经精神障碍。

Autism is a highly heritable neurodevelopmental disorder that has been linked to variants in many genes. However, the biological basis of autism remains poorly understood. To gain insight into the mechanisms that cause autism, we are focusing on the Timothy syndrome mutation, a variant in the CACNA1C voltage gated calcium channel (VGCC). The Timothy syndrome mutation causes autism with high penetrance, providing a powerful avenue for investigation of the molecular mechanisms that underlie autism. Our preliminary data indicate that the Timothy syndrome mutation disrupts axon targeting in C. elegans, providing a model for understanding the role of VGCC variants in autism. In aim 1, we will investigate how VGCCs regulate axon targeting and how the Timothy syndrome mutation alters this process to affect axonal connectivity and behavior. In aim 2, we will investigate how the Timothy syndrome mutation alters autophagy and how alterations in this process affect axon targeting. In aim 3, we will determine if other missense mutations in VGCCs can alter axon targeting. These studies will provide insight into the biological basis for autism and will identify interactions between autism-linked genes that could potentially be used to predict and diagnose autism. Moreover, the CACNA1C gene has also been associated with schizophrenia, bipolar disorder, major depression and attention deficit hyperactivity disorder, suggesting that our results are likely to be more broadly applicable to other neuropsychiatric disorders.