Convergent mechanisms for neurodevelopmental disorder genes

多亏了Simons Simplex Collection，科学界拥有数十个高度可靠的风险 通过在自闭症谱系障碍（ASD）患者中鉴定罕见的新生变异基因。什么 目前缺少的是将这些基因连接到一个聚合途径中的机制， 病因学在这个提议中，我们将检验ANK 2和SCN 2A这两个与肿瘤相关的顶级基因的假设。 ASD在分子水平上连接以控制树突的兴奋性。NaV1.2是SCN 2A基因的产物，是一种 主要在锥体神经元中发现的电压门控钠通道，其定位于轴突起始段 (AIS)早期发展。在发育后期，NaV1.2重新定位到树突，在树突中起关键作用， 突触可塑性和稳定性。NaV1.2远离AIS的亚细胞重定位的时间（~ 1年 在人类中）也与ASD患者的症状发作相关，这表明了解新的 NaV1.2在树突中的作用可能对确定SCN 2A相关ASD的病因至关重要。虽然我们的 小组和其他人已经表明，细胞内支架蛋白，锚蛋白-G（ANK 3），是必要的NaV1.2 尽管NaV1.2定位于AIS，但关于NaV1.2的树突定位的潜在机制知之甚少。 锚蛋白-B是ANK 2基因的产物，是锚蛋白基因家族的成员，具有显著的同源性 尽管它与抗-G结合，但它以高水平定位于树突，在那里它可能在NaV1.2树突中起关键作用。 本地化检验ANK 2和SCN 2A在分子水平上连接以控制树突状细胞的假设。 兴奋性将有积极的影响，通过增加我们对突触的机制的理解， ASD的改变，这可能为治疗干预提供新的靶点。

Thanks to the Simons Simplex Collection, the scientific community possesses dozens of highly reliable risk genes through the identification of rare de novo variants in patients with autism spectrum disorder (ASD). What is currently missing is a mechanism linking these genes into a convergent pathway that gives insight into disease etiology. In this proposal, we will test the hypothesis that ANK2 and SCN2A, two of the top genes implicated in ASD, are linked at the molecular level to control dendritic excitability. NaV1.2, product of the SCN2A gene, is a voltage-gated sodium channel found primarily in pyramidal neurons where it localizes to the axon initial segment (AIS) early in development. Later in development, NaV1.2 relocalizes to dendrites where it plays critical roles in synaptic plasticity and stability. The timing of the subcellular relocalization of NaV1.2 away from the AIS (~ 1 year in humans) also correlates with the onset of symptoms in ASD patients, suggesting that understanding the new role for NaV1.2 in dendrites may be critical for determining the etiology of SCN2A-associated ASD. While our group and others have shown that the intracellular scaffolding protein, ankyrin-G (ANK3), is necessary for NaV1.2 localization to the AIS, very little is known about the mechanisms underlying the dendritic localization of NaV1.2. Ankyrin-B, product of the ANK2 gene, is a member of the ankyrin gene family that shares significant homology with ankyrin-G, yet it is localized at high levels to dendrites where it may play a key role in NaV1.2 dendritic localization. Testing the hypothesis that ANK2 and SCN2A are linked at the molecular level to control dendritic excitability will have a positive impact by increasing our understanding of the mechanisms underlying synaptic alterations in ASD, which may provide novel targets for therapeutic intervention.