Convergent mechanisms for neurodevelopmental disorder genes

神经发育障碍基因的趋同机制

• 批准号: 10275804
• 负责人: Kevin J Bender
• 金额: $ 55.69万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-14 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10275804
• 关键词: ANK2 gene; ANK3 gene; ASD patient; Actins; Action Potentials; Affect; Amino Acids; Ankyrins; Axon; Binding; Biochemical; Biological Assay; Brain; Calcium; Cell Adhesion Molecules; Collaborations; Collection; Communities; Complementary DNA; Confocal Microscopy; Cytoskeleton; Data; Dendrites; Development; Disease; Electrophysiology (science); Etiology; Evoked Potentials; Family; Family member; Functional disorder; Gene Family; Generations; Genes; Heterozygote; Human; Image; Imaging Techniques; Immunoprecipitation; Impairment; In Vitro; Ion Channel; Knock-out; Length; Life; Ligation; Light; Link; Membrane; Modeling; Molecular; Mus; Mutation; Neurodevelopmental Disorder; Neurons; Participant; Pathway interactions; Patients; Phenocopy; Play; Population; Protein Isoforms; Publishing; Pyramidal Cells; Role; Scaffolding Protein; Sodium; Sodium Channel; Symptoms; Synapses; Synaptic plasticity; Testing; Therapeutic Intervention; Variant; Work; autism spectrum disorder; autistic children; base; de novo mutation; early onset; excitatory neuron; exome; exome sequencing; falls; genetic variant; hippocampal pyramidal neuron; human disease; imaging approach; insight; interest; link protein; loss of function; member; molecular array; neocortical; neuronal excitability; new therapeutic target; novel; postsynaptic; repetitive behavior; risk variant; scaffold; social communication; synaptic function; transmission process; two photon microscopy; voltage

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.

多亏了Simons Simplex收藏，科学界拥有数十个高度可靠的风险 通过鉴定自闭症谱系障碍患者（ASD）患者的稀有从头变异的基因。什么 目前缺少的是将这些基因与收敛途径联系起来的机制，该途径可深入了解疾病 病因。在此提案中，我们将检验以下假设：ANK2和SCN2A，两个涉及的两个基因 ASD在分子水平上链接以控制树突状兴奋性。 NAV1.2，SCN2A基因的产物，是一个 电压门控钠通道主要发现在锥体神经元中 （AI）开发的早期。在开发的后期，NAV1.2将其重新定位到树突，在该树突中起着至关重要的作用 突触可塑性和稳定性。 NAV1.2远离AIS的亚细胞重新定位的时间（〜1年） 在人类中）还与ASD患者的症状发作有关，这表明了解新的 NAV1.2在树突中的作用对于确定与SCN2A相关的ASD的病因可能至关重要。而我们的 组和其他人已经表明，NAV1.2是必需的细胞内支架蛋白Ankyrin-G（Ank3）。 对AI的本地化，对NAV1.2的树突定位的机制知之甚少。 Ank2基因的产物Ankyrin-B是Ankyrin基因家族的成员，具有重要的同源性 使用Ankyrin-G，但它位于较高的树突上，它可能在NAV1.2树突中发挥关键作用 本土化。测试ANK2和SCN2A在分子水平上连接以控制树突状的假设 兴奋性将通过增加我们对突触基础机制的理解，从而产生积极的影响 ASD的改变，这可能为治疗干预提供新的靶标。