Metabolic changes underlying 16p11.2 deletion syndrome

修改后的项目摘要/摘要部分 项目总结 FAM57B是自闭症的危险基因，也是16p11.2疾病基因座的一部分。16pdel综合征是一种严重且流行的(1：2000人)单倍体不足的疾病，由~600kb的16号染色体缺失引起。该综合征与自闭症、语言和智力障碍、癫痫、ADHD、低眼压和肥胖密切相关，但每种症状的遗传作用尚不清楚。我们的建议解决了新的假设，即FAM57B功能的改变与自闭症和16pdel综合征有关，这是通过改变神经酰胺途径的细胞脂类来实现的。脂质队列改变可能改变神经细胞质膜成分和相关蛋白，从而改变突触活性，从而导致16pdel症状。我们定义了一个16p11.2功能相互作用组，并确定FAM57B是一个关键的‘Hub’基因(McCammon等人)。2017年)。FAM57B还被确定为自闭症风险基因(Satterstrom等人)。2019年)。FAM57B含有神经酰胺合成酶(CERs)中的TLC结构域，但没有CERs活性所需的残基。斑马鱼模型中FAM57B功能的丧失导致脑脂类物质的显著变化。值得注意的是，我们还观察到质膜结构改变，突触蛋白错位，运动抑制和脑活动减少。目的将确定FAM57B在神经酰胺合成中的作用及其对神经元和大脑功能的影响。我们假设FAM57B通过与CERs相互作用来调节神经酰胺水平。我们进一步假设FAM57B维持对神经递质胞吐起作用的突触脂质和蛋白质队列。我们将测定FAM57B人和斑马鱼同源物的活性；描绘FAM57B缺失后神经元突触的分子变化；并测定斑马鱼大脑中FAM567B的活性。这一目标将解决FAM57B的功能，使人们深入了解自闭症的潜在机制和16pdel综合征的表型。

Modified Project Summary/Abstract Section PROJECT SUMMARY FAM57B is an autism risk gene, and part of the 16p11.2 disease locus. 16pdel syndrome is a severe and prevalent (1:2000 people) haploinsufficient disorder, caused by deletion of ~600 kb of chromosome 16. This syndrome is tightly associated with autism, language and intellectual disability, seizures, ADHD, hypotonia and obesity, however genetic contributions to each symptom are unclear. Our proposal addresses the novel hypothesis that alteration of FAM57B function is associated with autism and 16pdel syndrome, by changing cellular lipids of the ceramide pathway. Lipid cohort alteration may change neuronal plasma membrane composition and associated proteins, so altering synaptic activity and contributing to 16pdel symptoms. We defined a 16p11.2 functional interactome, and identified FAM57B as a pivotal ‘hub’ gene (McCammon et al. 2017). FAM57B has been additionally identified as an autism risk gene (Satterstrom et al. 2019). FAM57B contains a TLC domain found in ceramide synthase enzymes (CerS), but residues required for CerS activity are absent. Loss of function of fam57b in the zebrafish model led to significant changes in brain lipid species. Strikingly, we also observed altered plasma membrane architecture, mis-localization of synaptic proteins, depressed movement and decreased brain activity. The Aim will determine the role of FAM57B in ceramide synthesis and its impact on neuronal and brain function. We hypothesize that FAM57B regulates ceramide levels by interacting with CerS. We further hypothesize that FAM57B maintains the synaptic lipid and protein cohort contributing to neurotransmitter exocytosis. We will determine activity of FAM57B human and zebrafish homologues; delineate molecular changes at the neuronal synapse after loss of FAM57B and determine activity of fam567b in the zebrafish brain. This Aim will solve the function of FAM57B, giving insight into mechanisms underlying autism and 16pdel syndrome phenotypes.