A Novel Essential Gene for Human Cognitive Function

描述(申请人提供)：智力障碍(ID)和自闭症谱系障碍(ASD)是高度普遍的发育迟缓障碍，有很大的重叠。ID和ASD具有高度的遗传性，但由于遗传异质性，只有大约15%的ASD患者和50%的ID患者具有特定的基因诊断。已确定的ASD和ID的遗传原因表明，疾病发病中的常见遗传途径包括突触功能障碍、脊柱发育过程中的细胞骨架动力学、Ras-MAPK途径和组蛋白修饰。最近，我与我的赞助人克里斯托弗·A·沃尔什(Christopher A.Walsh)实验室的两名同事合作，确认了一个来自沙特阿拉伯王国和阿拉伯联合酋长国的大家庭，他们患有隐性遗传的带有自闭症特征的ID。我们已经在这个家族中所有受影响的个体中发现了一种新的、未确定特征的基因的截断突变。发育神经生物学中一个悬而未决的问题是，在正常的认知发育中，包含已识别的ASD和ID基因的各种细胞通路是如何协调的。了解该基因的功能，可以洞察ASD和ID认知发育障碍的细胞通路之间的协调。我建议通过以下实验来研究该基因的功能。在特定的目标1中，我将确定该家族中的截断突变是否是功能等位基因的丢失，并将在其他ID和ASD患者中寻找该基因的其他功能等位基因丢失。在具体目标2中，我将对该基因编码的蛋白质的亚细胞定位、相互作用伙伴和甲基转移酶活性进行表征。在具体目标3中，我将与我的共同赞助人迈克尔·格林伯格的实验室合作，在缺乏这种基因的情况下，表征神经元的形态和活性依赖的基因表达。

DESCRIPTION (provided by applicant): Intellectual disabilities (ID) and autism spectrum disorders (ASD) are highly prevalent disorders of developmental delay with substantial overlap. ID and ASD are highly heritable, but because of genetic heterogeneity only about 15% of ASD patients and 50% of ID patients have a specific genetic diagnosis. Identified genetic causes of ASD and ID suggest common genetic pathways in disease pathogenesis including synaptic dysfunction, cytoskeletal dynamics in spine development, the Ras-MAPK pathway, and histone modification. In collaboration with two fellows in the laboratory of my sponsor, Christopher A. Walsh, I have recently identified a large family from the Kingdom of Saudi Arabia and the United Arab Emirates with recessively inherited ID with autistic features. We have identified a truncating mutation in a novel, uncharacterized gene in all affected individuals from this family. An unanswered question in developmental neurobiology is how the various cellular pathways that contain identified ASD and ID genes are coordinated in normal cognitive development. Understanding the function of this gene, a predicted methyltransferase that may regulate multiple genes through protein modification, can provide insight into coordination between cellular pathways for cognitive development disrupted in ASD and ID. I propose the following experiments to investigate the function of this gene. In Specific Aim 1, I will determine if the truncating mutation in this family is a loss of function allele, and will search for additional loss of function alleles in this gene in other ID and ASD patients. In Specific Aim 2, I will characterize subcellular localization, interaction partners, and methyltransferase activity of the protein encoded by this gene. In Specific Aim 3, I will collaborate with the lab of my co-sponsor, Michael Greenberg, to characterize neuron morphology and activity-dependent gene expression in the absence of this gene.