A Novel Essential Gene for Human Cognitive Function

描述（由申请人提供）：智力残疾（ID）和自闭症谱系障碍（ASD）是高度流行的发育迟缓障碍，具有大量重叠。ID和ASD具有高度遗传性，但由于遗传异质性，只有约15%的ASD患者和50%的ID患者具有特定的遗传诊断。ASD和ID的确定的遗传原因表明疾病发病机制中的共同遗传途径，包括突触功能障碍、脊柱发育中的细胞骨架动力学、Ras-MAPK途径和组蛋白修饰。我与我的赞助人克里斯托弗·A·卡耐基实验室的两名研究员合作，沃尔什，我最近发现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，他们有自闭症特征的遗传性ID。我们已经确定了一个新的截断突变，在一个未知的基因在所有受影响的个人从这个家庭。发育神经生物学中一个尚未回答的问题是，含有已鉴定的ASD和ID基因的各种细胞通路如何在正常的认知发育中协调。了解这个基因的功能，一个预测的甲基转移酶，可以通过蛋白质修饰调节多个基因，可以提供深入了解ASD和ID中断的认知发展的细胞通路之间的协调。我提出了以下实验来研究这个基因的功能。在具体目标1中，我将确定这个家族中的截短突变是否是功能丧失等位基因，并将在其他ID和ASD患者中寻找该基因中的其他功能丧失等位基因。在具体目标2中，我将描述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。在具体目标3中，我将与我的共同赞助人Michael Greenberg的实验室合作，在缺乏该基因的情况下表征神经元形态和活性依赖性基因表达。

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.