Molecular Mechanisms of Intellectual Disability

 描述（由申请人提供）：智力残疾（ID）是一种常见的无法治疗的神经系统疾病，影响了美国人口的很大一部分。身份证是一个主要负担 由于相关的医疗保健费用高昂，而且ID患者的日常生活活动经常依赖家庭成员。关于ID的遗传和分子机制知之甚少，治疗选择仅限于支持性治疗。改善ID疗法的一种方法可能是通过识别调节神经发育和功能的新遗传途径。从这些研究中获得的知识将有助于ID患者临床相关治疗方案的未来发展，以及改善家庭遗传咨询。 使用全外显子组测序;我在遗传性进行性小头畸形和ID家族中发现了3个新的基因突变。这些基因编码参与mRNA加工和核输出的蛋白质。因此，我假设这些基因的突变将影响神经活力所需的mRNA子集的加工或细胞定位。为了验证这一假设，我提出了以下目标：1。研究这些基因的突变如何影响神经祖细胞的活力和生长，以及体外和体内神经元的成熟。2.确定这些基因中的突变是否改变mRNA剪接、丰度和细胞定位。3.通过RNA免疫沉淀和测序（RIP-seq）鉴定这些蛋白质的直接mRNA靶点。了解疾病的发病和进展以及与致病ID基因突变相关的潜在细胞和分子变化将提供对ID患者的基本人类发育过程以及新疾病机制的深入了解。

 DESCRIPTION (provided by applicant): Intellectual disability (ID) is a common untreatable neurological disorder that affects a significant portion of the US population. ID is a major burden to the family as associated health care costs are high and patients with ID are frequently reliant upon family members for their activities of daily living. Little is known about the genetic and molecular mechanisms underlying ID and treatment options are limited to supportive care. One way to improve therapies for ID could be by identifying novel genetic pathways regulating neural development and function. The knowledge gained from these studies will be useful for future development of clinically relevant treatment options for ID patients as well as improve genetic counseling for families. Using whole exome sequencing; I have identified a 3 novel gene mutations in families with inherited progressive microcephaly and ID. These genes encode proteins involved in mRNA processing and nuclear export. Therefore, I hypothesize that mutations in these genes will affect the processing or cellular localization of a subset of mRNAs required for neural viability. To test this hypothesis, I have proposed the following aims: 1. Investigate how mutations in these genes affect neural progenitor cell viability and growth, and maturation of neurons in vitro and in vivo. 2. Determine whether the mutations in these genes alter mRNA splicing, abundance, and cellular localization. 3. Identify direct mRNA targets of these proteins by performing RNA immunoprecipitation and sequencing (RIP-seq). Understanding disease onset and progression as well as the underlying cellular and molecular changes associated with mutations in causal ID genes will provide insight into basic human developmental processes in addition to novel disease mechanisms in patients with ID.