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愈的神经疾病，影响到很大一部分美国人口。ID是一个主要的负担 对家庭来说，由于相关的医疗保健费用很高，而且智障患者的日常生活活动往往依赖家庭成员。对于ID背后的遗传和分子机制知之甚少，治疗方案仅限于支持性护理。改善ID治疗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未来为ID患者开发临床相关的治疗方案，以及改善对家庭的遗传咨询。通过外显子全序列测定，我在遗传性进行性小头畸形和ID家系中发现了3个新的基因突变，这些基因编码与mRNA加工和核输出有关的蛋白。因此，我假设这些基因的突变将影响神经生存所需的mRNAs子集的处理或细胞定位。为了验证这一假说，我提出了以下目标：1.研究这些基因的突变如何影响神经前体细胞的存活和生长，以及神经细胞在体外和体内的成熟。2.确定这些基因的突变是否改变了mRNA的剪接、丰度和细胞定位。3.通过RNA免疫沉淀和测序(RIP-SEQ)鉴定这些蛋白的直接mRNA靶点。了解疾病的发生和发展，以及与原因ID基因突变相关的潜在细胞和分子变化，将有助于深入了解人类基本的发育过程，以及ID患者的新疾病机制。

 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.