ID of Genes Responsible for X-Linked Mental Retardation

描述(申请人提供)：智力低下是导致儿童和年轻人残疾的最常见原因，占总人口的2%-3%。X-连锁精神发育迟滞(XLMR)发生在600名男性中就有1名，并且具有遗传异质性。据估计，在X染色体上150-200个负责基因座中，只有不到40个基因被克隆。阐明XLMR的分子基础将有助于我们理解人类的认知发展，并将导致制定XLMR患者的临床治疗策略。 应聘者对XLMR的分子机制研究感兴趣，长期的职业目标是成为一名成功的临床科学家。为了实现这一目标，他制定了一项全面的职业发展计划，并在约翰·霍普金斯大学实施。研究计划有三个关键部分：(1)生物信息学和基因组研究方面的培训；(2)对智力低下患者的临床评估和护理方面的培训；(3)以患者为导向的临床调查方面的培训。候选人将参加有关基因组研究和临床研究原理的研究生课程和研讨会。他将接受有关精神发育迟滞患者的临床评估和护理方面的指导培训。他将负责为该项目制定临床研究方案。此外，候选人还将参加约翰·霍普金斯医院每周一次的遗传诊所和肯尼迪·克里格研究所的智力低下诊所。他开发了一种策略，利用人类X染色体特异的cDNA微阵列来识别相关基因。这种方法旨在检测由于启动子突变、基因缺失以及与无义介导的mRNA衰退相关的无义或移码突变等机制而导致的mRNA丰度变化的突变。一旦确定了候选基因，将使用Northern印迹和实时聚合酶链式反应(Real-time PCR)来验证mRNA的减少，然后对先证者进行突变分析。随后将进行更多的体外和体内研究，以描绘每个已识别基因的XLMR的分子机制。通过实验室研究和临床培训相结合的方式，希望为智障患者的研究和临床护理积累坚实的知识基础和宝贵的经验。这对候选人成为一名独立的内科科学家的职业发展将是无价的。

DESCRIPTION (provided by applicant): Mental retardation is the most common cause of handicap in children and young adults and accounts for 2-3% in the general population. X-linked mental retardation (XLMR) occurs in 1 in 600 males and is genetically heterogeneous. Among the estimated more than 150-200 responsible loci on the X chromosome, less than 40 genes have been cloned. Delineation of the molecular basis of XLMR will contribute to our understanding of human cognitive development, and will lead to development of strategies for clinical management of XLMR patients. The candidate is interested in the study of the molecular mechanism of XLMR, with a long-term career goal to become a successful clinician scientist. To accomplish this goal, he developed a comprehensive career development plan to be carried at the Johns Hopkins University. There are three key components to the research plan: (1) training in bioinformatics and genomic research; (2) training in the clinical evaluation and care for patients with mental retardation; and (3) training in the patient-oriented clinical investigation. The candidate will attend graduate courses and seminars on genome research and on principles of clinical investigation. He will receive mentored training in clinical evaluation and care for patients with mental retardation. He will be responsible for the development of a clinical research protocol for this project. In addition, the candidate will participate in the weekly Genetic Clinic at the Johns Hopkins Hospital and the Mental Retardation Clinic at the Kennedy Krieger Institute. He has developed a strategy of using human X chromosome-specific cDNA microarray to identify responsible genes. This approach is designed to detect mutations that result in a change in the abundance of mRNA due to mechanism such as promoter mutations, gene deletions, and nonsense or frameshift mutations associated with nonsense-mediated mRNA decay. Once a candidate gene is identified, Northern blot and real-time PCR will be used to verify mRNA reduction followed by mutation analysis in the proband. Additional in vitro and in vivo studies will then be carried out to delineate the molecular mechanism of XLMR for each identified gene. Through the combined laboratory research and clinical training, the candidate wishes to develop a solid knowledge base and gain precious experiences in research and clinical care for patients with mental retardation. This will be invaluable to the advancement of the candidate's career to become an independent physician scientist.