X chromosome cDNA microarray Screening and Functional Study of Novel XLMR genes

描述（由申请人提供）：智力迟钝（MR）是儿童和年轻人中最常见的残疾原因，占总人口的2-3%。MR患者往往需要长期的医疗和支持性护理或服务，给家庭和社会带来巨大的成本和负担。据估计，MR患者的平均终生成本超过100万美元。x连锁智力迟钝（XLMR）发生在600个男性中有1个，并且是遗传异质性的。在X染色体上的bbb150 -200个负责位点中，克隆的基因不足60个。XLMR基因的鉴定对诊断、咨询、预防、患者管理和合理制定有效治疗方案具有重要意义。它还将为人类认知功能的机制提供洞见。我们的长期目标是了解x连锁智力低下的分子基础和机制。在这个申请中，我们希望利用我们使用人类X染色体cDNA微阵列（XCM）鉴定新的XLMR基因的试点研究的令人兴奋的结果。该XCM将用于筛选来自XLMR雄性淋巴母细胞的RNA，以鉴定在转录水平上显示显着改变的基因。这一策略是基于这样一个事实，即在任何给定位点上的一小部分突变（估计约为30%）会导致稳态转录本丰度的急剧变化。该方法旨在检测由于启动子突变、基因缺失或复制、与移码突变相关的异常RNA剪接以及与无义介导的mRNA相关的无义突变等机制而导致mRNA丰度变化的突变。它具有快速筛选整个X染色体上的基因的优点，而不需要大的谱系。具体来说，我们将(1)使用XCM筛选来自XLMR雄性的120个淋巴母细胞系，以鉴定新的候选基因；(2)通过先证和大量XLMR雄性的新候选基因测序来鉴定相关的遗传缺陷；(3)对4-6个新XLMR基因进行功能研究，以了解它们在人类认知中的生理作用，以及这些基因突变如何导致智力迟钝。本研究结果将有助于提高我们对智力发育迟滞的遗传原因的认识，并为认知功能障碍患者的诊断、遗传咨询、预防和临床护理制定合理的策略。

DESCRIPTION (provided by applicant): Mental retardation (MR) is the most common cause of handicaps in children and young adults and accounts for 2-3% in the general population. Patients with MR often require long-term medical and supportive care or services and accumulate enormous costs and burden to the families and the society. The average lifetime costs per person with MR were estimated to be more than $1 million. X-linked mental retardation (XLMR) occurs in 1 in 600 males and is genetically heterogeneous. Among the > 150-200 responsible loci on the X chromosome, <60 genes have been cloned. Identification of XLMR genes is essential for diagnosis, counseling, prevention, patient management, and rational development of effective therapy. It will also provide insight into the mechanism of human cognitive function. Our long-term goals are to understand the molecular basis and mechanism of X-linked mental retardation. In this application, we wish to capitalize on the exciting results from our pilot study of using a human X chromosome cDNA microarray (XCM) to identify novel XLMR genes. This XCM will be used to screen RNA from lymphoblasts of XLMR males to identify genes that show significant alterations in transcript levels. This strategy is based on the fact that a fraction of the mutations (estimated to be >30%) at any given locus result in dramatic alternations in the abundance of steady state transcripts. 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 or duplications, and abnormal RNA splicing associated with frameshift mutation and nonsense mutations associated with nonsense-mediated mRNA. It carries the advantage of fast screening of genes on the entire X chromosome without the need for large pedigree. Specifically we will (1) use XCM to screen 120 lymphoblast cell lines from XLMR males to identify novel candidate genes (2) identify responsible genetic defects by sequencing of the novel candidate genes in proband and in a large collection of XLMR males (3) functional studies of 4-6 novel XLMR genes to understand their physiological roles in human cognition and how mutations in these gene cause mental retardation. Results of the study will help to advance our knowledge on the genetic causes of mental retardation and to develop rational strategies for diagnosis, genetic counseling, prevention, and clinical care of patients with impairment of cognitive function.