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

精神发育迟滞（MR）是儿童和年轻人残疾的最常见原因， 占总人口的2-3%。MR患者通常需要长期的医疗和支持性护理， 服务，并积累了巨大的成本和负担的家庭和社会。平均寿命 据估计，MR患者的人均成本超过100万美元。X连锁精神发育迟滞（XLMR） 每600名男性中有1名发生，并且具有遗传异质性。在X染色体上> 150-200个负责基因座中， 染色体，<60个基因已被克隆。XLMR基因的鉴定对于诊断是必不可少的， 咨询、预防、患者管理和合理开发有效治疗。它还将 提供了对人类认知功能机制的深入了解。我们的长期目标是了解 X连锁精神发育迟滞的分子基础和机制。在本申请中，我们希望利用 令人兴奋的结果，从我们的试点研究，使用人类X染色体cDNA微阵列（XCM），以确定 新的XLMR基因。该XCM将用于从XLMR雄性的淋巴母细胞中筛选RNA，以鉴定 在转录水平上显示出显著改变的基因。这一战略是基于这样一个事实， 的突变（估计>30%）在任何给定的基因座导致显着的变化，在丰富的 稳定状态的记录这种方法被设计用于检测导致基因突变的突变。 由于启动子突变、基因缺失或复制等机制导致的mRNA丰度，以及 与移码突变相关的异常RNA剪接和与 无义介导的mRNA。它具有快速筛选整个X染色体上的基因的优点 而不需要很大的血统。具体而言，我们将（1）使用XCM筛选120个淋巴母细胞系 从XLMR男性中鉴定新的候选基因（2）通过测序鉴定负责的遗传缺陷， 先证者和大量XLMR男性患者中的新候选基因（3）4-6的功能研究 新的XLMR基因，以了解它们在人类认知中的生理作用，以及这些基因的突变是如何发生的。 基因导致智力迟钝。这项研究的结果将有助于提高我们对遗传学的认识。 精神发育迟滞的原因，并制定合理的诊断，遗传咨询，预防， 认知功能障碍患者的临床护理。

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 alternations 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 congnition 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..