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

智力低下(MR)是导致儿童和年轻人残疾的最常见原因。 占总人口的2%-3%。患有MR的患者通常需要长期的医疗和支持护理或 这给家庭和社会带来了巨大的成本和负担。平均寿命 据估计，患MR的人均费用超过100万美元。X连锁智力低下(XLMR) 每600名男性中就有1名发生，并且在遗传上是异质性的。在X-gt；150-200个责任基因座中 染色体，已经克隆了60个基因。XLMR基因的鉴定是诊断的关键， 咨询、预防、患者管理，合理制定有效的治疗方法。它还将 提供对人类认知功能机制的洞察。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 我们使用人类X染色体基因芯片(XCM)进行鉴定的初步研究取得了令人兴奋的结果 新的XLMR基因。该XCM将用于从XLMR雄性淋巴母细胞中筛选RNA以识别 转录水平发生显著变化的基因。这一策略是基于这样一个事实，即 任何给定基因座上的突变(估计为30%)会导致丰度的戏剧性变化 稳定状态的记录。这种方法被设计用来检测导致 由于启动子突变、基因缺失或复制等机制而导致的mRNA丰度，以及 与移码突变和无义突变相关的RNA剪接异常 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势 而不需要大的血统。具体地说，我们将(1)使用XCM筛选120个淋巴母细胞系 从XLMR雄性中识别新的候选基因(2)通过测序确定负责的遗传缺陷 先证者和大量XLMR男性中的新候选基因(3)4-6的功能研究 了解XLMR新基因在人类认知中的生理作用以及这些基因的突变 基因会导致智力低下。这项研究的结果将有助于增进我们对基因的认识 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..