Molecular Analysis of del(17)(p11.2)

del(17) 的分子分析(p11.2)

基本信息

批准号：
6637065
负责人：
Sarah H. ELSEA
金额：
$ 22.96万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-08-01 至 2004-06-30
项目状态：
已结题

项目摘要

Smith-Magenis syndrome (SMS) is a multiple congenital anomalies/mental retardation syndrome associated with an interstitial deletion of chromosome 17p11.2. Phenotypic characteristics include mental retardation, self- injurious behavior, myopia, hearing loss, delayed physical and motor development, craniofacial and skeletal anomalies, and sleep disturbances. The deletions observed in patients can range from less than 2 to greater than 9 megabases of DNA and may include more than 100 genes. The average size of the common deletion on chromosome 17 is estimated to be 4-5 Mb, while the critical interval for chromosome involvement is approximately 1.5-2 Mb. Even though the molecular basis of Smith-Magenis syndrome is unknown, 17p11.2 has been found to be an extremely gene-rich region. We have mapped several genes within the SMS region, although none of these genes have truly been implicated in the SMS phenotype. Since it is likely the SMS phenotype is caused by haploinsufficiency for several genes, it is critical to identify all genes and assess the potential role of each of these genes within the critical deletion interval. The ultimate goals of this project are to identify sequence, and characterize genes within the critical interval toward understanding their potential role in the SMS phenotype. In order to achieve these goals, a transcriptional map will be generated. Expressed sequences are being obtained from this interval through a variety of standard positional cloning techniques, including contig generation, direct sequencing, and cDNA library screening. All identified genes will be analyzed, their expression patterns determined, and possible functions elucidated in an attempt to identify potentially dosage-sensitive genes from among the many genes we may find within this deletion interval. Genes may be discovered that are involved in neurological development, behavior, skeletal and craniofacial development, and sleep/circadian rhythm. Importantly, these genes may have greater implication in other disease entities that exhibit partial phenotypes with similarity to SMS. Detailed analysis will initially focus on one gene within the critical interval called developmentally regulated GTP-binding protein 2 (DRG2). We have cloned the Drosophila DRG2 homolog, and studies are currently underway towards it characterization in fly embryos. The molecular dissection of a microdeletion syndrome required detailed analysis of all genes within the critical region towards determining the potential effect of haploinsufficiency and the role these genes may play in the generation of the phenotype. The work proposed here will lay the foundation on which the gene(s) responsible for SMS and other developmental process may be elucidated.

Smith-Magenis综合征（SMS）是多个先天性异常/精神降低综合征，与染色体17p11.2的间隙缺失相关。表型的特征包括智力低下，自我伤害行为，近视，听力损失，延迟的身体和运动发育，颅面和骨骼异常以及睡眠障碍。在患者中观察到的缺失范围从小于2到9兆瓦的DNA范围，并且可能包括100多个基因。 17染色体上公共缺失的平均大小估计为4-5 MB，而染色体受累的临界区间约为1.5-2 MB。即使史密斯 - 麦加尼综合征的分子基础尚不清楚，但发现17p11.2是一个极其富基因的区域。我们已经在SMS区域绘制了几个基因，尽管这些基因都没有真正与SMS表型有关。由于SMS表型可能是由于几种基因的单倍型引起的，因此鉴定所有基因并评估这些基因在关键缺失间隔内的潜在作用至关重要。该项目的最终目标是识别序列，并在关键间隔内表征基因，以了解其在SMS表型中的潜在作用。为了实现这些目标，将生成转录图。通过各种标准的位置克隆技术，包括重叠群生成，直接测序和cDNA库筛选，从此间隔中获得了表达的序列。将分析所有已鉴定的基因，确定其表达模式，并阐明了可能的功能，以试图从我们可能在此缺失间隔内发现的许多基因中识别潜在的剂量敏感基因。可以发现与神经系统发育，行为，骨骼和颅面发育以及睡眠/昼夜节律有关的基因。重要的是，这些基因可能对表现出与SMS相似的部分表型的其他疾病实体具有更大的影响。详细的分析最初将集中在称为发育调节的GTP结合蛋白2（DRG2）的关键间隔内。我们已经克隆了果蝇DRG2同源物，目前正在进行研究中的IT表征。微骨骼综合征的分子解剖需要对关键区域内所有基因的详细分析，以确定单倍弥漫的潜在影响以及这些基因在表型产生中的作用。这里提出的工作将奠定负责SMS和其他发展过程的基础。