The Cohesin Complex and Cornelia de Lange Syndrome

描述（由申请方提供）：科尔内利亚德兰格综合征（CdLS）是一种常染色体显性遗传疾病，具有多种先天性异常，包括特征性面部特征、上肢复位缺陷、胃食管功能障碍、生长迟缓和神经发育迟缓。 NIPBL中的突变已被鉴定为导致CdLS。 NIPBL作为粘附素的一个亚基参与了姐妹染色单体的凝聚，粘附素在DNA复制前将凝聚素加载到染色体上起着重要作用。 Cohesin由四个亚基组成：Smc 1，Smc 3，Stromalin和Rad 21。 在其他作用中，粘着蛋白被认为防止姐妹染色单体的过早分离。 除了NIPBL，许多其他蛋白质，包括Pds 5和Eco 1已涉及适当的加载，定位和调节的粘附素。 最近，其他成员的姐妹染色单体凝聚力复合体已牵连在人类先天性疾病。 Eco 1的人类同源物中的突变已被发现导致Roberts和SC短肢综合征。 最近，在X连锁变异的CdLS患者中发现了人类Smc 1同源物（SMC 1 L1）的突变。 该候选人假设，在CdLS和相关发育障碍中会发现粘附素复合物及其调节蛋白的其他成员的突变。 本申请旨在研究NIPBL和其他粘附素复合物成员中的突变对CdLS和相关疾病的发病机制的贡献，并开发管理数据和表征基因型-表型相关性的工具。 该申请列出了一个为期五年的研究和培训计划，最终目标是将候选人转变为独立的医生科学家。 他的导师和顾问是临床畸形学，基因发现和人类发展领域的领导者。 他将充分利用他的环境，无论是在费城儿童医院和宾夕法尼亚大学的丰富资源。

DESCRIPTION (provided by applicant): Cornelia de Lange syndrome (CdLS) is an autosomal dominant disorder of multiple congenital anomalies including characteristic facial features, upper extremity reduction defects, gastroesophageal dysfunction, growth retardation, and neurodevelopmental delay. Mutations in NIPBL have been identified that cause CdLS. NIPBL has been implicated in sister chromatid cohesion as a subunit of adherin, which plays a major role in loading cohesin onto chromosomes prior to DNA replication. Cohesin consists of four subunits: Smc1, Smc3, Stromalin, and Rad21. Among other roles, cohesin is believed to prevent premature separation of sister chromatids. In addition to NIPBL, a number of other proteins including Pds5 and Eco1 have been implicated in the proper loading, positioning, and regulation of cohesin. Recently, other members of the sister chromatid cohesion complex have been implicated in human congenital disease. Mutations in the human homolog of Eco1 have been found cause Roberts and SC phocomelia syndrome. Most recently, mutations in a human Smc1 homolog (SMC1L1) have been found in patients with an X-linked variant of CdLS. The candidate hypothesizes that mutations in additional members of the cohesin complex and its regulatory proteins will be found in CdLS and related developmental disorders. This application seeks to investigate the contribution that mutations in NIPBL and other cohesin complex members make to the pathogenesis of CdLS and related diseases, and to develop tools to manage data and characterize genotype-phenotype correlations. This application lays out a five-year research and training program with the ultimate goal to transition the candidate to an independent physician-scientist. His mentors and advisors are leaders in the fields of clinical dysmorphology, gene discovery, and human development. He will take advantage of the ample resources of his environment, both at The Children's Hospital of Philadelphia and at the University of Pennsylvania.