The Cohesin Complex and Cornelia de Lange Syndrome

粘连蛋白复合体和科妮莉亚·德·朗格综合症

基本信息

批准号：
8010723
负责人：
MATTHEW A DEARDORFF
金额：
$ 1.49万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-12 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8010723
关键词：
Amino Acids Bruck-de Lange syndrome Candidate Disease Gene Cell division Characteristics Chromosomes Clinical Clinical Research Collection Complementary DNA Complex DNA biosynthesis Data Databases Defect Disease Drosophila genus Dysmorphology Electrophoresis Environment Exons Face Family Finding by Cause Functional RNA Functional disorder Gene Mutation Genes Genomics Genotype Goals Growth Hirsutism Homologous Gene Human Human Development Limb structure Link Mental Retardation Mentors Modeling Molecular Molecular Conformation Mutate Mutation Mutation Detection Nucleic Acid Regulatory Sequences Online Mendelian Inheritance In Man Pathogenesis Patients Pediatric Hospitals Pennsylvania Phenotype Philadelphia Phocomelia Physicians Play Positioning Attribute Proteins Recruitment Activity Regulation Research Personnel Research Training Resources Roberts-SC phocomelia syndrome Role Scientist Screening procedure Sister Chromatid Structure Time Training Programs Universities Upper Extremity Variant Work Yeasts cleft lip and palate cohesin cohesion developmental disease gene discovery genetic linkage analysis genetic regulatory protein member premature prevent proband programs sample collection segregation tool yeast two hybrid system

项目摘要

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.

描述（由申请人提供）：Cornelia de Lange综合征（CDLS）是多种先天异常的常染色体显性疾病，包括特征性面部特征，上肢减少缺陷，胃食管反尼功能障碍，生长延迟，生长障碍和神经发育延迟。已经确定了导致CDL的NIPBL突变。 NIPBL已与姐妹染色单体内聚力有关，作为粘附蛋白的亚基，在DNA复制之前，在将粘着蛋白加载到染色体上起着重要作用。粘着蛋白由四个亚基组成：SMC1，SMC3，Stromalin和Rad21。除其他角色外，粘合素被认为可以防止姐妹染色单体的过早分离。除NIPBL外，许多其他包括PDS5和ECO1在内的蛋白质还与粘着蛋白的适当负载，定位和调节有关。最近，姐妹染色单体凝聚络合物的其他成员与人类先天性疾病有关。已经发现人类ECO1同源物中的突变引起了罗伯茨和SC嗜酸菌综合征。最近，在具有CDL的X连锁变体的患者中发现了人类SMC1同源物（SMC1L1）的突变。候选人假设在CDL和相关发育障碍中发现粘蛋白复合物及其调节蛋白的其他成员的突变。该应用程序旨在调查NIPBL和其他粘着素复合构件的突变对CDL和相关疾病的发病机理的贡献，并开发工具来管理数据并表征基因型 - 表型相关性。该应用程序阐明了一项为期五年的研究和培训计划，其最终目标是将候选人转变为独立的医师科学家。他的导师和顾问是临床畸形，基因发现和人类发展领域的领导者。他将在费城儿童医院和宾夕法尼亚大学利用他的环境充足的环境资源。