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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：
7435304
负责人：
MATTHEW A DEARDORFF
金额：
$ 13.39万
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：
2007
资助国家：
美国
起止时间：
2007-06-05 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7435304
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 Disruption 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 Numbers 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 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(申请人提供)：Cornelia de Lange综合征(CDLS)是一种常染色体显性遗传病，由多种先天性畸形组成，包括特征性面部特征、上肢缩小缺陷、胃食道功能障碍、生长迟缓和神经发育迟缓。NIPBL中的突变已被确定为导致CDLS。NIPBL作为粘附素的一个亚单位，在DNA复制之前将粘附素装载到染色体上起着重要的作用，与姐妹染色单体的凝聚力有关。粘附素由四个亚基组成：Smc1、Smc3、StroMalin和Rad21。在其他作用中，粘附素被认为可以防止姐妹染色单体的过早分离。除了NIPBL，包括Pds5和Eco1在内的许多其他蛋白质也参与了粘附素的正确加载、定位和调节。最近，姐妹染色单体内聚复合体的其他成员也被认为与人类先天性疾病有关。人类Eco1同源基因的突变已被发现导致Roberts和SC光眼综合征。最近，在X连锁的CDLS变种患者中发现了人类Smc1同源基因(SMC1L1)的突变。候选人假设，在CDL和相关的发育障碍中，将发现粘附素复合体及其调节蛋白的更多成员的突变。这项应用旨在调查NIPBL和其他粘附素复合体成员的突变在CDLS和相关疾病的发病机制中的贡献，并开发工具来管理数据和表征基因-表型的相关性。这份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一名独立的内科科学家。他的导师和顾问是临床畸形学、基因发现和人类发育领域的领导者。他将利用他在费城儿童医院和宾夕法尼亚大学的丰富环境资源。