Identification of new mechanisms for human congenital disorders

识别人类先天性疾病的新机制

• 批准号: 7873943
• 负责人: Elena V Semina
• 金额: $ 22.5万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7873943
• 关键词: Affect; Animal Model; Anophthalmos; Biological Assay; Biology; Candidate Disease Gene; Code; Collection; Congenital Disorders; Copy Number Polymorphism; DNA; DNA Sequence; Data; Deletion Mutation; Development; Diagnosis; Disease; Exclusion; Family; Gene Deletion; Genes; Genetic; Genetic Counseling; Genetic Screening; Genomics; Human; In Situ Hybridization; Individual; Knowledge; Krause-Kivlin syndrome; Lead; Location; Modeling; Mutation; Patients; Phenotype; Play; Point Mutation; Regulatory Element; Research Personnel; Rieger syndrome; Role; Sampling; Screening procedure; Sequence Analysis; Syndrome; Technology; Time; Variant; Zebrafish; base; craniofacial; empowered; gene function; genome-wide; human DNA; human disease; improved; insight; interest; novel; public health relevance

DESCRIPTION (provided by applicant): Significant progress has been achieved in the identification of genetic causes for congenital human syndromes. At the same time, mutations in known genes still explain only a small portion of the broad spectrum of human craniofacial phenotypes. This may be due, in part, to screening limitations, since the majority of current genetic screens focus on sequence analysis of the coding region(s) of a gene(s) and, therefore, fail to detect gene deletion(s)/duplication(s) or changes in regulatory elements important in gene function. In addition, the genetic causes for many congenital human conditions are still unknown and thus cannot be evaluated in human patients. In this proposal, we plan to expand genetic studies of craniofacial phenotypes through genome-wide copy number variation analysis. This effort will result in identification of additional mutations (deletions/duplications) associated with known genes and will direct discovery of novel factors, therefore empowering human researchers with new insight into disease mechanisms. Candidate genes will be identified based on their location within a genomic region of interest and functional studies in animal models. Mutation screening in affected individuals will provide additional support for a causative role for the gene in human disease. In this proposal, we plan to utilize our collection of DNA samples from patients with human congenital conditions involving craniofacial anomalies which was already examined for mutations in genes known to play a role in the corresponding phenotypes. Our preliminary analysis of a subset of our sample for copy number variants resulted in identification of numerous alterations involving known genes as well as changes in novel, previously unreported, regions. Therefore, we believe that our study will generate critical data that will lead to the identification of new genetic causes for human craniofacial syndromes and thus will have a high impact in the field of human craniofacial biology. Specifically, we plan to identify genomic regions that are affected in human craniofacial syndromes by copy number variation analysis (Aim 1); evaluate candidate genes associated with these genomic region(s) for their potential role in the syndrome(s) using the zebrafish model (Aim 2); and examine best candidate genes for point mutations in human patient DNA to further confirm/ characterize their role in the corresponding syndromes (Aim 3). PUBLIC HEALTH RELEVANCE: Our project is aimed at identification of the novel genetic causes of human craniofacial syndromes using new genomic screening technology and studies in animal models. The knowledge obtained from this project will provide insight into disease mechanisms(s) and eventually lead to improved diagnosis, genetic counseling and treatment of affected patients and their families.

描述（由申请人提供）：在鉴定人类先天性综合征的遗传原因方面取得了重大进展。与此同时，已知基因的突变仍然只能解释人类颅面表型的一小部分。这可能部分是由于筛选限制，因为大多数当前的遗传筛选集中于基因的编码区的序列分析，因此不能检测基因缺失/重复或在基因功能中重要的调控元件的变化。此外，许多先天性人类疾病的遗传原因仍然未知，因此无法在人类患者中进行评估。在这个提议中，我们计划通过全基因组拷贝数变异分析来扩大颅面表型的遗传研究。这一努力将导致与已知基因相关的其他突变（缺失/重复）的鉴定，并将指导新因子的发现，从而使人类研究人员对疾病机制有新的见解。候选基因将根据其在基因组目标区域内的位置和动物模型中的功能研究进行鉴定。在受影响的个体中进行突变筛查将为该基因在人类疾病中的致病作用提供额外的支持。在这项提案中，我们计划利用我们收集的涉及颅面异常的人类先天性疾病患者的DNA样本，这些患者已经检查了已知在相应表型中发挥作用的基因突变。我们对样本的一个子集进行了拷贝数变异的初步分析，结果发现了许多涉及已知基因的改变，以及新的、以前未报道的区域的改变。因此，我们相信我们的研究将产生关键数据，这些数据将导致人类颅面综合征新遗传原因的鉴定，从而对人类颅面生物学领域产生重大影响。具体而言，我们计划通过拷贝数变异分析来鉴定在人类颅面综合征中受影响的基因组区域（Aim 1）;使用斑马鱼模型来评估与这些基因组区域相关的候选基因在综合征中的潜在作用（Aim 2）;并检查人类患者DNA中点突变的最佳候选基因，以进一步确认/表征它们在相应综合征中的作用（目标3）。 公共卫生相关性：我们的项目旨在利用新的基因组筛选技术和动物模型研究来鉴定人类颅面综合征的新遗传原因。从该项目中获得的知识将提供对疾病机制的深入了解，并最终改善受影响患者及其家人的诊断，遗传咨询和治疗。