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Mechanistic analysis of novel genetic loci for split hand foot malformation

手足劈裂畸形新基因位点的机制分析

基本信息

批准号：
9906909
负责人：
Kristin Artinger
金额：
$ 9.86万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-05 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9906909
关键词：
17q12 Animal Model Biology CRISPR/Cas technology Cartilage Cells Clinical Collaborations Complex Congenital Abnormality Craniofacial Abnormalities Data Defect Development Developmental Biology Disease Ectoderm Embryo Epigenetic Process Etiology Face Family Fibroblast Growth Factor Foundations Future Gene Expression Profiling Generations Genes Genetic Genetic Counseling Genetic Models Genetic Transcription Genomics Genotype Goals Hand Human Inherited Knowledge Laboratories Limb Development Limb structure Link Live Birth Mesenchyme Mission Molecular Morphogenesis Mutate Mutation Neural Crest Neural Crest Cell PRDM1 gene Patients Penetrance Peripheral Nervous System Phenocopy Phenotype Play Population Positioning Attribute Prevention strategy Public Health Regulator Genes Research Role Scientist Signal Transduction Signaling Molecule Skeleton Syndrome Testing Therapeutic Time Tissues United States National Institutes of Health Variant Zebrafish Zinc Fingers autosomal dominant mutation bone cell fate specification cell type chromosomal location craniofacial craniofacial development design developmental genetics disability foot genetic association genome sequencing genomic locus in vivo insight malformation migration next generation sequencing novel transcription factor transcriptome sequencing variant of unknown significance whole genome

项目摘要

Summary A fundamental question in developmental biology and genetics is how defects in cell fate specification and differentiation results in specific birth defects. This represents an important problem, because defects in limb and neural crest development underlie many human congenital birth defects including split hand foot malformation (SHFM). SHFM is a devastating congenital birth defect that presents with hands and feet that have a median cleft as well as craniofacial abnormalities that occurs in about 1:18,000 live births. Because there is limited information regarding genetic loci for SHFM, there is a critical need for clinical scientists to partner with basic developmental biologists to identify novel genetic loci and provide a mechanistic basis for this malformation such that treatments and genetic counseling can be developed. Here, we will identify novel loci for SHFM including the newly identified linkage with PRDM1. We hypothesize that PRDM1 functions as a transcriptional and epigenetic regulator required for NCC and limb development and when mutated, results in SHFM. The rationale for the proposed studies is that an in depth understanding of specific genetic loci responsible for SHFM will provide insights into both basic biology and the etiology of congenital birth defects. We will test this hypothesis in the following specific aims: 1) Determine the comprehensive patient phenotype and causative genetic loci for SHFM in humans. 2) Test the hypothesis that PRDM1 functions to regulate craniofacial and limb development and when mutated is causative for SHFM. Together, these studies will identify and test the function of new genetic loci for SHFM and once identified, determine the cellular and molecular mechanisms by which specific variant mutations function and the basis of the variability in phenotype. These data will provide a foundation for the design of therapeutic strategies for neural crest associated birth defects.

概括发育生物学和遗传学的一个基本问题是细胞命运规范的缺陷如何分化会导致特定的出生缺陷。这代表了一个重要的问题，因为缺陷肢体和神经嵴发育是许多人类先天性缺陷的基础，包括手脚裂开畸形（SHFM）。 SHFM 是一种毁灭性的先天性出生缺陷，表现为手脚大约有 1:18,000 的活产婴儿有中裂和颅面畸形。因为关于 SHFM 遗传位点的信息有限，临床科学家迫切需要与基础发育生物学家合作，识别新的遗传位点并提供机制基础这种畸形可以开发治疗方法和遗传咨询。在这里，我们将识别小说 SHFM 基因座，包括新确定的与 PRDM1 的连锁。我们假设 PRDM1 作为 NCC 和肢体发育所需的转录和表观遗传调节因子当突变时，会导致 SHFM。拟议研究的基本原理是深入了解负责 SHFM 的特定基因位点将提供对基础生物学和病因学的见解先天性出生缺陷。我们将通过以下具体目标来检验这一假设： 1）确定人类 SHFM 的综合患者表型和致病基因位点。 2) 测试 PRDM1 的功能是调节颅面和肢体发育，当突变时，这一假设是 SHFM 的病因。这些研究将共同鉴定和测试 SHFM 新基因位点的功能一旦确定，确定特定变异突变的细胞和分子机制功能和表型变异的基础。这些数据将为设计提供基础神经嵴相关出生缺陷的治疗策略。