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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.

总结