Mechanistic analysis of novel genetic loci for split hand foot malformation

总结 发育生物学和遗传学中的一个基本问题是细胞命运特化中的缺陷如何 分化导致特定的出生缺陷。这代表了一个重要的问题，因为 肢体和神经嵴的发育是许多人类先天性出生缺陷的基础，包括手足分裂 畸形（SHFM）。SHFM是一种毁灭性的先天性出生缺陷， 有正中裂和颅面畸形，发生率约为1：18，000。因为 关于SHFM基因位点的信息有限，临床科学家迫切需要 与基础发育生物学家合作，确定新的遗传位点，并为以下方面提供机制基础： 这种畸形，以便治疗和遗传咨询可以开发。在这里，我们将确定新的 SHFM的基因座，包括新发现的与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发挥作用， 突变后会导致SHFM拟议研究的理由是，深入了解 负责SHFM的特定遗传位点将为SHFM的基础生物学和病因学提供见解。 先天性出生缺陷我们将在以下具体目标中检验这一假设：1）确定 人类SHFM的综合患者表型和致病遗传基因座。2)测试 假设PRDM1的功能是调节颅面和肢体发育， 引起SHFM。总之，这些研究将确定和测试SHFM的新遗传位点的功能 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 神经嵴相关出生缺陷的治疗策略。

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.