Studying Pentalogy of Cantrell in Humans and Mice

点击翻译按钮获取中文摘要

Project One: The major purpose of this research is to identify the mutation(s) in gene(s) that result in Pentalogy of Cantrell (POC) in humans. We suspect that one of these genes will be NM IIB, based on a mouse model that we have generated which has a point mutation in NM IIB and demonstrates a phenotype similar to humans with the diagnosis of POC. However, it is likely that other genes, in addition to NM IIB, could be causative and therefore we plan to look for mutations in any gene(s) we may find in patients with the diagnosis of POC that appear to be causative. We are currently recruiting and collecting samples from patients (and their relatives) with the diagnosis of POC. With the help of our collaborators, we plan to obtain samples from other institutions where there are identified cases of POC. We then plan to carry out whole exomic sequencing. Since nonmuscle myosins are known to directly and indirectly interact with a large number of proteins, we also will be looking for any mutations in other genes from patients with the diagnosis of POC. Should a mutation be identified, we will characterize the myosin (or other protein) in vitro or in mouse models to confirm that it is causative. Project Two: Our lab has generated a mouse with a point mutation (R709C) in NM IIB which develops a number of congenital heart defects, including septal defects, overriding aorta, and incomplete valve development. To investigate these abnormal findings, we utilized immunohistological analysis to identify expression patterns of extracellular and matricellular proteins that have been affected by the mutation in NM IIB and therefore may be downstream of NM IIB's role in heart development. We are working to create a valve cushion explant culture system to further explore the role of NM IIB in valve cell migration, matrix organization, and proliferation/apoptosis, all of which are important in proper valve formation. We are also working to create a tissue specific mutation in the cardiomyocytes of mice in order to elucidate the role of NM IIB in outflow tract myocardialization and misalignment.