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 is born with a phenotype similar to humans with a diagnosis of POC. However it is likely that other genes, in addition to 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 they have 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 whether it is causative. Project Two: Our lab has generated a mouse with a point mutation (R709C) in NM IIB which develops a cleft palate. To investigate this abnormal finding, we established a palatal explant culture system with the help of our collaborators. We exposed the palatal explants to nonmuscle myosin II inhibitors to investigate how nonmuscle myosin II affects palatal development. We suspect that it plays an important role in the elevation of the palatal shelves. This hypothesis is supported by our mutant mouse, which develops a cleft palate with defects in palatal elevation. However, to date we were not able to demonstrate how nonmuscle myosin II affects elevation using the explant culture system. We are currently injecting pregnant mice with nonmuscle myosin II inhibitors in order to investigate palatal formation in vivo.

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National Heart, Lung, and Blood Institute
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