Rare & Mosaic Disorders Molecular Research

National Human Genome Research Institute

Investigators

Linked publications & trials

Abstract

Overall Approach of the laboratory The laboratory uses a translational research approach to study human malformations and overgrowth disorders. In the clinical arena (study HG200388), we operate several clinical research protocols to assess the range of severity, spectrum of malformations, natural history of pleiotropic developmental and overgrowth disorders, and therapeutic studies. We use the tools of modern molecular biology to determine the molecular pathogenesis of these disorders. These include high throughput sequencing, positional cloning, microarray expression and microarray CGH analysis, cell and tissue culture studies to assess cell biologic functions and abnormalities of gene products, and the creation and analysis of animal mouse models of human genetic disease, and now we have developed therapeutic protocols for Proteus syndrome. Overgrowth syndromes We have now identified targets for therapeutic intervention in mosaic overgrowth disorders. These discoveries have shown that the mutations that cause mosaic overgrowth also are major contributors to the pathogenesis of cancer. Because of the intense work in the pharmaceutical industry on cancer drugs, we have used two such agents for therapeutics of overgrowth. Having successfully negotiated a substantial CRADA agreement with Merck, we have launched a Phase 2 trial with this agent. Our recruitment is on target, with enrollment of 14 of the projected 15 patients for the primary outcome cohort of CCTN growth arrest. Modeling Proteus syndrome Following on our discovery of the cause of this disorder in 2011 we have been successful in modeling this disorder in mice. While the Happle hypothesis (mosaicism for a mutation lethal in the non-mosaic state) is completely consistent with all recognized features of the disorder, it is impossible to prove this in human studies. To that end, we have created a mouse model of Proteus syndrome by creating a conditional knock-in allele for the p.Glu17Lys mutation (the mutation that affects all known patients with this disorder). We have shown that these animals have the predicted 100% embryonic lethality and a range of abnormalities consistent with the human syndrome. We are now planning therepeutic experiments for this model system. We have also demonstrated abnormalities in vascular remodeling. Most recently, we have shown partial rescue of the murine phenotype with prenatal therapy. Finally, we have developed a hypothesis regarding biomechanical stress and overgrowth in Proteus syndrome and are testing that with the Prrx-Cre inducible mutation in our model system. Genotype-Phenotype studies in mosaic disorders We have also initiated studies of the molecular pathogenesis of tumors in Proteus syndrome in collaboration with NCI.