NIH Research Festival
The lymphatic system provides essential functions to human health including tissue fluid homeostasis, immune cell transport, and dietary lipid absorption. However, developmental errors, some due to genetic pathogenic variants, lead to lymphatic malformations. Although these may be managed with interventions, understanding the molecular cause of the lymphatic malformation is essential for combinatorial medical therapy that may target the underlying dysregulation of signaling pathways.
We identified a recurrent mosaic variant in IDH1 in macrocystic lymphatic malformation tissue that was absent in a saliva sample. IDH1 encodes the enzyme isocitrate dehydrogenase which catalyzes the oxidative dephosphorylation of isocitrate to alpha-ketoglutarate in fatty acid synthesis. Pathogenic variants of IDH1 have been found in a variety of cancers, spindle cell hemangiomas and endochondromas, but have not been previously identified in lymphatic malformations.
To test the hypothesis that this pathogenic variant in IDH1 can cause lymphatic malformations, we created transient transgenics using the Tol2 system to simulate the mosaicism seen in the patient. Using the mrc1a promoter, wild-type IDH1 or IDH1 c.295G>A expressed in venous and lymphatic endothelium resulted in lymphovenous cysts and dilated intersegmental vessels by 3 days post-fertilization and pericardial edema by 7 days post-fertilization. Applying deep phenotyping and functional analysis to these mutants will elucidate the role IDH1 and its downstream products in the regulation of gene expression and cell proliferation. Establishing our model for the patient-derived IDH1 pathogenic variants will allow us to better understand the variety of disease mechanisms and evaluate potential new treatments for patients with these rare conditions.
Scientific Focus Area: Developmental Biology
This page was last updated on Monday, September 25, 2023