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Primary Lymphedema Genetic Study Reveals Role for Angiopoietin Gene

NEW YORK – A new study is expanding the collection of genetic alterations that can contribute to primary lymphedema, a condition that is often characterized by lymphatic fluid build up that can lead to limb swelling and other complications.

"Lymphedema is caused by development and functional defects of the lymphatic vascular system that result in accumulation of protein-rich fluid in tissues, resulting in edema," co-senior authors Kari Alitalo, with the Wihuri Research Institute and the University of Helsinki's Translational Cancer Medicine Program, and Miikka Vikkula, a human molecular genetics researcher at the University of Louvain in Belgium, and their colleagues wrote in a paper published in Science Translational Medicine on Wednesday.

Past studies have uncovered more than two-dozen primary lymphedema-related genes, including genes from a vascular endothelial growth factor receptor signaling pathway that contains FLT4 as well as related transcription factors, the researchers noted. Even so, alterations in the 28 known lymphedema genes account for fewer than one-third of cases, suggesting there are more contributors yet to be unearthed.

With that in mind, the team used exome sequencing and targeted sequencing on candidate genes to search for suspicious alterations in five primary lymphedema-affected pedigrees and in nearly 550 unrelated individuals with primary lymphedema. The screens largely focused on angiopoietin-coding genes such as ANGPT1 and ANGPT2 that interact with the TIE1-TIE2 receptor complex during the formation of blood vessels and lymphatic vessels in developing human embryos as well as mature vasculature functions.

The researchers uncovered several ANGPT2 alterations in the primary lymphedema cases, ranging from a de novo heterozygous deletion in the angiopoietin 2 gene to four cases marked by missense changes affecting a single copy of the ANGPT2 gene. Based on functional, genetic, and structural analyses, they concluded that missense mutations in the gene likely have dominant negative consequences on the broader ANGPT2 signaling pathway, leading to lower-than-usual secretion of the ANGPT2 gene product.

"[W]e identified ANGPT2 mutations with a dominant pattern of inheritance and variable penetrance in patients with primary lymphedema," the authors reported.

The team went on to explore TIE1-TIE2 interactions for wild type ANGPT2, as well as two mutant versions of the gene, using an autocrine assay approach in human lymphatic endothelial cells, molecular modeling, biophysics approaches, and mouse model experiments.

"Because ANGPT2 functions as an autocrine TIE2 and TIE1 agonist [in] lymphatic endothelium, our results indicate that ANGPT2 haploinsufficiency, [loss of function] mutations, or hypermorphic alleles may contribute to primary lymphedema with incomplete penetrance in humans," the authors wrote, noting that the current results provided a clearer look at the ways that ANGPT2 can interact with and influence the TIE1-TIE2 pathway.