An international collaboration led by scientists at The University of South Australia, SA Pathology in Adelaide, and the de Duve Institute, University of Louvain, Belgium, has discovered biallelic MDFIC pathogenic variants underlying the severe lymphatic disorder, central conducting lymphatic anomaly (CCLA), in seven people from six separate families.

These findings pave the way for the development of novel therapeutics to effectively treat CCLA, a devastating lymphatic malformation, for which few effective treatments are available, the authors reported in the March 2, 2022, edition of Science Translational Medicine.

"This is the first study to identify biallelic mutations in MDFIC underlying CCLA," said study co-leader Natasha Harvey, a professor and director of the Centre for Cancer Biology at The University of South Australia and SA Pathology in Adelaide.

Individuals with CCLA were identified by testing "hundreds of families, who had either lost pregnancies due to stillbirth or had family members affected by symptoms of lymphatic disease, including lymphedema," said Harvey.

Lymphatic vasculature development defects occurring during embryogenesis often result in fetal or perinatal death, due to the adverse impact of excessive fluid accumulation on pulmonary and cardiac development and function.

In CCLA, development and function of the large collecting lymphatic vessels is affected, with the disease presenting as chylothorax, or the accumulation of chyle, a fluid that forms during the digestion of fatty foods and is usually taken up by the lymph system, in the thoracic cavity. Other symptoms of CCLA can include pleural effusions, chylous ascites, and lymphedema.

Although pathogenic gain-of-function variants in RAS/mitogen activated protein kinase (MAPK) signaling pathway components have recently been documented in some patients with CCLA, in most cases the genetic etiology of the disorder remains unknown.

This was investigated in the present study, which was co-led by Harvey, Hamish Scott, a professor in the Centre for Cancer Biology at The University of South Australia and head of the Department of Genetics and Molecular Pathology at SA Pathology, and Miikka Vikkula, a professor of human genetics and co-director of the de Duve Institute.

The researchers identified biallelic pathogenic variants in MDFIC, the gene encoding the MyoD family inhibitor domain containing protein, in seven individuals with CCLA from six independent families.

Clinical manifestations of affected fetuses and children were found to include nonimmune hydrops fetalis (NIHF), pleural and pericardial effusions, and lymphedema.

The generation of a mouse model of human MDFIC truncation variants then revealed that homozygous mutant mice all died perinatally exhibiting chylothorax.

"All of the mice that we have generated carrying homozygous Mdfic mutations died exhibiting chylothorax, which is similar to the symptoms experienced by human CCLA patients," noted Harvey.

"Our mouse model will therefore provide a [means whereby] potential therapeutics for CCLA treatment caused by Mdfic mutations can be tested," she told BioWorld.

Examination of the lymphatic vasculature of homozygous Mdfic mutant mice showed that it was profoundly mispatterned and showed major defects in lymphatic vessel valve development.

Mechanistically, the researchers determined that MDFIC controls collective cell migration, an important early event during the formation of lymphatic vessel valves, by regulating integrin b1 activation and the interaction between lymphatic endothelial cells and their surrounding extracellular matrix.

This work therefore identifies MDFIC variants underlying human lymphatic disease and reveals an important, previously unrecognized role for MDFIC in the lymphatic vasculature.

An improved understanding of the genetic and mechanistic basis of CCLA will facilitate the development and implementation of new therapeutic approaches to effectively treat this complex and potentially devastating disease.

"Some signaling pathways that are affected in CCLA have been identified and existing drugs that target these pathways have been repurposed to treat CCLA," said Harvey.

"By investigating how MDFIC controls the growth and development of lymphatic vessels, we can identify the signaling pathways affected in patients that have CCLA as a result of MDFIC mutations.

"This will provide the opportunity to intervene in these pathways using existing drugs, or develop new therapeutic agents that target MDFIC controlled pathways."

Looking ahead, "our ultimate goal is to develop therapeutics able to effectively treat CCLA and provide better outcomes for patients," she said.

"Our identification of a genetic cause of CCLA will enable it to be better diagnosed and treated and will allow affected families to plan future healthy pregnancies." Meanwhile, "our current research is investigating the signaling pathways controlled by MDFIC in lymphatic vessels."