Pathogenic variants in MDFIC cause recessive central conducting lymphatic anomaly with lymphedema

Abstract

Central conducting lymphatic anomaly (CCLA), characterized by the dysfunction of core collecting lymphatic vessels including the thoracic duct and cisterna chyli, and presenting as chylothorax, pleural effusions, chylous ascites, and lymphedema, is a severe disorder often resulting in fetal or perinatal demise. Although pathogenic variants in RAS/mitogen activated protein kinase (MAPK) signaling pathway components have been documented in some patients with CCLA, the genetic etiology of the disorder remains uncharacterized in most cases. Here, we identified biallelic pathogenic variants in MDFIC , encoding the MyoD family inhibitor domain containing protein, in seven individuals with CCLA from six independent families. Clinical manifestations of affected fetuses and children included nonimmune hydrops fetalis (NIHF), pleural and pericardial effusions, and lymphedema. Generation of a mouse model of human MDFIC truncation variants revealed that homozygous mutant mice died perinatally exhibiting chylothorax. The lymphatic vasculature of homozygous Mdfic mutant mice was profoundly mispatterned and exhibited major defects in lymphatic vessel valve development. Mechanistically, we determined that MDFIC controls collective cell migration, an important early event during the formation of lymphatic vessel valves, by regulating integrin β 1 activation and the interaction between lymphatic endothelial cells and their surrounding extracellular matrix. Our work identifies MDFIC variants underlying human lymphatic disease and reveals a crucial, previously unrecognized role for MDFIC in the lymphatic vasculature. Ultimately, understanding the genetic and mechanistic basis of CCLA will facilitate the development and implementation of new therapeutic approaches to effectively treat this complex disease.

MyoD-family inhibitor proteins act as auxiliary subunits of Piezo channels

“…This provided strong validation for both affinity-capture strategies. The second protein identified was the sparsely studied transcriptional regulator MyoD (myoblast determination) family–inhibitor domain-containing protein (MDFIC) ( 18 , 19 ). MS provided 39 ± 14% coverage of MDFIC protein averaged over the three groups (Fig.…”

“…Because both PIEZO1 and MDFIC are essential for lymphatic development in mice and humans ( 19 , 25 , 26 ), we investigated using the ClinVar database whether any disease-causing mutations were located within this binding interface. We found mutations in both PIEZO1 (human V2171f; Fig.…”

“…We next asked whether genetic loss of MDFIC could modify the kinetics of native PIEZO1 currents. To investigate this, we used a mouse model of a complex lymphatic anomaly known as central conducting lymphatic anomaly, bearing a truncated variant of MDFIC that lacked the complete conserved C-terminal but retained the N-terminal region ( 19 ). Our assessment of PIEZO1 activity in embryonic cardiac fibroblasts isolated from embryonic day 16.5 (E16.5) wild-type (WT/WT), heterozygous (WT/M131fs*), and homozygous mice (M131fs*/M131fs*) revealed that fibroblasts harboring C-terminally truncated MDFIC had smaller PIEZO1 currents that inactivated more rapidly (Fig.…”

Pathogenic variants inPIK3CAare associated with clinical phenotypes of kaposiform lymphangiomatosis, generalized lymphatic anomaly, and central conducting lymphatic anomaly

“…Diagnosis is often made by imaging 1,2 . JAG1 , EPHB4 , ARAF , and MDFIC pathogenic variants have been described in CCLA, and a recent cohort study has demonstrated an association between RASopathies, Trisomy 21, 22q11.2 deletion syndrome, and PIEZO1 generalized lymphatic dysplasia in CCLA 8–12 …”

“…1,2 JAG1, EPHB4, ARAF, and MDFIC pathogenic variants have been described in CCLA, and a recent cohort study has demonstrated an association between RASopathies, Trisomy 21, 22q11.2 deletion syndrome, and PIEZO1 generalized lymphatic dysplasia in CCLA. [8][9][10][11][12] Treatment of KLA and GLA has thus far involved sirolimus and interventional procedures such as sclerotherapy and lymphatic embolization. Treatment of CCLA consisted of surgical or interventional procedures to redirect or obliterate aberrant lymph flow, but novel therapies are still needed given the diffuse nature of the disease.…”