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https://hdl.handle.net/2440/134762
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Type: | Journal article |
Title: | Pathogenic variants in MDFIC cause recessive central conducting lymphatic anomaly with lymphedema |
Author: | Byrne, A.B. Brouillard, P. Sutton, D.L. Kazenwadel, J. Montazaribarforoushi, S. Secker, G.A. Oszmiana, A. Babic, M. Betterman, K.L. Brautigan, P.J. White, M. Piltz, S.G. Thomas, P.Q. Hahn, C.N. Rath, M. Felbor, U. Korenke, G.C. Smith, C.L. Wood, K.H. Sheppard, S.E. et al. |
Citation: | Science Translational Medicine, 2022; 14(634):eabm4869-1-eabm4869-15 |
Publisher: | American Association for the Advancement of Science |
Issue Date: | 2022 |
ISSN: | 1946-6234 1946-6242 |
Statement of Responsibility: | Alicia B. Byrne ... Peer Arts .. Christopher P. Barnett ... Eric A. Haan ... Christopher N. Hahn ... Natasha L. Harvey ... Saba Montazaribarforoushi ... Lynette Moore ... Hamish S. Scott ... Paul Q. Thomas ... Melissa A. White ... et. al |
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 β1 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. |
Keywords: | Variants; valve defects; and lymphatic dysfunction |
Rights: | © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works |
DOI: | 10.1126/scitranslmed.abm4869 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1146352 http://purl.org/au-research/grants/nhmrc/1146800 http://purl.org/au-research/grants/nhmrc/1123341 http://purl.org/au-research/grants/nhmrc/GNT1113531 http://purl.org/au-research/grants/nhmrc/1023059 http://purl.org/au-research/grants/nhmrc/GNT1113531 |
Published version: | http://dx.doi.org/10.1126/scitranslmed.abm4869 |
Appears in Collections: | Medicine publications |
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