期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 14, 期 634, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.abm4869
关键词
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资金
- NHMRC [1146352, 1146800, 1123341, 1023059, GNT1113531]
- Medical Research Future Fund (MRFF)
- Genomics Health Futures Mission grant [GHFM76777 NHMRC (APP1123341)]
- Australian Genomic Health Alliance NHMRC Targeted Call for Research into Preparing Australia [GNT1113531]
- Australian Cancer Research Foundation
- Cancer Council SA's Beat Cancer Project
- State Government of South Australia through the Department of Health
- Australian Government Research Training Program Scholarship
- Australian Genomics Health Alliance PhD Award
- Hospital Research Foundation Fellowship
- Royal Adelaide Hospital Mary Overton Early Career Fellowship
- Gerhard Domagk program of the University Medicine Greifswald
- Phenomics Australia through the Australian Government's National Collaborative Research Infrastructure Strategy
- Fonds de la Recherche Scientifique (FNRS) [T.0026.14, T.0247.19, T.0146.16]
- Fund Generet by the King Baudouin Foundation [2018-J1810250-211305]
- la Region wallonne dans le cadre du financement de l'axe strategique FRFS-WELBIO [WELBIO-CR-2019C-06]
- National Lottery, Belgium
- Foundation against Cancer, Belgium [2010-101]
- FNRS equipment grant [U.N035.17]
- CHOP
- Uplifting Athletes
- Lymphangiomatosis and Gorham's Disease Alliance
- National Health and Medical Research Council of Australia [1146800, 1146352, 1123341] Funding Source: NHMRC
Central conducting lymphatic anomaly (CCLA) is a severe disorder of the lymphatic system often resulting in fetal or perinatal demise. This study identified pathogenic variants in the MDFIC gene in individuals with CCLA and revealed a crucial role for MDFIC in lymphatic vessel development.
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 beta(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.
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