دورية أكاديمية
Pathogenic variants in cause recessive central conducting lymphatic anomaly with lymphedema.
| العنوان: | Pathogenic variants in cause recessive central conducting lymphatic anomaly with lymphedema. |
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| المؤلفون: | Byrne, Alicia B, Brouillard, Pascal, Sutton, Drew L, Kazenwadel, Jan, Montazaribarforoushi, Saba, Secker, Genevieve A, Oszmiana, Anna, Babic, Milena, Betterman, Kelly L, Brautigan, Peter J, White, Melissa, Piltz, Sandra G, Thomas, Paul Q, Hahn, Christopher N, Rath, Matthias, Felbor, Ute, Korenke, G Christoph, Smith, Christopher L, Wood, Kathleen H, Sheppard, Sarah E, Adams, Denise M, Kariminejad, Ariana, Helaers, Raphael, Boon, Laurence M, Revencu, Nicole, Moore, Lynette, Barnett, Christopher, Haan, Eric, Arts, Peer, Vikkula, Miikka, Scott, Hamish S, Harvey, Natasha L |
| المساهمون: | UCL - SSS/DDUV/GEHU - Génétique |
| المصدر: | Science translational medicine, Vol. 14, no.634, p. eabm4869 (2022) |
| سنة النشر: | 2022 |
| المجموعة: | DIAL@USL-B (Université Saint-Louis, Bruxelles) |
| الوصف: | 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 , 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 truncation variants revealed that homozygous mutant mice died perinatally exhibiting chylothorax. The lymphatic vasculature of homozygous 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 activation and the interaction between lymphatic endothelial cells and their surrounding extracellular matrix. Our work identifies 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 1946-6242 |
| العلاقة: | boreal:259284; http://hdl.handle.net/2078.1/259284Test; info:pmid/35235341; urn:EISSN:1946-6242 |
| DOI: | 10.1126/scitranslmed.abm4869 |
| الإتاحة: | https://doi.org/10.1126/scitranslmed.abm4869Test http://hdl.handle.net/2078.1/259284Test |
| حقوق: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.36E4309B |
| قاعدة البيانات: | BASE |
| تدمد: | 19466242 |
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| DOI: | 10.1126/scitranslmed.abm4869 |