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
Centre for Cancer Biology, University of South Australia and SA Pathology, 5001 Adelaide, Australia.
Clinical and Health Sciences, University of South Australia, 5001 Adelaide, Australia.
Sci Transl Med. 2022 Mar 2;14(634):eabm4869. doi: 10.1126/scitranslmed.abm4869.
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.
中央传导性淋巴异常（CCLA）以包括胸导管和乳糜池在内的核心收集淋巴管功能障碍为特征，表现为乳糜胸、胸腔积液、乳糜性腹水和淋巴水肿，是一种严重的疾病，常导致胎儿或围产期死亡。尽管在一些CCLA患者中已记录到RAS/丝裂原活化蛋白激酶（MAPK）信号通路成分的致病变异，但在大多数情况下，该疾病的遗传病因仍未明确。在此，我们在来自六个独立家族的七名CCLA患者中鉴定出双等位基因致病变异，该变异位于编码含MyoD家族抑制域蛋白的基因中。受影响胎儿和儿童的临床表现包括胎儿非免疫性水肿（NIHF）、胸腔和心包积液以及淋巴水肿。人类截短变异体小鼠模型的构建显示，纯合突变小鼠在围产期死亡，表现出乳糜胸。纯合突变小鼠的淋巴管系统严重错构，在淋巴管瓣膜发育中表现出主要缺陷。从机制上讲，我们确定MDFIC通过调节整合素β激活以及淋巴管内皮细胞与其周围细胞外基质之间的相互作用来控制集体细胞迁移，这是淋巴管瓣膜形成过程中的一个重要早期事件。我们的工作确定了人类淋巴疾病的潜在变异，并揭示了MDFIC在淋巴管系统中以前未被认识的关键作用。最终，了解CCLA的遗传和机制基础将有助于开发和实施新的治疗方法，以有效治疗这种复杂疾病。
