EPHB4 kinase-inactivating mutations cause autosomal dominant lymphatic-related hydrops fetalis.
EPHB4 kinase-inactivating mutations cause autosomal dominant lymphatic-related hydrops fetalis.
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DOI：
10.1172/jci85794
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发表时间：
2016-08-01
期刊：
影响因子：
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通讯作者：
Ostergaard P
中科院分区：
文献类型：
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作者：
Martin-Almedina S;Martinez-Corral I;Holdhus R;Vicente A;Fotiou E;Lin S;Petersen K;Simpson MA;Hoischen A;Gilissen C;Jeffery H;Atton G;Karapouliou C;Brice G;Gordon K;Wiseman JW;Wedin M;Rockson SG;Jeffery S;Mortimer PS;Snyder MP;Berland S;Mansour S;Makinen T;Ostergaard P
胎儿水肿描述了至少2个胎儿隔室（包括腹腔、胸膜和心包）或身体组织中的液体积聚。大多数胎儿水肿病例是非免疫性疾病，表现为胎儿全身水肿，这些非免疫性病例中约有15%是淋巴异常所致。在这里，我们已经确定了一个常染色体显性遗传形式的水肿相关（非免疫）胎儿水肿（LRHF）。对2个具有与非免疫性胎儿水肿相关的宫内和新生儿死亡史的家族进行的独立外显子组测序项目发现了编码Eph受体B4（EPHB 4）的基因中的2个杂合错义变体。生化分析确定突变EPHB 4蛋白缺乏酪氨酸激酶活性，表明EPHB 4信号传导的丧失有助于LRHF发病机制。此外，在发育中的小鼠胚胎的淋巴管内皮细胞中Ephb4的失活导致有缺陷的淋巴静脉瓣形成和随后的皮下水肿。总之，这些发现将EPHB 4确定为早期淋巴管发育的关键调节因子，并证明该基因的突变可导致与高死亡率相关的常染色体显性LRHF。
Hydrops fetalis describes fluid accumulation in at least 2 fetal compartments, including abdominal cavities, pleura, and pericardium, or in body tissue. The majority of hydrops fetalis cases are nonimmune conditions that present with generalized edema of the fetus, and approximately 15% of these nonimmune cases result from a lymphatic abnormality. Here, we have identified an autosomal dominant, inherited form of lymphatic-related (nonimmune) hydrops fetalis (LRHF). Independent exome sequencing projects on 2 families with a history of in utero and neonatal deaths associated with nonimmune hydrops fetalis uncovered 2 heterozygous missense variants in the gene encoding Eph receptor B4 (EPHB4). Biochemical analysis determined that the mutant EPHB4 proteins are devoid of tyrosine kinase activity, indicating that loss of EPHB4 signaling contributes to LRHF pathogenesis. Further, inactivation of Ephb4 in lymphatic endothelial cells of developing mouse embryos led to defective lymphovenous valve formation and consequent subcutaneous edema. Together, these findings identify EPHB4 as a critical regulator of early lymphatic vascular development and demonstrate that mutations in the gene can cause an autosomal dominant form of LRHF that is associated with a high mortality rate.