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EPHB4 kinase–inactivating mutations cause autosomal dominant lymphatic-related hydrops fetalis
Silvia Martin-Almedina, … , Taija Makinen, Pia Ostergaard
Silvia Martin-Almedina, … , Taija Makinen, Pia Ostergaard
Published July 11, 2016
Citation Information: J Clin Invest. 2016;126(8):3080-3088. https://doi.org/10.1172/JCI85794.
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Research Article Genetics

EPHB4 kinase–inactivating mutations cause autosomal dominant lymphatic-related hydrops fetalis

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Abstract

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.

Authors

Silvia Martin-Almedina, Ines Martinez-Corral, Rita Holdhus, Andres Vicente, Elisavet Fotiou, Shin Lin, Kjell Petersen, Michael A. Simpson, Alexander Hoischen, Christian Gilissen, Heather Jeffery, Giles Atton, Christina Karapouliou, Glen Brice, Kristiana Gordon, John W. Wiseman, Marianne Wedin, Stanley G. Rockson, Steve Jeffery, Peter S. Mortimer, Michael P. Snyder, Siren Berland, Sahar Mansour, Taija Makinen, Pia Ostergaard

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Figure 1

Mutations in EPHB4 cause LRHF.

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Mutations in EPHB4 cause LRHF.
(A) Pedigree of GLDUK family. (B) Pedigre...
(A) Pedigree of GLDUK family. (B) Pedigree of GLDNOR family. Stars indicate which samples have been exome sequenced. Genotypes indicated by minus signs (–) represent the WT allele, and plus signs represent (+) the mutant allele. Top row of genotypes in GLDUK genogram shows EPHB4, and bottom row of genotypes shows MIER2. Triangles, first trimester miscarriages; IUD, intrauterine death. GLDNOR:III.3 had trisomy 18.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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