title: EPHB4 kinase-inactivating mutations cause autosomal dominant lymphatic-related hydrops fetalis.
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.forename: Silvia
authors.initials: S
authors.lastname: Martin-Almedina
authors.forename: Ines
authors.initials: I
authors.lastname: Martinez-Corral
authors.forename: Rita
authors.initials: R
authors.lastname: Holdhus
authors.forename: Andres
authors.initials: A
authors.lastname: Vicente
authors.forename: Elisavet
authors.initials: E
authors.lastname: Fotiou
authors.forename: Shin
authors.initials: S
authors.lastname: Lin
authors.forename: Kjell
authors.initials: K
authors.lastname: Petersen
authors.forename: Michael A
authors.initials: MA
authors.lastname: Simpson
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoischen
authors.forename: Christian
authors.initials: C
authors.lastname: Gilissen
authors.forename: Heather
authors.initials: H
authors.lastname: Jeffery
authors.forename: Giles
authors.initials: G
authors.lastname: Atton
authors.forename: Christina
authors.initials: C
authors.lastname: Karapouliou
authors.forename: Glen
authors.initials: G
authors.lastname: Brice
authors.forename: Kristiana
authors.initials: K
authors.lastname: Gordon
authors.forename: John W
authors.initials: JW
authors.lastname: Wiseman
authors.forename: Marianne
authors.initials: M
authors.lastname: Wedin
authors.forename: Stanley G
authors.initials: SG
authors.lastname: Rockson
authors.forename: Steve
authors.initials: S
authors.lastname: Jeffery
authors.forename: Peter S
authors.initials: PS
authors.lastname: Mortimer
authors.forename: Michael P
authors.initials: MP
authors.lastname: Snyder
authors.forename: Siren
authors.initials: S
authors.lastname: Berland
authors.forename: Sahar
authors.initials: S
authors.lastname: Mansour
authors.forename: Taija
authors.initials: T
authors.lastname: Makinen
authors.forename: Pia
authors.initials: P
authors.lastname: Ostergaard
mesh_terms: D000818:Animals; D042783:Endothelial Cells / Q000378:metabolism; D059472:Exome; D005260:Female; D017353:Gene Deletion; D005799:Genes, Dominant; D057809:HEK293 Cells; D006579:Heterozygote; D006801:Humans; D015160:Hydrops Fetalis / Q000235:genetics* / Q000378:metabolism*; D042601:Lymphatic Vessels / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009154:Mutation; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D036224:Receptor, EphB4 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D036224:Receptor, EphB4