hCALCRL mutation causes autosomal recessive nonimmune hydrops fetalis with lymphatic dysplasia

Duncan I Mackie, Fuad Al Mutairi, Reema B Davis, Daniel O Kechele, Natalie R Nielsen, Joshua C Snyder, Marc G Caron, Harvey J Kliman, Jonathan S Berg, John Simms, David R Poyner, Kathleen M Caron

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We report the first case of nonimmune hydrops fetalis (NIHF) associated with a recessive, in-frame deletion of V205 in the G protein-coupled receptor, Calcitonin Receptor-Like Receptor (hCALCRL). Homozygosity results in fetal demise from hydrops fetalis, while heterozygosity in females is associated with spontaneous miscarriage and subfertility. Using molecular dynamic modeling and in vitro biochemical assays, we show that the hCLR(V205del) mutant results in misfolding of the first extracellular loop, reducing association with its requisite receptor chaperone, receptor activity modifying protein (RAMP), translocation to the plasma membrane and signaling. Using three independent genetic mouse models we establish that the adrenomedullin-CLR-RAMP2 axis is both necessary and sufficient for driving lymphatic vascular proliferation. Genetic ablation of either lymphatic endothelial Calcrl or nonendothelial Ramp2 leads to severe NIHF with embryonic demise and placental pathologies, similar to that observed in humans. Our results highlight a novel candidate gene for human congenital NIHF and provide structure-function insights of this signaling axis for human physiology.

Original languageEnglish
Pages (from-to)2339-2353
Number of pages15
JournalJournal of Experimental Medicine
Issue number9
Early online date16 Aug 2018
Publication statusPublished - 3 Sept 2018

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