hCALCRL mutation causes autosomal recessive nonimmune hydrops fetalis with lymphatic dysplasia

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  • Mackie, Duncan I.
    • School of Medicine, Department of Cell Biology and Physiology
  • Mutairi, Fuad Al
    • Other Affiliation: Department of Pediatrics, King Abdulaziz Medical City, Riyadh, Saudi Arabia
  • Davis, Reema B.
    • School of Medicine, Department of Cell Biology and Physiology
  • Kechele, Daniel O.
    • School of Medicine, Department of Cell Biology and Physiology
  • Nielsen, Natalie R.
    • School of Medicine, Department of Cell Biology and Physiology
  • Snyder, Joshua C.
    • Other Affiliation: Department of Cell Biology, Duke University Medical Center, Durham, NC
  • Caron, Marc G.
    • Other Affiliation: Department of Cell Biology, Duke University Medical Center, Durham, NC
  • Kliman, Harvey J.
    • Other Affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT
  • Berg, Jonathan S.
    • School of Medicine, Department of Genetics
  • Simms, John
    • Other Affiliation: School of Life Sciences, Faculty of Health and Life Sciences, Coventry University, Coventry, England, UK
  • Poyner, David R.
    • Other Affiliation: School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham, England, UK
  • Caron, Kathleen M.
    • School of Medicine, Department of Cell Biology and Physiology
Abstract
  • 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.
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  • Article
Rights statement
  • In Copyright
License
  • Attribution-NonCommercial-ShareAlike 4.0 International
Journal title
  • Journal of Experimental Medicine
Journal volume
  • 215
Journal issue
  • 9
Page start
  • 2339
Page end
  • 2353
Version
  • Publisher
Funder
  • National Institute on Drug Abuse
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development
  • National Cancer Institute
  • American Heart Association
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Heart Lung and Blood Institute
  • Biotechnology and Biological Sciences Research Council
ISSN
  • 0022-1007
  • 1540-9538
Publisher
  • Rockefeller University Press

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