hCALCRL mutation causes autosomal recessive nonimmune hydrops fetalis with lymphatic dysplasia
Journal of Experimental Medicine
Mackie DI1, Al Mutairi F2,3,4, Davis RB1, Kechele DO1, Nielsen NR1, Snyder JC5,6, Caron MG5, Kliman HJ7, Berg JS8, Simms J9, Poyner DR10, Caron KM11,8.
1 Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC.
2 Department of Pediatrics, King Abdulaziz Medical City, Riyadh, Saudi Arabia email@example.com.
3 King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
4 King Abdullah International Medical Research Centre (KAIMRC), Riyadh, Saudi Arabia.
5 Department of Cell Biology, Duke University Medical Center, Durham, NC.
6 Department of Surgery, Duke University Medical Center, Durham, NC.
7 Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT.
8 Department of Genetics, University of North Carolina, Chapel Hill, NC.
9 School of Life Sciences, Faculty of Health and Life Sciences, Coventry University, Coventry, England, UK.
10 School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham, England, UK.
11 Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC Kathleen_caron@med.unc.edu
Year of Publication:
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.