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

doi:10.1084/jem.20180528

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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	2339-2353
Journal	Journal of Experimental Medicine
Volume	215
Issue number	9
DOIs	https://doi.org/10.1084/jem.20180528
Publication status	Published - 16 Aug 2018

Bibliographical note

© 2018 Mackie et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

Funding: NIH grants RO1-DK099156, RO1-HD060860, and RO1-HL129086 to K.M. Caron.; American Heart Association Innovator Award 16IRG27260077 to K.M. Caron; NIH grant F32-HL134279 to D.I. Mackie.; American Heart Association grant 15POST25270006 to R.B. Davis; NIH grant F31-CA174194 to D.O. Kechele, Biotechnology and Biological Sciences Research Council grant BB/M007529/1 to D.R. Poyner and J. Simms. NIH NCI K12 Training Grant 5K12-CA100639-10 and NIH NCI grant 1K22CA212058-01 were awarded to J.C. Snyder. National Institute of Drug Abuse grant 5P30-DA029925-06 to was awarded to M.G. Caron.

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10.1084/jem.20180528Licence: CC BY-NC-SA 3.0

hCALCRL mutation causes autosomal recessive nonimmune hydrops fetalis with lymphatic dysplasia
© 2018 Mackie et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
Final published version, 3.26 MBLicence: CC BY-NC-SA 3.0

Cite this

@article{f378e8831bb84e65bbc4ffec713a7b04,

title = "hCALCRL mutation causes autosomal recessive nonimmune hydrops fetalis with lymphatic dysplasia",

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.",

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

note = "{\textcopyright} 2018 Mackie et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). Funding: NIH grants RO1-DK099156, RO1-HD060860, and RO1-HL129086 to K.M. Caron.; American Heart Association Innovator Award 16IRG27260077 to K.M. Caron; NIH grant F32-HL134279 to D.I. Mackie.; American Heart Association grant 15POST25270006 to R.B. Davis; NIH grant F31-CA174194 to D.O. Kechele, Biotechnology and Biological Sciences Research Council grant BB/M007529/1 to D.R. Poyner and J. Simms. NIH NCI K12 Training Grant 5K12-CA100639-10 and NIH NCI grant 1K22CA212058-01 were awarded to J.C. Snyder. National Institute of Drug Abuse grant 5P30-DA029925-06 to was awarded to M.G. Caron. ",

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doi = "10.1084/jem.20180528",

language = "English",

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T1 - hCALCRL mutation causes autosomal recessive nonimmune hydrops fetalis with lymphatic dysplasia

AU - Mackie, Duncan I.

AU - Al Mutairi, Fuad

AU - Davis, Reema B.

AU - Kechele, Daniel O.

AU - Nielsen, Natalie R.

AU - Snyder, Joshua C.

AU - Caron, Marc G.

AU - Kliman, Harvey J.

AU - Berg, Jonathan S.

AU - Simms, John

AU - Poyner, David R.

AU - Caron, Kathleen M.

N1 - © 2018 Mackie et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). Funding: NIH grants RO1-DK099156, RO1-HD060860, and RO1-HL129086 to K.M. Caron.; American Heart Association Innovator Award 16IRG27260077 to K.M. Caron; NIH grant F32-HL134279 to D.I. Mackie.; American Heart Association grant 15POST25270006 to R.B. Davis; NIH grant F31-CA174194 to D.O. Kechele, Biotechnology and Biological Sciences Research Council grant BB/M007529/1 to D.R. Poyner and J. Simms. NIH NCI K12 Training Grant 5K12-CA100639-10 and NIH NCI grant 1K22CA212058-01 were awarded to J.C. Snyder. National Institute of Drug Abuse grant 5P30-DA029925-06 to was awarded to M.G. Caron.

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N2 - 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.

AB - 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.

UR - http://www.jem.org/lookup/doi/10.1084/jem.20180528

UR - https://doi.org/10.17036/researchdata.aston.ac.uk.00000369

U2 - 10.1084/jem.20180528

DO - 10.1084/jem.20180528

M3 - Article

SN - 0022-1007

VL - 215

SP - 2339

EP - 2353

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

IS - 9

ER -

hCALCRL mutation causes autosomal recessive nonimmune hydrops fetalis with lymphatic dysplasia

Abstract

Bibliographical note

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Molecular dynamic simulations of CLR/RAMP1 and CLR/RAMP2 heterodimers, with and without deletions of V205 in CLR

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hCALCRL mutation causes autosomal recessive nonimmune hydrops fetalis with lymphatic dysplasia

Abstract

Bibliographical note

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Datasets

Molecular dynamic simulations of CLR/RAMP1 and CLR/RAMP2 heterodimers, with and without deletions of V205 in CLR

Cite this