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ResearchIn-Press PreviewEndocrinology Open Access | 10.1172/JCI164915

Loss of LGR4/GPR48 causes severe neonatal salt-wasting due to disrupted WNT signaling altering adrenal zonation

Cécily Lucas,1 Kay-Sara Sauter,2 Michael Steigert,3 Delphine Mallet,1 James Wilmouth Jr.,4 Julie Olabe,5 Ingrid Plotton,6 Yves Morel,7 Daniel Aeberli,8 Franca Wagner,9 Hans Clevers,10 Amit V. Pandey,11 Pierre Val,12 Florence Roucher-Boulez,13 and Christa E. Fluck14

1Laboratoire de Biochimie et Biologie Moléculaire, UM Pathologies Endocrinie, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France

2Department of Pediatrics, Inselspital, University of Bern, Bern, Switzerland

3Department of Pediatrics, Kantonsspital Graubünden, Chur, Chur, Switzerland

4Génétique, Reproduction & Développement (GReD), CNRS UMR6293, INSERM U1103, Université Clermont Auvergne, Clermont-Ferrand, France

5CNRS, Inserm, GReD, Université Clermont Auvergne, Auvergne, France

6Centre de Biologie et Pathologie Est, CHU de Lyon HCL, Lyon, France

7Endocrinienne Et Moleculaire, INSERM-U 329 - Lab De Biochimie, 69322 Lyon Cedex 05, France

8Department of Rheumatology and Immunology, Inselspital - Bern University Hospital, Bern, Switzerland

9University Institute of Diagnostic and Interventional Neuroradiology, University Hospital Inselspital Bern, Bern, Switzerland

10Molecular Genetics & Developmental Biology and Stem Cell Research, University Medical Center Utrecht, The Netherlands, Utrecht, Netherlands

11Paediatric Endocrinology and Metabolism, University Children's Hospital Bern, Bern, Switzerland

12GReD, CNRS, INSERM, Université Clermont Auvergne, Clermont-Ferrand, France

13Molecular Endocrinology and Rare Diseases, Claude Bernard Lyon 1 University, Bron, France

14Pediatric Endocrinology, Diabetology and Metabolism, Department of BioMedic, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

Find articles by Lucas, C. in: JCI | PubMed | Google Scholar |

1Laboratoire de Biochimie et Biologie Moléculaire, UM Pathologies Endocrinie, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France

2Department of Pediatrics, Inselspital, University of Bern, Bern, Switzerland

3Department of Pediatrics, Kantonsspital Graubünden, Chur, Chur, Switzerland

4Génétique, Reproduction & Développement (GReD), CNRS UMR6293, INSERM U1103, Université Clermont Auvergne, Clermont-Ferrand, France

5CNRS, Inserm, GReD, Université Clermont Auvergne, Auvergne, France

6Centre de Biologie et Pathologie Est, CHU de Lyon HCL, Lyon, France

7Endocrinienne Et Moleculaire, INSERM-U 329 - Lab De Biochimie, 69322 Lyon Cedex 05, France

8Department of Rheumatology and Immunology, Inselspital - Bern University Hospital, Bern, Switzerland

9University Institute of Diagnostic and Interventional Neuroradiology, University Hospital Inselspital Bern, Bern, Switzerland

10Molecular Genetics & Developmental Biology and Stem Cell Research, University Medical Center Utrecht, The Netherlands, Utrecht, Netherlands

11Paediatric Endocrinology and Metabolism, University Children's Hospital Bern, Bern, Switzerland

12GReD, CNRS, INSERM, Université Clermont Auvergne, Clermont-Ferrand, France

13Molecular Endocrinology and Rare Diseases, Claude Bernard Lyon 1 University, Bron, France

14Pediatric Endocrinology, Diabetology and Metabolism, Department of BioMedic, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

Find articles by Sauter, K. in: JCI | PubMed | Google Scholar

1Laboratoire de Biochimie et Biologie Moléculaire, UM Pathologies Endocrinie, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France

2Department of Pediatrics, Inselspital, University of Bern, Bern, Switzerland

3Department of Pediatrics, Kantonsspital Graubünden, Chur, Chur, Switzerland

4Génétique, Reproduction & Développement (GReD), CNRS UMR6293, INSERM U1103, Université Clermont Auvergne, Clermont-Ferrand, France

5CNRS, Inserm, GReD, Université Clermont Auvergne, Auvergne, France

6Centre de Biologie et Pathologie Est, CHU de Lyon HCL, Lyon, France

7Endocrinienne Et Moleculaire, INSERM-U 329 - Lab De Biochimie, 69322 Lyon Cedex 05, France

8Department of Rheumatology and Immunology, Inselspital - Bern University Hospital, Bern, Switzerland

9University Institute of Diagnostic and Interventional Neuroradiology, University Hospital Inselspital Bern, Bern, Switzerland

10Molecular Genetics & Developmental Biology and Stem Cell Research, University Medical Center Utrecht, The Netherlands, Utrecht, Netherlands

11Paediatric Endocrinology and Metabolism, University Children's Hospital Bern, Bern, Switzerland

12GReD, CNRS, INSERM, Université Clermont Auvergne, Clermont-Ferrand, France

13Molecular Endocrinology and Rare Diseases, Claude Bernard Lyon 1 University, Bron, France

14Pediatric Endocrinology, Diabetology and Metabolism, Department of BioMedic, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

Find articles by Steigert, M. in: JCI | PubMed | Google Scholar

1Laboratoire de Biochimie et Biologie Moléculaire, UM Pathologies Endocrinie, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France

2Department of Pediatrics, Inselspital, University of Bern, Bern, Switzerland

3Department of Pediatrics, Kantonsspital Graubünden, Chur, Chur, Switzerland

4Génétique, Reproduction & Développement (GReD), CNRS UMR6293, INSERM U1103, Université Clermont Auvergne, Clermont-Ferrand, France

5CNRS, Inserm, GReD, Université Clermont Auvergne, Auvergne, France

6Centre de Biologie et Pathologie Est, CHU de Lyon HCL, Lyon, France

7Endocrinienne Et Moleculaire, INSERM-U 329 - Lab De Biochimie, 69322 Lyon Cedex 05, France

8Department of Rheumatology and Immunology, Inselspital - Bern University Hospital, Bern, Switzerland

9University Institute of Diagnostic and Interventional Neuroradiology, University Hospital Inselspital Bern, Bern, Switzerland

10Molecular Genetics & Developmental Biology and Stem Cell Research, University Medical Center Utrecht, The Netherlands, Utrecht, Netherlands

11Paediatric Endocrinology and Metabolism, University Children's Hospital Bern, Bern, Switzerland

12GReD, CNRS, INSERM, Université Clermont Auvergne, Clermont-Ferrand, France

13Molecular Endocrinology and Rare Diseases, Claude Bernard Lyon 1 University, Bron, France

14Pediatric Endocrinology, Diabetology and Metabolism, Department of BioMedic, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

Find articles by Mallet, D. in: JCI | PubMed | Google Scholar

1Laboratoire de Biochimie et Biologie Moléculaire, UM Pathologies Endocrinie, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France

2Department of Pediatrics, Inselspital, University of Bern, Bern, Switzerland

3Department of Pediatrics, Kantonsspital Graubünden, Chur, Chur, Switzerland

4Génétique, Reproduction & Développement (GReD), CNRS UMR6293, INSERM U1103, Université Clermont Auvergne, Clermont-Ferrand, France

5CNRS, Inserm, GReD, Université Clermont Auvergne, Auvergne, France

6Centre de Biologie et Pathologie Est, CHU de Lyon HCL, Lyon, France

7Endocrinienne Et Moleculaire, INSERM-U 329 - Lab De Biochimie, 69322 Lyon Cedex 05, France

8Department of Rheumatology and Immunology, Inselspital - Bern University Hospital, Bern, Switzerland

9University Institute of Diagnostic and Interventional Neuroradiology, University Hospital Inselspital Bern, Bern, Switzerland

10Molecular Genetics & Developmental Biology and Stem Cell Research, University Medical Center Utrecht, The Netherlands, Utrecht, Netherlands

11Paediatric Endocrinology and Metabolism, University Children's Hospital Bern, Bern, Switzerland

12GReD, CNRS, INSERM, Université Clermont Auvergne, Clermont-Ferrand, France

13Molecular Endocrinology and Rare Diseases, Claude Bernard Lyon 1 University, Bron, France

14Pediatric Endocrinology, Diabetology and Metabolism, Department of BioMedic, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

Find articles by Wilmouth Jr., J. in: JCI | PubMed | Google Scholar |

1Laboratoire de Biochimie et Biologie Moléculaire, UM Pathologies Endocrinie, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France

2Department of Pediatrics, Inselspital, University of Bern, Bern, Switzerland

3Department of Pediatrics, Kantonsspital Graubünden, Chur, Chur, Switzerland

4Génétique, Reproduction & Développement (GReD), CNRS UMR6293, INSERM U1103, Université Clermont Auvergne, Clermont-Ferrand, France

5CNRS, Inserm, GReD, Université Clermont Auvergne, Auvergne, France

6Centre de Biologie et Pathologie Est, CHU de Lyon HCL, Lyon, France

7Endocrinienne Et Moleculaire, INSERM-U 329 - Lab De Biochimie, 69322 Lyon Cedex 05, France

8Department of Rheumatology and Immunology, Inselspital - Bern University Hospital, Bern, Switzerland

9University Institute of Diagnostic and Interventional Neuroradiology, University Hospital Inselspital Bern, Bern, Switzerland

10Molecular Genetics & Developmental Biology and Stem Cell Research, University Medical Center Utrecht, The Netherlands, Utrecht, Netherlands

11Paediatric Endocrinology and Metabolism, University Children's Hospital Bern, Bern, Switzerland

12GReD, CNRS, INSERM, Université Clermont Auvergne, Clermont-Ferrand, France

13Molecular Endocrinology and Rare Diseases, Claude Bernard Lyon 1 University, Bron, France

14Pediatric Endocrinology, Diabetology and Metabolism, Department of BioMedic, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

Find articles by Olabe, J. in: JCI | PubMed | Google Scholar |

1Laboratoire de Biochimie et Biologie Moléculaire, UM Pathologies Endocrinie, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France

2Department of Pediatrics, Inselspital, University of Bern, Bern, Switzerland

3Department of Pediatrics, Kantonsspital Graubünden, Chur, Chur, Switzerland

4Génétique, Reproduction & Développement (GReD), CNRS UMR6293, INSERM U1103, Université Clermont Auvergne, Clermont-Ferrand, France

5CNRS, Inserm, GReD, Université Clermont Auvergne, Auvergne, France

6Centre de Biologie et Pathologie Est, CHU de Lyon HCL, Lyon, France

7Endocrinienne Et Moleculaire, INSERM-U 329 - Lab De Biochimie, 69322 Lyon Cedex 05, France

8Department of Rheumatology and Immunology, Inselspital - Bern University Hospital, Bern, Switzerland

9University Institute of Diagnostic and Interventional Neuroradiology, University Hospital Inselspital Bern, Bern, Switzerland

10Molecular Genetics & Developmental Biology and Stem Cell Research, University Medical Center Utrecht, The Netherlands, Utrecht, Netherlands

11Paediatric Endocrinology and Metabolism, University Children's Hospital Bern, Bern, Switzerland

12GReD, CNRS, INSERM, Université Clermont Auvergne, Clermont-Ferrand, France

13Molecular Endocrinology and Rare Diseases, Claude Bernard Lyon 1 University, Bron, France

14Pediatric Endocrinology, Diabetology and Metabolism, Department of BioMedic, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

Find articles by Plotton, I. in: JCI | PubMed | Google Scholar |

1Laboratoire de Biochimie et Biologie Moléculaire, UM Pathologies Endocrinie, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France

2Department of Pediatrics, Inselspital, University of Bern, Bern, Switzerland

3Department of Pediatrics, Kantonsspital Graubünden, Chur, Chur, Switzerland

4Génétique, Reproduction & Développement (GReD), CNRS UMR6293, INSERM U1103, Université Clermont Auvergne, Clermont-Ferrand, France

5CNRS, Inserm, GReD, Université Clermont Auvergne, Auvergne, France

6Centre de Biologie et Pathologie Est, CHU de Lyon HCL, Lyon, France

7Endocrinienne Et Moleculaire, INSERM-U 329 - Lab De Biochimie, 69322 Lyon Cedex 05, France

8Department of Rheumatology and Immunology, Inselspital - Bern University Hospital, Bern, Switzerland

9University Institute of Diagnostic and Interventional Neuroradiology, University Hospital Inselspital Bern, Bern, Switzerland

10Molecular Genetics & Developmental Biology and Stem Cell Research, University Medical Center Utrecht, The Netherlands, Utrecht, Netherlands

11Paediatric Endocrinology and Metabolism, University Children's Hospital Bern, Bern, Switzerland

12GReD, CNRS, INSERM, Université Clermont Auvergne, Clermont-Ferrand, France

13Molecular Endocrinology and Rare Diseases, Claude Bernard Lyon 1 University, Bron, France

14Pediatric Endocrinology, Diabetology and Metabolism, Department of BioMedic, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

Find articles by Morel, Y. in: JCI | PubMed | Google Scholar

1Laboratoire de Biochimie et Biologie Moléculaire, UM Pathologies Endocrinie, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France

2Department of Pediatrics, Inselspital, University of Bern, Bern, Switzerland

3Department of Pediatrics, Kantonsspital Graubünden, Chur, Chur, Switzerland

4Génétique, Reproduction & Développement (GReD), CNRS UMR6293, INSERM U1103, Université Clermont Auvergne, Clermont-Ferrand, France

5CNRS, Inserm, GReD, Université Clermont Auvergne, Auvergne, France

6Centre de Biologie et Pathologie Est, CHU de Lyon HCL, Lyon, France

7Endocrinienne Et Moleculaire, INSERM-U 329 - Lab De Biochimie, 69322 Lyon Cedex 05, France

8Department of Rheumatology and Immunology, Inselspital - Bern University Hospital, Bern, Switzerland

9University Institute of Diagnostic and Interventional Neuroradiology, University Hospital Inselspital Bern, Bern, Switzerland

10Molecular Genetics & Developmental Biology and Stem Cell Research, University Medical Center Utrecht, The Netherlands, Utrecht, Netherlands

11Paediatric Endocrinology and Metabolism, University Children's Hospital Bern, Bern, Switzerland

12GReD, CNRS, INSERM, Université Clermont Auvergne, Clermont-Ferrand, France

13Molecular Endocrinology and Rare Diseases, Claude Bernard Lyon 1 University, Bron, France

14Pediatric Endocrinology, Diabetology and Metabolism, Department of BioMedic, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

Find articles by Aeberli, D. in: JCI | PubMed | Google Scholar

1Laboratoire de Biochimie et Biologie Moléculaire, UM Pathologies Endocrinie, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France

2Department of Pediatrics, Inselspital, University of Bern, Bern, Switzerland

3Department of Pediatrics, Kantonsspital Graubünden, Chur, Chur, Switzerland

4Génétique, Reproduction & Développement (GReD), CNRS UMR6293, INSERM U1103, Université Clermont Auvergne, Clermont-Ferrand, France

5CNRS, Inserm, GReD, Université Clermont Auvergne, Auvergne, France

6Centre de Biologie et Pathologie Est, CHU de Lyon HCL, Lyon, France

7Endocrinienne Et Moleculaire, INSERM-U 329 - Lab De Biochimie, 69322 Lyon Cedex 05, France

8Department of Rheumatology and Immunology, Inselspital - Bern University Hospital, Bern, Switzerland

9University Institute of Diagnostic and Interventional Neuroradiology, University Hospital Inselspital Bern, Bern, Switzerland

10Molecular Genetics & Developmental Biology and Stem Cell Research, University Medical Center Utrecht, The Netherlands, Utrecht, Netherlands

11Paediatric Endocrinology and Metabolism, University Children's Hospital Bern, Bern, Switzerland

12GReD, CNRS, INSERM, Université Clermont Auvergne, Clermont-Ferrand, France

13Molecular Endocrinology and Rare Diseases, Claude Bernard Lyon 1 University, Bron, France

14Pediatric Endocrinology, Diabetology and Metabolism, Department of BioMedic, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

Find articles by Wagner, F. in: JCI | PubMed | Google Scholar |

1Laboratoire de Biochimie et Biologie Moléculaire, UM Pathologies Endocrinie, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France

2Department of Pediatrics, Inselspital, University of Bern, Bern, Switzerland

3Department of Pediatrics, Kantonsspital Graubünden, Chur, Chur, Switzerland

4Génétique, Reproduction & Développement (GReD), CNRS UMR6293, INSERM U1103, Université Clermont Auvergne, Clermont-Ferrand, France

5CNRS, Inserm, GReD, Université Clermont Auvergne, Auvergne, France

6Centre de Biologie et Pathologie Est, CHU de Lyon HCL, Lyon, France

7Endocrinienne Et Moleculaire, INSERM-U 329 - Lab De Biochimie, 69322 Lyon Cedex 05, France

8Department of Rheumatology and Immunology, Inselspital - Bern University Hospital, Bern, Switzerland

9University Institute of Diagnostic and Interventional Neuroradiology, University Hospital Inselspital Bern, Bern, Switzerland

10Molecular Genetics & Developmental Biology and Stem Cell Research, University Medical Center Utrecht, The Netherlands, Utrecht, Netherlands

11Paediatric Endocrinology and Metabolism, University Children's Hospital Bern, Bern, Switzerland

12GReD, CNRS, INSERM, Université Clermont Auvergne, Clermont-Ferrand, France

13Molecular Endocrinology and Rare Diseases, Claude Bernard Lyon 1 University, Bron, France

14Pediatric Endocrinology, Diabetology and Metabolism, Department of BioMedic, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

Find articles by Clevers, H. in: JCI | PubMed | Google Scholar

1Laboratoire de Biochimie et Biologie Moléculaire, UM Pathologies Endocrinie, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France

2Department of Pediatrics, Inselspital, University of Bern, Bern, Switzerland

3Department of Pediatrics, Kantonsspital Graubünden, Chur, Chur, Switzerland

4Génétique, Reproduction & Développement (GReD), CNRS UMR6293, INSERM U1103, Université Clermont Auvergne, Clermont-Ferrand, France

5CNRS, Inserm, GReD, Université Clermont Auvergne, Auvergne, France

6Centre de Biologie et Pathologie Est, CHU de Lyon HCL, Lyon, France

7Endocrinienne Et Moleculaire, INSERM-U 329 - Lab De Biochimie, 69322 Lyon Cedex 05, France

8Department of Rheumatology and Immunology, Inselspital - Bern University Hospital, Bern, Switzerland

9University Institute of Diagnostic and Interventional Neuroradiology, University Hospital Inselspital Bern, Bern, Switzerland

10Molecular Genetics & Developmental Biology and Stem Cell Research, University Medical Center Utrecht, The Netherlands, Utrecht, Netherlands

11Paediatric Endocrinology and Metabolism, University Children's Hospital Bern, Bern, Switzerland

12GReD, CNRS, INSERM, Université Clermont Auvergne, Clermont-Ferrand, France

13Molecular Endocrinology and Rare Diseases, Claude Bernard Lyon 1 University, Bron, France

14Pediatric Endocrinology, Diabetology and Metabolism, Department of BioMedic, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

Find articles by Pandey, A. in: JCI | PubMed | Google Scholar |

1Laboratoire de Biochimie et Biologie Moléculaire, UM Pathologies Endocrinie, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France

2Department of Pediatrics, Inselspital, University of Bern, Bern, Switzerland

3Department of Pediatrics, Kantonsspital Graubünden, Chur, Chur, Switzerland

4Génétique, Reproduction & Développement (GReD), CNRS UMR6293, INSERM U1103, Université Clermont Auvergne, Clermont-Ferrand, France

5CNRS, Inserm, GReD, Université Clermont Auvergne, Auvergne, France

6Centre de Biologie et Pathologie Est, CHU de Lyon HCL, Lyon, France

7Endocrinienne Et Moleculaire, INSERM-U 329 - Lab De Biochimie, 69322 Lyon Cedex 05, France

8Department of Rheumatology and Immunology, Inselspital - Bern University Hospital, Bern, Switzerland

9University Institute of Diagnostic and Interventional Neuroradiology, University Hospital Inselspital Bern, Bern, Switzerland

10Molecular Genetics & Developmental Biology and Stem Cell Research, University Medical Center Utrecht, The Netherlands, Utrecht, Netherlands

11Paediatric Endocrinology and Metabolism, University Children's Hospital Bern, Bern, Switzerland

12GReD, CNRS, INSERM, Université Clermont Auvergne, Clermont-Ferrand, France

13Molecular Endocrinology and Rare Diseases, Claude Bernard Lyon 1 University, Bron, France

14Pediatric Endocrinology, Diabetology and Metabolism, Department of BioMedic, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

Find articles by Val, P. in: JCI | PubMed | Google Scholar |

1Laboratoire de Biochimie et Biologie Moléculaire, UM Pathologies Endocrinie, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France

2Department of Pediatrics, Inselspital, University of Bern, Bern, Switzerland

3Department of Pediatrics, Kantonsspital Graubünden, Chur, Chur, Switzerland

4Génétique, Reproduction & Développement (GReD), CNRS UMR6293, INSERM U1103, Université Clermont Auvergne, Clermont-Ferrand, France

5CNRS, Inserm, GReD, Université Clermont Auvergne, Auvergne, France

6Centre de Biologie et Pathologie Est, CHU de Lyon HCL, Lyon, France

7Endocrinienne Et Moleculaire, INSERM-U 329 - Lab De Biochimie, 69322 Lyon Cedex 05, France

8Department of Rheumatology and Immunology, Inselspital - Bern University Hospital, Bern, Switzerland

9University Institute of Diagnostic and Interventional Neuroradiology, University Hospital Inselspital Bern, Bern, Switzerland

10Molecular Genetics & Developmental Biology and Stem Cell Research, University Medical Center Utrecht, The Netherlands, Utrecht, Netherlands

11Paediatric Endocrinology and Metabolism, University Children's Hospital Bern, Bern, Switzerland

12GReD, CNRS, INSERM, Université Clermont Auvergne, Clermont-Ferrand, France

13Molecular Endocrinology and Rare Diseases, Claude Bernard Lyon 1 University, Bron, France

14Pediatric Endocrinology, Diabetology and Metabolism, Department of BioMedic, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

Find articles by Roucher-Boulez, F. in: JCI | PubMed | Google Scholar |

1Laboratoire de Biochimie et Biologie Moléculaire, UM Pathologies Endocrinie, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France

2Department of Pediatrics, Inselspital, University of Bern, Bern, Switzerland

3Department of Pediatrics, Kantonsspital Graubünden, Chur, Chur, Switzerland

4Génétique, Reproduction & Développement (GReD), CNRS UMR6293, INSERM U1103, Université Clermont Auvergne, Clermont-Ferrand, France

5CNRS, Inserm, GReD, Université Clermont Auvergne, Auvergne, France

6Centre de Biologie et Pathologie Est, CHU de Lyon HCL, Lyon, France

7Endocrinienne Et Moleculaire, INSERM-U 329 - Lab De Biochimie, 69322 Lyon Cedex 05, France

8Department of Rheumatology and Immunology, Inselspital - Bern University Hospital, Bern, Switzerland

9University Institute of Diagnostic and Interventional Neuroradiology, University Hospital Inselspital Bern, Bern, Switzerland

10Molecular Genetics & Developmental Biology and Stem Cell Research, University Medical Center Utrecht, The Netherlands, Utrecht, Netherlands

11Paediatric Endocrinology and Metabolism, University Children's Hospital Bern, Bern, Switzerland

12GReD, CNRS, INSERM, Université Clermont Auvergne, Clermont-Ferrand, France

13Molecular Endocrinology and Rare Diseases, Claude Bernard Lyon 1 University, Bron, France

14Pediatric Endocrinology, Diabetology and Metabolism, Department of BioMedic, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

Find articles by Fluck, C. in: JCI | PubMed | Google Scholar |

Published December 20, 2022 - More info

J Clin Invest. https://doi.org/10.1172/JCI164915.
Copyright © 2022, Lucas et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published December 20, 2022 - Version history
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Abstract

Disorders of isolated mineralocorticoid deficiency causing potentially life-threatening salt-wasting crisis early in life have been associated with gene variants of aldosterone biosynthesis or resistance, but in some patients no such variants are found. WNT/β-catenin signaling is crucial for differentiation and maintenance of the aldosterone producing adrenal zona glomerulosa (zG). We describe a highly consanguineous family with multiple perinatal deaths or infants presenting at birth with failure to thrive, severe salt-wasting crises associated with isolated hypoaldosteronism, nail anomalies, short stature, and deafness. Whole exome sequencing revealed a homozygous splice variant in the R-SPONDIN receptor LGR4 gene (c.618-1G>C) regulating WNT signaling. The resulting transcripts affected protein function and stability, and resulted in loss of Wnt/β-catenin signaling in vitro. The impact of LGR4 inactivation was analyzed by adrenal cortex specific ablation of Lgr4, using Lgr4Flox/Flox mated with Sf1:Cre mice. Inactivation of Lgr4 within the adrenal cortex in the mouse model caused decreased WNT signaling, aberrant zonation with deficient zG and reduced aldosterone production. Thus, human LGR4 mutations establish a direct link between LGR4 inactivation and decreased canonical WNT signaling with abnormal zG differentiation and endocrine function. Therefore, variants in WNT signaling and its regulators should systematically be considered in familial hyperreninemic hypoaldosteronism.

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