2. Academic Validation
  3. Mutations in GREB1L Cause Bilateral Kidney Agenesis in Humans and Mice

Mutations in GREB1L Cause Bilateral Kidney Agenesis in Humans and Mice

  • Am J Hum Genet. 2017 Nov 2;101(5):803-814. doi: 10.1016/j.ajhg.2017.09.026.
Lara De Tomasi 1,  Pierre David 2,  Camille Humbert 3,  Flora Silbermann 3,  Christelle Arrondel 3,  Frédéric Tores 4,  Stéphane Fouquet 5,  Audrey Desgrange 6,  Olivier Niel 7,  Christine Bole-Feysot 8,  Patrick Nitschké 4,  Joëlle Roume 9,  Marie-Pierre Cordier 10,  Christine Pietrement 11,  Bertrand Isidor 12,  Philippe Khau Van Kien 13,  Marie Gonzales 14,  Marie-Hélène Saint-Frison 15,  Jelena Martinovic 16,  Robert Novo 17,  Juliette Piard 18,  Christelle Cabrol 18,  Ishwar C Verma 19,  Ratna Puri 19,  Hubert Journel 20,  Jacqueline Aziza 21,  Laurent Gavard 22,  Marie-Hélène Said-Menthon 23,  Laurence Heidet 24,  Sophie Saunier 3,  Cécile Jeanpierre 25
Affiliations

Affiliations

  • 1 Laboratory of Hereditary Kidney Diseases, INSERM UMR 1163, Imagine Institute, 75015 Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France; Paris Diderot University, 75013 Paris, France.
  • 2 Transgenesis Platform, Laboratoire d'Expérimentation Animale et Transgenèse (LEAT), Imagine Institute, Structure Fédérative de Recherche Necker INSERM US24/CNRS UMS3633, 75015 Paris, France.
  • 3 Laboratory of Hereditary Kidney Diseases, INSERM UMR 1163, Imagine Institute, 75015 Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.
  • 4 Bioinformatic Platform, INSERM UMR 1163, Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.
  • 5 Imaging Platform, Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR_S968 and CNRS UMR7210, Institut de la Vision, 75012 Paris, France.
  • 6 Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France; Laboratory of Heart Morphogenesis, INSERM UMR 1163, Imagine Institute-Pasteur Institute, 75015 Paris, France.
  • 7 APHP, Pediatric Nephrology Department, Hôpital Robert Debré, 75019 Paris, France.
  • 8 Genomic Platform, INSERM UMR 1163, Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.
  • 9 Unité de Génétique Médicale, Centre de Référence des Maladies rares du Développement (AnD DI Rares), CHI Poissy - St Germain en Laye, 78300 Poissy, France.
  • 10 Service de Génétique, Groupement Hospitalier Est, 69677 Bron, France.
  • 11 Unité de Néphrologie Pédiatrique, CHU Reims, 51100 Reims, France.
  • 12 Service de Génétique Médicale, CHU Nantes, 44093 Nantes, France.
  • 13 Unité de Génétique Médicale, Nîmes University Hospital, CHU Carémeau, 30900 Nîmes, France.
  • 14 APHP, Département de Génétique Médicale, Hôpital Armand Trousseau, Université Pierre et Marie Curie, 75571 Paris, France and APHP, Unité d'EmbryoFœtopathologie, Service d'Histologie-Embryologie-Cytogénétique, Hôpital Necker-Enfants Malades, 75015 Paris, France.
  • 15 APHP, Département de Génétique, Unité de Fœtopathologie, Hôpital Robert Debré, 75019 Paris, France.
  • 16 APHP, Unit of Fetal Pathology, Antoine Béclère Hospital, 92140 Clamart, France.
  • 17 Centre Hospitalier Universitaire de Lille, Hôpital Jeanne de Flandre, Service de Néphrologie Pédiatrique, 59000 Lille, France.
  • 18 Centre de Génétique Humaine, CHU Besançon, Université de Franche-Comté, 25000 Besançon, France.
  • 19 Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi 110060, India.
  • 20 Service de Génétique Médicale, Hôpital Chubert, 56000 Vannes, France.
  • 21 Département d'Anatomie et Cytologie Pathologiques, IUCT-Oncopole, 31100 Toulouse, France.
  • 22 Service de Gynécologie-Obstétrique, Hôpital Louis Mourier, 92700 Colombes, France.
  • 23 Service de Pédiatrie, Hôpitaux du Léman, 74203 Thonon les Bains, France.
  • 24 APHP, Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte (MARHEA), Hôpital Necker-Enfants Malades, 75015 Paris, France; APHP, Service de Néphrologie Pédiatrique, Hôpital Necker-Enfants Malades, 75015 Paris, France.
  • 25 Laboratory of Hereditary Kidney Diseases, INSERM UMR 1163, Imagine Institute, 75015 Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France. Electronic address: cecile.jeanpierre@inserm.fr.
PMID: 29100091 DOI: 10.1016/j.ajhg.2017.09.026
Abstract

Congenital anomalies of the kidney and urinary tract (CAKUT) constitute a major cause of chronic kidney disease in children and 20% of prenatally detected anomalies. CAKUT encompass a spectrum of developmental kidney defects, including renal agenesis, hypoplasia, and cystic and non-cystic dysplasia. More than 50 genes have been reported as mutated in CAKUT-affected case subjects. However, the pathophysiological mechanisms leading to bilateral kidney agenesis (BKA) remain largely elusive. Whole-exome or targeted exome Sequencing of 183 unrelated familial and/or severe CAKUT-affected case subjects, including 54 fetuses with BKA, led to the identification of 16 heterozygous variants in GREB1L (growth regulation by estrogen in breast Cancer 1-like), a gene reported as a target of retinoic acid signaling. Four loss-of-function and 12 damaging missense variants, 14 being absent from GnomAD, were identified. Twelve of them were present in familial or simplex BKA-affected case subjects. Female BKA-affected fetuses also displayed uterus agenesis. We demonstrated a significant association between GREB1L variants and BKA. By in situ hybridization, we showed expression of Greb1l in the nephrogenic zone in developing mouse kidney. We generated a Greb1l knock-out mouse model by CRISPR-Cas9. Analysis at E13.5 revealed lack of kidneys and genital tract anomalies in male and female Greb1l-/- embryos and a slight decrease in ureteric bud branching in Greb1l+/- embryos. We showed that Greb1l invalidation in mIMCD3 cells affected tubulomorphogenesis in 3D-collagen culture, a phenotype rescued by expression of the wild-type human protein. This demonstrates that GREB1L plays a major role in early metanephros and genital development in mice and humans.

Keywords

3DISCO; CAKUT; GREB1L; genital tract; heart defect; kidney agenesis; kidney development; mouse model; nephrogenesis; tubulogenesis.

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