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Mutations in GREB1L Cause Bilateral Kidney Agenesis in Humans and Mice.
Am J Hum Genet 2017; 101(5):803-814AJ

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.

Authors+Show Affiliations

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.Transgenesis Platform, Laboratoire d'Expérimentation Animale et Transgenèse (LEAT), Imagine Institute, Structure Fédérative de Recherche Necker INSERM US24/CNRS UMS3633, 75015 Paris, France.Laboratory of Hereditary Kidney Diseases, INSERM UMR 1163, Imagine Institute, 75015 Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.Laboratory of Hereditary Kidney Diseases, INSERM UMR 1163, Imagine Institute, 75015 Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.Laboratory of Hereditary Kidney Diseases, INSERM UMR 1163, Imagine Institute, 75015 Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.Bioinformatic Platform, INSERM UMR 1163, Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.Imaging Platform, Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR_S968 and CNRS UMR7210, Institut de la Vision, 75012 Paris, France.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.APHP, Pediatric Nephrology Department, Hôpital Robert Debré, 75019 Paris, France.Genomic Platform, INSERM UMR 1163, Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.Bioinformatic Platform, INSERM UMR 1163, Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.Unité de Génétique Médicale, Centre de Référence des Maladies rares du Développement (AnD DI Rares), CHI Poissy - St Germain en Laye, 78300 Poissy, France.Service de Génétique, Groupement Hospitalier Est, 69677 Bron, France.Unité de Néphrologie Pédiatrique, CHU Reims, 51100 Reims, France.Service de Génétique Médicale, CHU Nantes, 44093 Nantes, France.Unité de Génétique Médicale, Nîmes University Hospital, CHU Carémeau, 30900 Nîmes, France.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.APHP, Département de Génétique, Unité de Fœtopathologie, Hôpital Robert Debré, 75019 Paris, France.APHP, Unit of Fetal Pathology, Antoine Béclère Hospital, 92140 Clamart, France.Centre Hospitalier Universitaire de Lille, Hôpital Jeanne de Flandre, Service de Néphrologie Pédiatrique, 59000 Lille, France.Centre de Génétique Humaine, CHU Besançon, Université de Franche-Comté, 25000 Besançon, France.Centre de Génétique Humaine, CHU Besançon, Université de Franche-Comté, 25000 Besançon, France.Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi 110060, India.Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi 110060, India.Service de Génétique Médicale, Hôpital Chubert, 56000 Vannes, France.Département d'Anatomie et Cytologie Pathologiques, IUCT-Oncopole, 31100 Toulouse, France.Service de Gynécologie-Obstétrique, Hôpital Louis Mourier, 92700 Colombes, France.Service de Pédiatrie, Hôpitaux du Léman, 74203 Thonon les Bains, France.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.Laboratory of Hereditary Kidney Diseases, INSERM UMR 1163, Imagine Institute, 75015 Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.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.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29100091

Citation

De Tomasi, Lara, et al. "Mutations in GREB1L Cause Bilateral Kidney Agenesis in Humans and Mice." American Journal of Human Genetics, vol. 101, no. 5, 2017, pp. 803-814.
De Tomasi L, David P, Humbert C, et al. Mutations in GREB1L Cause Bilateral Kidney Agenesis in Humans and Mice. Am J Hum Genet. 2017;101(5):803-814.
De Tomasi, L., David, P., Humbert, C., Silbermann, F., Arrondel, C., Tores, F., ... Jeanpierre, C. (2017). Mutations in GREB1L Cause Bilateral Kidney Agenesis in Humans and Mice. American Journal of Human Genetics, 101(5), pp. 803-814. doi:10.1016/j.ajhg.2017.09.026.
De Tomasi L, et al. Mutations in GREB1L Cause Bilateral Kidney Agenesis in Humans and Mice. Am J Hum Genet. 2017 Nov 2;101(5):803-814. PubMed PMID: 29100091.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mutations in GREB1L Cause Bilateral Kidney Agenesis in Humans and Mice. AU - De Tomasi,Lara, AU - David,Pierre, AU - Humbert,Camille, AU - Silbermann,Flora, AU - Arrondel,Christelle, AU - Tores,Frédéric, AU - Fouquet,Stéphane, AU - Desgrange,Audrey, AU - Niel,Olivier, AU - Bole-Feysot,Christine, AU - Nitschké,Patrick, AU - Roume,Joëlle, AU - Cordier,Marie-Pierre, AU - Pietrement,Christine, AU - Isidor,Bertrand, AU - Khau Van Kien,Philippe, AU - Gonzales,Marie, AU - Saint-Frison,Marie-Hélène, AU - Martinovic,Jelena, AU - Novo,Robert, AU - Piard,Juliette, AU - Cabrol,Christelle, AU - Verma,Ishwar C, AU - Puri,Ratna, AU - Journel,Hubert, AU - Aziza,Jacqueline, AU - Gavard,Laurent, AU - Said-Menthon,Marie-Hélène, AU - Heidet,Laurence, AU - Saunier,Sophie, AU - Jeanpierre,Cécile, PY - 2017/07/10/received PY - 2017/09/28/accepted PY - 2017/11/4/entrez PY - 2017/11/4/pubmed PY - 2017/11/14/medline KW - 3DISCO KW - CAKUT KW - GREB1L KW - genital tract KW - heart defect KW - kidney agenesis KW - kidney development KW - mouse model KW - nephrogenesis KW - tubulogenesis SP - 803 EP - 814 JF - American journal of human genetics JO - Am. J. Hum. Genet. VL - 101 IS - 5 N2 - 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. SN - 1537-6605 UR - https://www.unboundmedicine.com/medline/citation/29100091/Mutations_in_GREB1L_Cause_Bilateral_Kidney_Agenesis_in_Humans_and_Mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0002-9297(17)30418-4 DB - PRIME DP - Unbound Medicine ER -