Mutations in GREB1L Cause Bilateral Kidney Agenesis in Humans and Mice.

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: Lara De Tomasi, Pierre David, Camille Humbert, Flora Silbermann, Christelle Arrondel, Frédéric Tores, Stéphane Fouquet, Audrey Desgrange, Olivier Niel, Christine Bole-Feysot, Patrick Nitschké, Joëlle Roume, Marie-Pierre Cordier, Christine Pietrement, Bertrand Isidor, Philippe Khau Van Kien, Marie Gonzales, Marie-Hélène Saint-Frison, Jelena Martinovic, Robert Novo, Juliette Piard, Christelle Cabrol, Ishwar C Verma, Ratna Puri, Hubert Journel, Jacqueline Aziza, Laurent Gavard, Marie-Hélène Said-Menthon, Laurence Heidet, Sophie Saunier, Cécile Jeanpierre
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 101 Issue 5 Pg. 803-814 (Nov 02 2017) ISSN: 1537-6605 [Electronic] United States
• PMID: 29100091 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Chemical References

• GREB1 protein, human
• KIAA0575 protein, mouse
• Membrane Proteins
• Neoplasm Proteins
• Proteins

Topics

• Animals
• Child
• Congenital Abnormalities (genetics)
• Exome (genetics)
• Female
• Fetus (abnormalities)
• Heterozygote
• Humans
• Kidney (abnormalities)
• Kidney Diseases (congenital, genetics)
• Male
• Membrane Proteins
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mutation (genetics)
• Neoplasm Proteins (genetics)
• Phenotype
• Proteins (genetics)
• Urinary Tract (abnormalities)
• Urogenital Abnormalities (genetics)