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Journal Articles American Journal of Human Genetics Year : 2017

Mutations in GREB1L Cause Bilateral Kidney Agenesis in Humans and Mice

Marie-Pierre Cordier
  • Function : Author
Marie-Hélène Saint-Frison
  • Function : Author
Robert Novo
  • Function : Author
Juliette Piard
  • Function : Author
Hubert Journel
  • Function : Author
Jacqueline Aziza
  • Function : Author
Laurent Gavard
  • Function : Author
Marie-Hélène Said-Menthon
  • Function : Author
Laurence Heidet
  • Function : Author


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.
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Dates and versions

pasteur-03931320 , version 1 (09-01-2023)





Lara de Tomasi, Pierre David, Camille Humbert, Flora Silbermann, Christelle Arrondel, et al.. Mutations in GREB1L Cause Bilateral Kidney Agenesis in Humans and Mice. American Journal of Human Genetics, 2017, 101 (5), pp.803-814. ⟨10.1016/j.ajhg.2017.09.026⟩. ⟨pasteur-03931320⟩
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