Mutations in GREB1L Cause Bilateral Kidney Agenesis in Humans and Mice

American Journal of Human Genetics
Lara De TomasiCécile Jeanpierre

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 genera...Continue Reading

Citations

Nov 6, 2018·Human Molecular Genetics·Madeline Louise ReillyAlexandre Benmerah
Aug 26, 2018·Journal of the American Society of Nephrology : JASN·Amelie T van der VenFriedhelm Hildebrandt
Aug 10, 2018·Nature Reviews. Nephrology·Zachary WareJoncasStephen C Ekker
Aug 19, 2020·Nature Reviews. Nephrology·Emily E GroopmanAli G Gharavi
Aug 21, 2020·Orphanet Journal of Rare Diseases·Morten Krogh HerlinMats Brännström
May 16, 2019·Journal of the American Society of Nephrology : JASN·Sophia Cameron-ChristieAli G Gharavi
Feb 15, 2020·Indian Journal of Pediatrics·Veronica AroraIshwar Chander Verma
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Jul 1, 2020·Genetic Testing and Molecular Biomarkers·Ancong WangXiangyu Zhao
Feb 7, 2021·European Journal of Medical Genetics·Isaac Kyei Barffour, Roselind Kyei Baah Kwarkoh
Jan 15, 2021·Differentiation; Research in Biological Diversity·Rex A HessBarry T Hinton
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