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Abstract: TH-PO705

Exome Sequencing in Human Bladder Exstrophy and Knockdown Studies in Zebrafish Implicate SLC20A1 as Candidate Gene and Major Regulator of Urinary Tract Development

Session Information

Category: Genetic Diseases of the Kidney

  • 1002 Genetic Diseases of the Kidney: Non-Cystic


  • Schmidt, Johanna Magdalena M., Faculty of Medicine, University of Bonn, Bonn, Germany
  • Yilmaz, Öznur, Faculty of Medicine, University of Bonn, Bonn, Germany
  • Zhang, Rong, Faculty of Medicine, University of Bonn, Bonn, Germany
  • Japp, Anna Sophia, Faculty of Medicine, University of Bonn, Bonn, Germany
  • Reutter, Heiko M., Faculty of Medicine, University of Bonn, Bonn, Germany
  • Odermatt, Benjamin, Faculty of Medicine, University of Bonn, Bonn, Germany

Bladder exstrophy-epispadias complex (BEEC) represents the severe end of human congenital anomalies of the kidney and urinary tract (CAKUT). Exome and Sanger sequencing in BEEC patients identified two novel de novo variants (p.G237R; p.V298A) and one novel maternally transmitted variant (p.K441Q) from an affected mother in SLC20A1. All three variants were predicted to be disease causing.
SLC20A1 encodes for a Na+/PO4 cotransporter known to play a role in proliferation and TNF-induced apoptosis. We investigated the developmental function of slc20a1a in developing zebrafish larvae (zfl) performing Morpholino (MO) knockdown (KD) experiments.
The urinary tract in zfl consists of two pronephric ducts, similar in segmentation to human nephrons, that fuse at the cloaca. Slc20a1a is frequently used as pronephric in situ hybridization (ISH) marker.


Slc20a1a KD was done by injecting ATG-binding MOs in 1-2 cell staged eggs, blocking the gene’s translation. Specificity was shown by Western Blot and rescue experiments by co-injection of human mRNA transcripts of SLC20A1. For phenotype characterization different assays were used such as sulforhodamine 101 excretion, ISH, immunohistochemistry (IHC) on paraffin sections and the transgenic zf reporter line Tg(wt1b:GFP).


MO KD of slc20a1a in zfl results in a severe lethal phenotype affecting multiple organ systems. Focusing on urinary tract, we see formation of pronephric cysts and disorganization of the cloaca. Excretion assay uncovers severe opening defects of the cloaca for the intestine, similar to our index patient with cloacal exstrophy and an imperforate anus. Yolk endocytosis defects resemble abdominal wall fusion deficiencies. IHC shows defects in proliferation and apoptosis.


Our data suggests slc20a1a as major player in urinary tract development of zf. Mild MO phenotypes present with urinary tract abnormalities. Severe MO phenotypes present with a high lethality among zfl - underlining the overall importance of slc20a1a during embryonic development. In conclusion, exome sequencing in human bladder exstrophy and developmental biology studies in zfl implicate SLC20A1 as disease gene for human BEEC and therefore CAKUT and as major regulator of urinary tract development.