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Kidney Week

Abstract: TH-PO691

A Novel Zebrafish Drug-Screening Model for Cystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidney

  • 1001 Genetic Diseases of the Kidney: Cystic


  • Khosravi, Maryam, University College London, London , United Kingdom
  • Nazmutdinova, Katia, University College London , London, United Kingdom
  • Martins, Tiago, University College London , London, United Kingdom
  • Beales, Philip, University College London , London, United Kingdom
  • Giles, Rachel H., University Medical Center Utrecht, Utrecht, Netherlands
  • Wilson, Stephen, University College London, London , United Kingdom

Cystic kidney disease affects millions of people worldwide, and is most commonly associated with dysfunction of cilia. Ciliopathies are a highly heterogeneous disease group, continually expanding with the discovery of new genes and availability of genetic diagnostics. However, treatment options for ciliopathy lag far behind. We are using zebrafish to understand the genetic basis of ciliopathies and we have identified a new zebrafish model of ciliopathy that manifests cysts in the pronephric kidney of the zebrafish embryo and have developed this model for drug discovery.


In a forward genetic approach, mutagenesis of the zebrafish genome was carried out using an alkylating agent to cause random mutations, followed by screening over several generations to select for phenotypes of interest; which included body curvature and organ laterality defects. Further phenotypic characterisation of one mutant line revealed pronephric cysts. RNA sequencing was conducted to find a missense mutation in the highly conserved WD-40 domain of the Intraflagellar Transport protein - Ift144. This ciliopathy model was then used to screen selected drugs with known effect on kidney cysts. Zebrafish were dechorionated at 24 hours post fertilisation and exposed to treatment (drug in DMSO solvent, in E3 media) at 28°C until 4 days post fertilisation, and assessed under brightfield microscopy.


The cyst area of ift144 -/- embryos was measured repeatedly across three independent experiments to ensure both experimental and biological repeats. We observed significant reduction of cyst size compared to control, by Student’s t-test for all treatment groups (see figure).


We present a novel zebrafish model for ciliopathy with a mutation in the ciliary gene ift144, which consistently presents with kidney cysts that can be rescued with drugs that are known to ameliorate cyst size. This model has significant advantages for use as a high throughput drug-screening system.