Glenn van de Hoek
Thesis: Functional modeling of genetic renal disease in the zebrafish
Promotor: Prof. dr. N.V.A.M. Knoers
Copromotoren: Dr. R.H. Giles, Dr. K.Y. Renkema
Defense date: 27 November 2018
Establishing a relationship between genotype and phenotype remains one of the most challenging issues in human genetics, as we aim to provide patients with predictions of disease progress and potential response to therapeutics based on their genetic data. The genetics landscape of human disease can be extremely complicated and -in many cases- unexplainable with our current understanding of (disease) genetics. Add to that the ever-expanding complexity of human disease phenotypes and linking the fields of genotype and phenotype can become a difficult problem. Animal models have had an important role in resolving genotype-phenotype correlations and will continue to do so.
In my thesis I have presented the zebrafish model as a tool to understand the genetic influences behind human congenital kidney disease. We have modeled several candidate gene variants and demonstrated pathogenicity. Furthermore, we have accurately modeled disease phenotypes in zebrafish for several genes: We demonstrate a link between mutations in transmembrane protein 104 (TMEM104) and autosomal dominant tubulointerstitial kidney disease (ADTKD). We show a renal phenotype in a zebrafish model for von Hippel-Lindau (VHL) syndrome. We uncover a role for a classic primary ciliary dyskinesia (PCD) gene, dynein axonemal assembly factor 1 (DNAAF1), associated with renal cysts in zebrafish, in human and zebrafish congenital heart disease, and we have developed a novel zebrafish model for human nephropathic cystinosis.
The zebrafish is an established model in the field of development biology, and in recent decades we and others have adapted this model organism to functionally test variant alleles for diagnostic support. With favorable characteristics such as rapid transparent development and high progeny numbers, and with the recent advances in mutagenesis protocols as shown in my thesis, the zebrafish model organism is likely to gain a prominent role in the genetics field as the community aims to model thousands of disease candidate genes and alleles.