Modelling Lowe syndrome and Dent-2 disease using zebrafish

Abstract

Lowe syndrome and Dent-2 disease are caused by mutations in the gene encoding OCRL, an inositol 5-phosphatase. The phenotype manifests in the eyes, brain and kidney, with the extra-renal features milder in the case of Dent-2 disease. Zebrafish has been used to study OCRL function in vivo and to successfully model these two rare genetic conditions. OCRL-deficient zebrafish have neurodevelopmental defects, which may lie downstream of disrupted endosomal trafficking or primary cilia function. OCRL-deficient zebrafish also have a renal tubular phenotype, with defective endocytosis, abnormal lysosomal function, and shortening of the renal tubule. These defects can account for the low molecular weight proteinuria seen in Lowe syndrome and Dent-2 disease and may explain the other renal features seen in both conditions. Chemical and genetic rescue experiments indicate that zebrafish can be used to test potential therapeutic approaches for Lowe syndrome and Dent-2 disease, raising the possibility of a phenotypic screen for these conditions in zebrafish. Alongside other models, zebrafish has proven its worth in studying Lowe syndrome and Dent-2 disease and should continue to serve as a valuable model going forwards.

Keywords: Dent-2 disease; Lowe syndrome; ciliogenesesis; endocytosis; neurological; renal; zebrafish.

FIGURE 1

Summary of the zebrafish OCRL model phenotypes. Indicated are the neurological and renal phenotypes observed in the different OCRL-deficient zebrafish models.

FIGURE 2

Renal impairment in the OCRL zebrafish model and possible drug screening approach. (A) Loss of endocytic tracer uptake in zebrafish OCRL genetrap mutant larvae shown by fluorescence microscopy, indicating defective endocytosis. Note that uptake normally occurs in the proximal region of the larval kidney tubule, as is the case in the mammalian nephron. (B) High throughput assay for drug screening in zebrafish larvae. The nanoluciferase (NL)-receptor associated protein D3 region (D3) reporter is expressed in the liver and secreted into the bloodstream, from where it is filtered at the glomerulus and reabsorbed into the proximal tubule by endocytosis. Defective glomerular filtration or renal tubular absorption results in the reporter being excreted into the water, which can be measured by luminescence. The high throughput format allows for chemical screening to identify compounds that reduce urinary excretion of the reporter and rescue the phenotype.