Renal and Extra Renal Manifestations in Adult Zebrafish Model of Cystinosis.

Sante Princiero Berlingerio,Tomas Norton,Junling He,Pieter Baatsen,Lies De Groef,Bianca Goffredo,Lambertus Van Den Heuvel,Hans J Baelde,Harold Taeter,Sara Cairoli,Elena Levtchenko,Peter De Witte

doi:10.3390/ijms22179398

Abstract

Cystinosis is a rare, incurable, autosomal recessive disease caused by mutations in the CTNS gene. This gene encodes the lysosomal cystine transporter cystinosin, leading to lysosomal cystine accumulation in all cells of the body, with kidneys being the first affected organs. The current treatment with cysteamine decreases cystine accumulation, but does not reverse the proximal tubular dysfunction, glomerular injury or loss of renal function. In our previous study, we have developed a zebrafish model of cystinosis through a nonsense mutation in the CTNS gene and have shown that zebrafish larvae recapitulate the kidney phenotype described in humans. In the current study, we characterized the adult cystinosis zebrafish model and evaluated the long-term effects of the disease on kidney and extra renal organs through biochemical, histological, fertility and locomotor activity studies. We found that the adult cystinosis zebrafish presents cystine accumulation in various organs, altered kidney morphology, impaired skin pigmentation, decreased fertility, altered locomotor activity and ocular anomalies. Overall, our data indicate that the adult cystinosis zebrafish model reproduces several human phenotypes of cystinosis and may be useful for studying pathophysiology and long-term effects of novel therapies.

Highlights

Cystinosis is an autosomal recessive storage disorder caused by mutations in the CTNS gene which encodes the lysosomal cystine proton co-transporter cystinosin, carrying cystine from the lysosomal lumen to the cytosol
We found a 54-fold increase in cystine content in the whole body (Figure 1A) and a 146-fold increase in the kidney (Figure 1B) of ctns−/− zebrafish compared with wild-type zebrafish
Cystinosis has transformed from a fatal disease of childhood into a treatable metabolic disorder with which patients can survive into adulthood and reach advanced age [21,22]

Summary

Introduction

Cystinosis is an autosomal recessive storage disorder caused by mutations in the CTNS gene which encodes the lysosomal cystine proton co-transporter cystinosin, carrying cystine from the lysosomal lumen to the cytosol. The current therapeutic approach consists of cysteamine, which is a cystine-depleting amino thiol that breaks the disulfide bridge of cystine, resulting in the formation of amino acid cysteine and a cysteamine-cysteine mixed disulfide. This latter molecule can exit lysosomes via the amino acid transporter PQLC2 [2]. One of the most used models is the Ctns−/− C57BL/6 mouse, which develops cystine accumulation and mild proximal tubulopathy It does not show glomerular damage and the phenotype has been found dependent on the genetic background [8]

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Conclusion