Abstract
The human ubiquitous protein cystinosin is responsible for transporting the disulphide amino acid cystine from the lysosomal compartment into the cytosol. In humans, Pathogenic mutations of CTNS lead to defective cystinosin function, intralysosomal cystine accumulation and the development of cystinosis. Kidneys are initially affected with generalized proximal tubular dysfunction (renal Fanconi syndrome), then the disease rapidly affects glomeruli and progresses towards end stage renal failure and multiple organ dysfunction. Animal models of cystinosis are limited, with only a Ctns knockout mouse reported, showing cystine accumulation and late signs of tubular dysfunction but lacking the glomerular phenotype. We established and characterized a mutant zebrafish model with a homozygous nonsense mutation (c.706 C > T; p.Q236X) in exon 8 of ctns. Cystinotic mutant larvae showed cystine accumulation, delayed development, and signs of pronephric glomerular and tubular dysfunction mimicking the early phenotype of human cystinotic patients. Furthermore, cystinotic larvae showed a significantly increased rate of apoptosis that could be ameliorated with cysteamine, the human cystine depleting therapy. Our data demonstrate that, ctns gene is essential for zebrafish pronephric podocyte and proximal tubular function and that the ctns-mutant can be used for studying the disease pathogenic mechanisms and for testing novel therapies for cystinosis.
Highlights
Deplete cystine in the lysosomal compartment and can delay the progression of the disease; it does not prevent the renal Fanconi syndrome and does not restore the lost renal function[3]
The murine model of cystinosis has a milder renal phenotype compared to humans and does not show signs of glomerular dysfunction starting in humans in early childhood[17]
No paralogue gene to ctns has been reported in zebrafish
Summary
Deplete cystine in the lysosomal compartment and can delay the progression of the disease; it does not prevent the renal Fanconi syndrome and does not restore the lost renal function[3]. Zebrafish (Danio rerio) was introduced as an attractive alternative to study pathogenic aspects in many genetic diseases[18,19,20,21,22,23] This is due to their rapid in vitro development, high fecundity, lower maintenance cost, optical transparency of the fertilized embryo, sequenced genome and the availability of gene down-regulation and gene editing technologies[24]. The zebrafish embryonic kidney, which is a functional pronephros, consists of a pair of segmented nephrons sharing a single glomerulus and showing astonishing histologic and functional similarities to the human nephron This structure is formed approximately 24 hours post fertilization (24 hpf) and actual blood filtration starts approximately at 48 hpf 27 offering a rapid and simple anatomical model for nephron patterning[28], disease modelling[29,30], identification of new genes affecting glomerular function and tubulogenesis[16,31,32] and drug testing[33]. We elucidated the main pathophysiological defects causing the diseased phenotype, which can be used for targeting novel therapeutic approaches
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