2 Cystinosis (ctns) zebrafish mutant shows pronephric glomerular and tubular dysfunction 19 Introduction Nephropathic cystinosis (MIM 219800) is an autosomal recessive lysosomal storage disorder characterized by the accumulation of the amino-acid cystine in the lysosomes of different body cells. It is caused by pathogenic mutations in the human CTNS gene encoding for cystinosin, the protein transporting cystine out of lysosomes1. In humans, cystinotic infants are born asymptomatic and stay healthy with normal growth parameters until approximately 6 months of life. After 6 months, infants manifest with dehydration, polyuria, polydipsia and rickets. The kidneys are initially affected in the form of defective proximal tubular reabsorption and increased urinary losses of amino-acids, glucose, phosphate, bicarbonate and proteins, or what is known as the renal Fanconi syndrome; however, this is usually rapidly followed by progressive glomerular damage, stunted growth and multiple organ dysfunction2. The aminothiol cysteamine, currently used as a specific treatment for cystinosis, can successfully deplete cystine in the lysosomal compartment and can delay the progression of the disease; however, it does not prevent the renal Fanconi syndrome and does not restore the lost renal function3. Over the past decade much interest has been given to study different pathogenic mechanisms of nephropathic cystinosis in an attempt to find better therapeutic agents targeting mechanisms other than cystine accumulation like autophagy4,5, oxidative stress6,7 and inflammation8,9. A successful mouse model for cystinosis was developed recently10 and was beneficial in revealing many pathogenic aspects of the disease11-15. However, the experimentation on mammalian models is usually time consuming, expensive and limited to a small number of test subjects16. Moreover, 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 childhood17. Zebrafish (Danio rerio) was introduced as an attractive alternative to study pathogenic aspects in many genetic diseases18-23. This isdue 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 technologies24. Furthermore, they emerged as a promising vertebrate model to study renal biology and associated medical conditions, especially in the fish embryonic and larval stages25,26. 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 hpf27 offering a rapid and simple anatomical model for nephron
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