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Patrick Niaudet, MD
Section Editor
Tej K Mattoo, MD, DCH, FRCP
Deputy Editor
Melanie S Kim, MD


Cystinosis is a metabolic disease characterized by an accumulation of cystine in different organs and tissues, leading to potentially severe organ dysfunction [1,2]. Three forms of cystinosis have been described: the infantile (nephropathic) form (MIM #219800), the late-onset (juvenile) form (MIM #219900); and the adult (benign) form (MIM #219750). Nephropathic cystinosis, which is by far the most common, has been estimated to affect 1 of every 100,000 to 200,000 children, with an incidence of nearly 6 per 100,000 in Newfoundland, Canada [3-5].


Cystine is derived from protein degradation within the lysosomes of cells. Free cystine is normally transported through the lysosomal membrane to the cytosol where it is reutilized after its transformation to cysteine. In cystinosis, cystine accumulates inside the lysosomes because of a defect in the gene that encodes cystinosin, the protein that transports cystine across the lysosomal membrane [6-10]. Cystine is poorly soluble and forms crystals as its concentration increases.

It is not clear how cystine accumulation results in cellular dysfunction [2]. A proposed mechanism is cysteinylation of protein kinase delta by accumulated cystine resulting in increased apoptosis of the cystine-laden renal proximal tubular cell, which causes tubular dysfunction [11]. It has also been shown that cystine accumulation in proximal tubular cells in vitro is associated with ATP depletion and inhibition of Na+ dependent transporters [12,13]. A study using a cystinosin knockout mice model showed decreased expression of megalin, cubilin, and sodium transporters at the apical surface of proximal tubular cells [14]. Inhibition of adenylate cyclase activity by cystine in rat brain is prevented by cysteamine [15]. In addition, cellular cystine accumulation may inhibit pyruvate kinase and creatine kinase activity in rat brain or pig retina [16-18]. Cystine depletes the glutathione cell pool, thereby favoring oxidative stress and apoptosis [19,20].

Genetics — Cystinosis is transmitted as an autosomal recessive trait. Multiple observations indicate that the same gene is involved in all forms of the disease [21]. Both the infantile and juvenile forms can occur in a given family. In addition, complementation studies using fibroblasts from patients' different types of cystinosis have shown the absence of correction of the metabolic defect [22]. It therefore appears that there is no genetic heterogeneity and that the differences in the clinical manifestations result from mutations occurring in a single gene (allelic mutation).

The gene for cystinosis has been mapped to chromosome 17p13 and identified [23]. The gene, CTNS, consists of 12 exons and encodes for a 367 amino acid lysosomal membrane protein, named cystinosin [23-25]. It appears to be a novel hydrogen ion driven transporter that is responsible for exporting cystine from lysosomes [26].


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Literature review current through: Sep 2016. | This topic last updated: Dec 21, 2015.
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