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Cystinosis

INTRODUCTION

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, the intermediate (adolescent, late-onset) form; and the adult (benign) form. Nephropathic cystinosis, which is by far the most common, has been estimated to affect one of every 100,000 to 200,000 children, with an incidence of nearly 6 per 100,000 in Newfoundland, Canada [3-5].

PATHOGENESIS

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 transport system [6-10]. Cystine is poorly soluble and forms crystals as its concentration increases.

It is not clear how cystine accumulation results in renal tubular cell dysfunction [2]. A proposed mechanism is cysteinylation of protein kinase delta by accumulated cystine results increased apoptosis of the cystine-laden renal proximal tubular cell leading to tubular dysfunction [11].

Genetics — Cystinosis is transmitted as an autosomal recessive trait. Multiple observations indicate that the same gene is involved in all forms of the disease [12]. Both the infantile and adolescent 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 [13]. 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 nephropathic cystinosis has been mapped to chromosome 17p13 and identified [14]. The gene, CTNS, consists of 12 exons and encodes for a 367 amino acid lysosomal membrane protein, named cystinosin [14-16]. It appears to be a novel hydrogen ion driven transporter that is responsible for exporting cystine from lysosomes [17].
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