Lack of complementation in somatic cell hybrids between fibroblasts from patients with different forms of cystinosis.

Pellett, Ocean L.; Smith, Micah J.; Greene, Alice A.; Schneider, Jerry A.

doi:10.1073/pnas.85.10.3531

Cited by 20 publications

(6 citation statements)

References 31 publications

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“…The most common mutation associated with cystinosis is a 57-kilobase (kb) deletion [11,13] that removes the 5′ region of the gene upstream of, and including, exon 10 [14]. CTNS mutations have been detected in all forms of the disease [11,17,18,19,20,21,22,23] confirming their allelic status [24]. Polymerase chain reaction-based de-208 Fig.…”

Section: Causative Gene and Mutationsmentioning

confidence: 99%

New aspects of the pathogenesis of cystinosis

Kalatzis

Antignac

2003

Pediatr Nephrol

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Cystinosis is a lysosomal transport disorder characterized by an intra-lysosomal accumulation of cystine, the disulfide of the amino acid cysteine. It is the most common inherited cause of the renal Fanconi syndrome. There are various clinical forms, infantile, juvenile, and ocular, based on age of onset and severity of symptoms. The first clinical description appeared in the early 1900s, but it was not until 1998 that the causative gene, CTNS, was identified. CTNS encodes cystinosin, a novel seven transmembrane domain (TM) protein. Cystinosin is a lysosomal membrane protein that requires two lysosomal targeting signals: a classic GYDQL motif in its C-terminal tail and a novel conformational motif, the core of which is YFPQA, situated in the fifth inter-TM loop. Cystinosin is the lysosomal cystine transporter and its activity is H + -driven. A mouse model of cystinosis was recently generated and Ctns -/mice accumulate cystine in all tissues. A high level of cystine accumulates in the kidney, but these mice do not present with proximal tubulopathy or renal dysfunction. The Ctns -/mouse model may provide clues to the cause of the Fanconi syndrome associated with cystinosis, the origin of which remains poorly understood.

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Section: Causative Gene and Mutationsmentioning

confidence: 99%

New aspects of the pathogenesis of cystinosis

Kalatzis

Antignac

2003

Pediatr Nephrol

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“…Further clinical signs, such as diabetes, portal hypertension, hypothyroidism, and hypogonadism, as well as muscular and neurological deterioration, subsequently appear due to the accumulation of cystine in all tissues (17). Two other less-severe forms, juvenile and ocular cystinosis, have also been described and have been shown to be allelic by complementation studies (27). The juvenile form (MIM 219900) usually appears between 12 and 15 years, and affected individuals present with photophobia and glomerular renal impairment but not necessarily the Fanconi syndrome (17).…”

mentioning

confidence: 99%

Intralysosomal Cystine Accumulation in Mice Lacking Cystinosin, the Protein Defective in Cystinosis

Cherqui

Sevin

Hamard

et al. 2002

Molecular and Cellular Biology

149

143

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Cystinosis is an autosomal recessive disorder characterized by an accumulation of intralysosomal cystine. The causative gene, CTNS, encodes cystinosin, a seven-transmembrane-domain protein, which we recently showed to be a lysosomal cystine transporter. The most severe and frequent form of cystinosis, the infantile form, appears around 6 to 12 months, with a proximal tubulopathy (de Toni-Debré-Fanconi syndrome) and ocular damage. End-stage renal failure is reached by 10 years of age. Accumulation of cystine in all tissues eventually leads to multisystemic disease. Treatment with cysteamine, which reduces the concentration of intracellular cystine, delays disease progression but has undesirable side effects. We report the first Ctns knockout mouse model generated using a promoter trap approach. We replaced the last four Ctns exons by an internal ribosome entry site-␤gal-neo cassette and showed that the truncated protein was mislocalized and nonfunctional. Ctns ؊/؊ mice accumulated cystine in all organs tested, and cystine crystals, pathognomonic of cystinosis, were observed. Ctns ؊/؊ mice developed ocular changes similar to those observed in affected individuals, bone defects and behavioral anomalies. Interestingly, Ctns ؊/؊ mice did not develop signs of a proximal tubulopathy, or renal failure. A preliminary therapeutic trial using an oral administration of cysteamine was carried out and demonstrated the efficiency of this treatment for cystine clearance in Ctns ؊/؊ mice. This animal model will prove an invaluable and unique tool for testing emerging therapeutics for cystinosis.

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“…One report suggests that significant residual lysosomal transport activity (9-29%) remains in the benign form, but no significant lysosomal transport of cystine was seen in fibroblasts from an intermediate type [34]. Complementation analysis by somatic cell hybridization between the nephropathic and benign types, or between the nephropathic and intermediate types, showed no complementation with either cross [35]. These results suggest that all three forms of eystinosis are allelic mutations.…”

Section: L-fucosementioning

confidence: 93%