Cystinosis. Intracellular cystine depletion by aminothiols in vitro and in vivo.

Thoene, Jess G.; Oshima, Robert G.; Crawhall, J. C.; Olson, D.L.; Schneider, Jerry A.

doi:10.1172/jci108448

Cited by 315 publications

(173 citation statements)

References 29 publications

(20 reference statements)

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“…Cysteamine therapy remains the most effective treatment for cystinosis (40)(41)(42). The current model, based on early biochemical data (20,43), posits that the compound enters the lysosome and condenses with lysosomal cystine, thus generating a cysteaminecysteine mixed disulfide (MxD) that resembles lysine (Fig.…”

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confidence: 99%

Heptahelical protein PQLC2 is a lysosomal cationic amino acid exporter underlying the action of cysteamine in cystinosis therapy

Jézégou

Llinares

Anne

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

153

184

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Cystinosin, the lysosomal cystine exporter defective in cystinosis, is the founding member of a family of heptahelical membrane proteins related to bacteriorhodopsin and characterized by a duplicated motif termed the PQ loop. PQ-loop proteins are more frequent in eukaryotes than in prokaryotes; except for cystinosin, their molecular function remains elusive. In this study, we report that three yeast PQ-loop proteins of unknown function, Ypq1, Ypq2, and Ypq3, localize to the vacuolar membrane and are involved in homeostasis of cationic amino acids (CAAs). We also show that PQLC2, a mammalian PQ-loop protein closely related to yeast Ypq proteins, localizes to lysosomes and catalyzes a robust, electrogenic transport that is selective for CAAs and strongly activated at low extracytosolic pH. Heterologous expression of PQLC2 at the yeast vacuole rescues the resistance phenotype of an ypq2 mutant to canavanine, a toxic analog of arginine efficiently transported by PQLC2. Finally, PQLC2 transports a lysine-like mixed disulfide that serves as a chemical intermediate in cysteamine therapy of cystinosis, and PQLC2 gene silencing trapped this intermediate in cystinotic cells. We conclude that PQLC2 and Ypq1–3 proteins are lysosomal/vacuolar exporters of CAAs and suggest that small-molecule transport is a conserved feature of the PQ-loop protein family, in agreement with its distant similarity to SWEET sugar transporters and to the mitochondrial pyruvate carrier. The elucidation of PQLC2 function may help improve cysteamine therapy. It may also clarify the origin of CAA abnormalities in Batten disease.

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confidence: 99%

Heptahelical protein PQLC2 is a lysosomal cationic amino acid exporter underlying the action of cysteamine in cystinosis therapy

Jézégou

Llinares

Anne

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

153

184

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“…When glomerular failure supervenes, dialysis or kidney transplantation is required. In addition, specific therapy directed at intracellular cystine depletion involves administration of oral cysteamine bitartrate, or Cystagon (Mylan Pharmaceuticals, Morgantown, WV) (19). Chronic use of oral cysteamine, now accepted as the treatment of choice for cystinosis throughout the world, retards renal glomerular deterioration (20,21), enhances growth, and obviates the need for l-thyroxine replacement in patients with cystinosis (22).…”

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confidence: 99%

Coronary Artery and Other Vascular Calcifications in Patients with Cystinosis after Kidney Transplantation

Ueda¹,

O’Brien²,

Rosing³

et al. 2006

Clinical Journal of the American Society of Nephrology

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Cystinosis, an autosomal recessive disorder of lysosomal cystine accumulation, results from mutations in the CTNS gene that encodes the lysosomal cystine transporter, cystinosin. Renal tubular Fanconi syndrome occurs in infancy, followed by rickets, growth retardation, photophobia, and renal failure, which requires renal transplantation at approximately 10 yr of age. Treatment with cysteamine decreases cellular cystine levels, retards renal deterioration, and allows for normal growth. Patients with a history of inadequate cystine depletion therapy may survive, after renal transplantation, into the third to fifth decades but will experience other, extrarenal complications of the disease. Routine chest and head computed tomography scans of 41 posttransplantation patients with cystinosis were reviewed for vascular calcification. The radiologic procedures had been performed to examine lung and brain parenchyma, so there was little ascertainment bias. Thirteen of the 41 patients had vascular calcification, including 11 with coronary artery calcification. One 25-yr-old man required three-vessel coronary artery bypass graft surgery. There were no significant differences between the 13 patients with calcification and the 28 without calcification in the following parameters: Time on dialysis, frequency of transplantation, hypertension, hypercholesterolemia, homozygosity for the 57-kb deletion in CTNS, serum creatinine, and calcium-phosphate product. However, the finding of vascular calcification correlated directly with duration of life without cysteamine therapy and inversely with duration of life under good cystine-depleting therapy. The accumulation of intracellular cystine itself maybe a risk factor for vascular calcifications, and older patients with cystinosis should be screened for this complication.

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“…Cystine is the disulfide of the amino acid cysteine, and cysteine has been found to exit the lysosome freely in cystinotic cells, implying that the cysteine transporter is independent of the cystine transporter (12). This finding has been exploited for the treatment of cystinosis as the currently used drug, cysteamine, is an aminothiol that reacts with cystine to form cysteine and a cystein-cysteamine mixed disulfide that can also readily exit the cystinotic lysosome (13). Thus, cysteamine, if used early and in high doses, delays the progression of cystinosis in affected individuals by reducing intra-lysosomal cystine levels (14).…”

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confidence: 99%

The Targeting of Cystinosin to the Lysosomal Membrane Requires a Tyrosine-based Signal and a Novel Sorting Motif

Cherqui

Kalatzis

Trugnan

et al. 2001

Journal of Biological Chemistry

122

120

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Cystinosis is a lysosomal transport disorder characterized by an accumulation of intra-lysosomal cystine. Biochemical studies showed that the lysosomal cystine transporter was distinct from the plasma membrane cystine transporters and that it exclusively transported cystine. The gene underlying cystinosis, CTNS, encodes a predicted seven-transmembrane domain protein called cystinosin, which is highly glycosylated at the N-terminal end and carries a GY-XX-⌽ (where ⌽ is a hydrophobic residue) lysosomal-targeting motif in its carboxyl tail. We constructed cystinosin-green fluorescent protein fusion proteins to determine the subcellular localization of cystinosin in transfected cell lines and showed that cystinosin-green fluorescent protein colocalizes with lysosomal-associated membrane protein 2 (LAMP-2) to lysosomes. Deletion of the GY-XX-⌽ motif resulted in a partial redirection to the plasma membrane as well as sorting to lysosomes, demonstrating that this motif is only partially responsible for the lysosomal targeting of cystinosin and suggesting the existence of a second sorting signal. A complete relocalization of cystinosin to the plasma membrane was obtained after deletion of half of the third cytoplasmic loop (amino acids 280 -288) coupled with the deletion of the GY-DQ-L motif, demonstrating the presence of the second signal within this loop. Using site-directed mutagenesis studies we identified a novel conformational lysosomalsorting motif, the core of which was delineated to YF-PQA (amino acids 281-285).

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Cystinosis. Intracellular cystine depletion by aminothiols in vitro and in vivo.

Cited by 315 publications

References 29 publications

Heptahelical protein PQLC2 is a lysosomal cationic amino acid exporter underlying the action of cysteamine in cystinosis therapy

Heptahelical protein PQLC2 is a lysosomal cationic amino acid exporter underlying the action of cysteamine in cystinosis therapy

Coronary Artery and Other Vascular Calcifications in Patients with Cystinosis after Kidney Transplantation

The Targeting of Cystinosin to the Lysosomal Membrane Requires a Tyrosine-based Signal and a Novel Sorting Motif

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