Cystinosis: from gene to disease

Kalatzis, Vasiliki

doi:10.1093/ndt/17.11.1883

Cited by 39 publications

(35 citation statements)

References 22 publications

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“…Apparently, this common mutation is restricted to the Northern European/American populations and, to a lesser extent, to countries of possible genetic contact as in Italy (Mason et al 2003) and Mexico (AlcÄntara-Ortigoza et al 2008). This supports the theory that this founder mutation originated very recently during human evolution, perhaps less than 2,000 years ago somewhere in Northern Europe (Kalatzis and Antignac 2002); so it has not got the chance to spread to remote ethnicities. Based on these observations, we do not recommend anymore the routine screening for the 57-kb deletion before CTNS sequencing in populations outside its geographical distribution, at least in the region of the Middle East.…”

Section: Discussionsupporting

confidence: 67%

Mutational Spectrum of the CTNS Gene in Egyptian Patients with Nephropathic Cystinosis

et al. 2014

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Background: Nephropathic cystinosis is a rare autosomal recessive disorder caused by mutations in the CTNS gene, encoding for cystinosin, a carrier protein transporting cystine out of lysosomes. Its deficiency leads to cystine accumulation and cell damage in multiple organs, especially in the kidney. In this study, we aimed to provide the first report describing the mutational spectrum of Egyptian patients with nephropathic cystinosis and their genotype-phenotype correlation.Methods: Fifteen Egyptian patients from 13 unrelated families with infantile nephropathic cystinosis were evaluated clinically, biochemically, and genetically. Screening for the common 57-kb deletion was performed by standard multiplex PCR, followed by direct sequencing of the ten coding exons, exon-intron interfaces, and promoter region.

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Section: Discussionsupporting

confidence: 67%

Mutational Spectrum of the CTNS Gene in Egyptian Patients with Nephropathic Cystinosis

et al. 2014

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“…An isolate of cystinotic patients bearing a W138X mutation exists among French Canadians [21]. More than 50 additional genetic mutations have been described [20][21][22][23][24]. Patients with classical cystinosis have deletions or other mutations associated with the loss of a functional protein, whereas milder cases (with intermediate or ocular cystinosis) are heterozygous for a severe (e.g.…”

Section: Genetics and Basic Defectmentioning

confidence: 99%

Nephropathic cystinosis: late complications of a multisystemic disease

2008

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Cystinosis is a rare autosomal recessive disorder due to impaired transport of cystine out of cellular lysosomes. Its estimated incidence is 1 in 100,000 live births. End-stage renal disease (ESRD) is the most prominent feature of cystinosis and, along with dehydration and electrolyte imbalance due to renal tubular Fanconi syndrome, has accounted for the bulk of deaths from this disorder. Prior to renal transplantation and cystine-depleting therapy with cysteamine for children with nephropathic cystinosis, their lifespan was approximately 10 years. Now, cystinotic patients have survived through their fifth decade, but the unremitting accumulation of cystine has created significant non-renal morbidity and mortality. In this article we review the classic presentation of nephropathic cystinosis and the natural history, diagnosis, and treatment of the disorder's systemic involvement. We also emphasize the role of oral cysteamine therapy in preventing the late complications of cystinosis.

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“…Lysosomes are responsible for the intracellular protein digestion, and the products of the degradation process leave the organelle by specific transporters for reuse or excretion (26). Nephropathic cystinosis is an autosomal recessive lysosomal storage disorder caused by a defective transport of cystine out of the lysosomes due to mutations in the transporter cystinosin (27,28). Lysosomal accumulation of the poorly soluble cystine results in crystal formation that in turn leads to disorders that include renal failure, growth retardation, and crystal formation in the cornea (29).…”

Section: Table 1 Selected Fits Of Iron K-edge Exafs Data For Resting mentioning

confidence: 99%

Probes of the Catalytic Site of Cysteine Dioxygenase

Chai

Bruyere

Maroney

2006

Journal of Biological Chemistry

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The first major step of cysteine catabolism, the oxidation of cysteine to cysteine sulfinic acid, is catalyzed by cysteine dioxygenase (CDO). In the present work, we utilize recombinant rat liver CDO and cysteine derivatives to elucidate structural parameters involved in substrate recognition and x-ray absorption spectroscopy to probe the interaction of the active site iron center with cysteine. Kinetic studies using cysteine structural analogs show that most are inhibitors and that a terminal functional group bearing a negative charge (e.g. a carboxylate) is required for binding. The substrate-binding site has no stringent restrictions with respect to the size of the amino acid. Lack of the amino or carboxyl groups at the ␣-carbon does not prevent the molecules from interacting with the active site. In fact, cysteamine is shown to be a potent activator of the enzyme without being a substrate. CDO was also rendered inactive upon complexation with the metal-binding inhibitors azide and cyanide. Unlike many non-heme iron dioxygenases that employ ␣-keto acids as cofactors, CDO was shown to be the only dioxygenase known to be inhibited by ␣-ketoglutarate.The first major step in cysteine catabolism involves its conversion to cysteine sulfinic acid by cysteine dioxygenase (CDO), 2 which is a nonheme iron-containing dioxygenase present in mammalian tissues. CDO plays an important role in the formation of essential metabolites such as taurine and sulfate. Because cysteine is toxic at high levels (1), CDO assists in maintaining low intracellular cysteine levels without compromising its availability for incorporation into proteins and synthesis of major metabolites.Since the early studies on CDO by Sörbo and Ewetz (2), there have been great advances in understanding the regulation and biochemical properties of this enzyme. However, there is little information regarding the active site of CDO and its specificity for the only known substrate, L-cysteine (3).Herein we report the results of probing the active site requirements of CDO with cysteine structural analogs and the substrate binding mode with x-ray absorption spectroscopy. In addition to exploring the features required for enzyme inhibition, using substrate derivatives has attracted attention in the development of potent and target-specific drugs (4, 5). Because CDO is at a crucial branching point of cysteine catabolism, and several diseases have been linked to this metalloenzyme (6 -8), information about substrate recognition also provides insights for drug design. Many of the cysteine analogs utilized in our current work are metabolites that are present in mammalian cells, and their interaction with CDO could aid in unraveling thiol homeostasis and regulation. MATERIALS AND METHODSChemicals-Cysteine, cysteine sulfinic acid, and heptafluorobutyric acid were obtained from Aldrich Chemical Co. Sodium phosphate, sodium chloride, and ferrous sulfate were purchased from Fisher Scientific. Yeast extract, Tryptone, phenylmethylsulfonyl fluoride, ampicillin, chloramphenicol...

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Cystinosis: from gene to disease

Cited by 39 publications

References 22 publications

Mutational Spectrum of the CTNS Gene in Egyptian Patients with Nephropathic Cystinosis

Mutational Spectrum of the CTNS Gene in Egyptian Patients with Nephropathic Cystinosis

Nephropathic cystinosis: late complications of a multisystemic disease

Probes of the Catalytic Site of Cysteine Dioxygenase

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