A novel gene encoding an integral membrane protein is mutated in nephropathic cystinosis

Town, Margaret; Jean, G; Cherqui, Stéphanie; Attard, Marlene; Forestier, Lionel; Whitmore, Scott A.; Callen, David F.; Gribouval, Olivier; Broyer, M.; Bates, Gillian P.; Hoff, William van’t; Antignac, Corinne

doi:10.1038/ng0498-319

Cited by 559 publications

(468 citation statements)

References 24 publications

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“…Despite a growing understanding of the genetic, pathophysiological and therapeutic aspects of cystinosis [1][2][3][4][5][6][7][36][37][38], only limited information is available on the longterm developmental and psychosocial outcome of this disease. This study provides further information on intellectual and motor performance (IP and MP), quality of life (QOL) and psychosocial adjustment (PA) in children and adolescents with cystinosis.…”

Section: Discussionmentioning

confidence: 99%

Intellectual and motor performance, quality of life and psychosocial adjustment in children with cystinosis

et al. 2009

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Cystinosis is a rare multisystemic progressive disorder mandating lifelong medical treatment. Knowledge on the intellectual and motor functioning, health-related quality of life and psychosocial adjustment in children with cystinosis is limited. We have investigated nine patients (four after renal transplantation) at a median age of 9.7 years (range 5.3-19.9 years). Intellectual performance (IP) was analysed with the Wechsler Intelligence Scale for Children-III (seven children) and the Kaufman Assessment Battery for Children (two children). Motor performance (MP) was evaluated using the Zurich Neuromotor Assessment Test, and quality of life (QOL) was studied by means of the Netherlands Organization for Applied Scientific Research Academical Medical Center Child Quality of Life Questionnaire. Psychosocial adjustment was assessed by the Child Behavior Checklist. The overall intelligence quotient (IQ) of our patient cohort (median 92, range 71-105) was significantly lower than that of the healthy controls (p=0.04), with two patients having an IQ<85. Verbal IQ (93, range 76-118) was significantly higher than performance IQ (90, range 68-97; p=0.03). The MP was significantly below the norm for pure motor, pegboard and static balance, as well as for movement quality. The patients' QOL was normal for six of seven dimensions (exception being positive emotions), whereas parents reported significant impairment in positive emotions, autonomy, social and cognitive functions. Significant disturbance was noted in terms of psychosocial adjustment. Based on the results from our small patient cohort, we conclude that intellectual and motor performance, healthrelated QOL and psychosocial adjustment are significantly impaired in children and adolescents with cystinosis.

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Section: Discussionmentioning

confidence: 99%

Intellectual and motor performance, quality of life and psychosocial adjustment in children with cystinosis

et al. 2009

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“…It is caused by defective activity of cystinosin, a proton/cystine symporter that is ubiquitously expressed on lysosomal membranes, which leads to cystine accumulation into lysosomes and crystal formations in many tissues (1). One of the first symptoms of NC is renal Fanconi syndrome, secondary to a global dysfunction of proximal tubular cells.…”

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confidence: 99%

Cystinosin-LKG rescues cystine accumulation and decreases apoptosis rate in cystinotic proximal tubular epithelial cells

et al. 2016

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Background: Nephropathic cystinosis is a lysosomal storage disease that is caused by mutations in the CTNS gene encoding a cystine/proton symporter cystinosin and an isoform cystinosin-LKG which is generated by an alternative splicing of exon 12. We have investigated the physiological role of the cystinosin-LKG that is widely expressed in epithelial tissues. Methods: We have analyzed the intracellular localization and the function of the cystinosin-LKG conjugated with DsRed (cystinosin-LKG-RFP) in Madin-Darby canine kidney cells (MDCK II) and in proximal tubular epithelial cells carrying a deletion of the CTNS gene (cystinotic PTEC), respectively. results: Cystinosin-LKG-RFP colocalized with markers of lysosomes, late endosomes and was also expressed on the apical surface of polarized MDCK II cells. Moreover, immuneelectron microscopy images of MDCK II cells overexpressing cystinosin-LKG-RFP showed stacked lamellar membranes inside perinuclear lysosomal structures. To study the role of LKG-isoform, we have investigated cystine accumulation and apoptosis that have been described in cystinotic cells. Cystinosin-LKG decreased cystine levels by approximately 10-fold similarly to cystinosin-RFP. The levels of TNFα-and actinomycin D-inducted apoptosis dropped in cystinotic cells expressing LKG-isoform. This effect was also similar to the main isoform. conclusion: Our results suggest that cystinosin-LKG and cystinosin move similar functional activities in cells.n ephropathic cystinosis (NC) is a rare lysosomal storage disease. It is caused by defective activity of cystinosin, a proton/cystine symporter that is ubiquitously expressed on lysosomal membranes, which leads to cystine accumulation into lysosomes and crystal formations in many tissues (1). One of the first symptoms of NC is renal Fanconi syndrome, secondary to a global dysfunction of proximal tubular cells. During their lifetimes, patients with NC develop several others symptoms in particular, if they are not well treated with cysteamine (2,3).Recent works have demonstrated an involvement of cystinosin in lysosomal kinetics and exocytosis (4), vesicle trafficking (4,5), autophagy, (6) and in sensing cell oxidative state (7). Studies using a cystinotic mouse model have shown decreased expression of the multi-ligand receptors megalin and cubilin in proximal tubules; this was associated with cell dedifferentiation and apoptosis (5,8). Also, enhanced cell death due to activation of proapoptotic signals probably occurs in other tissues (9-11).Cystinosin (accession number: NP_004928) is composed of seven transmembrane domains that bear two lysosomal targeting motifs (GYDQL and YFPQA) and seven N-glycosylation sites in the amino-terminal region (12). The aceview database reports various alternative splicing transcripts for the CTNS gene that encodes the cystinosin (http://www.ncbi.nlm.nih. gov/IEB/Research/Acembly). In 2008, we have identified a 400 amino acid cystinosin isoform that derives from alternative splicing of CTNS gene exon 12 (accession number: NP_001026...

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“…It is caused by pathogenic mutations in CTNS , a gene that encodes for the lysosomal cystine/proton symporter cystinosin. Mutations in CTNS lead to the lysosomal accumulation of cystine throughout the body and cause irreversible damage to various organs, particularly the kidneys (Town et al, 1998). Cysteamine, the only treatment available to date, can reduce lysosomal accumulation of cystine and postpone the disease progression (Thoene, Oshima, Crawhall, Olson, & Schneider, 1976).…”

Section: Introductionmentioning

confidence: 99%

Quantification of cystine in human renal proximal tubule cells using liquid chromatography–tandem mass spectrometry

Jamalpoor

Sparidans

Casellas

et al. 2018

Biomedical Chromatography

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Nephropathic cystinosis is characterized by abnormal intralysosomal accumulation of cystine throughout the body, causing irreversible damage to various organs, particularly the kidneys. Cysteamine, the currently available treatment, can reduce lysosomal cystine and postpone disease progression. However, cysteamine poses serious side effects and does not address all of the symptoms of cystinosis. To screen for new treatment options, a rapid and reliable high‐performance liquid chromatography–tandem mass spectrometry (HPLC‐MS/MS) method was developed to quantify cystine in conditionally immortalized human proximal tubular epithelial cells (ciPTEC). The ciPTEC were treated with N‐ethylmaleimide, lysed and deproteinized with 15% (w/v) sulfosalicylic acid. Subsequently, cystine was measured using deuterium‐labeled cystine‐D4, as the internal standard. The assay developed demonstrated linearity to at least 20 μmol/L with a good precision. Accuracies were between 97.3 and 102.9% for both cell extracts and whole cell samples. Cystine was sufficiently stable under all relevant analytical conditions. The assay was successfully applied to determine cystine levels in both healthy and cystinotic ciPTEC. Control cells showed clearly distinguishable cystine levels compared with cystinotic cells treated with or without cysteamine. The method developed provides a fast and reliable quantification of cystine, and is applicable to screen for potential drugs that could reverse cystinotic symptoms in human kidney cells.

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A novel gene encoding an integral membrane protein is mutated in nephropathic cystinosis

Cited by 559 publications

References 24 publications

Intellectual and motor performance, quality of life and psychosocial adjustment in children with cystinosis

Intellectual and motor performance, quality of life and psychosocial adjustment in children with cystinosis

Cystinosin-LKG rescues cystine accumulation and decreases apoptosis rate in cystinotic proximal tubular epithelial cells

Quantification of cystine in human renal proximal tubule cells using liquid chromatography–tandem mass spectrometry

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