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At least 19 recordsLinked to original sources
PubMed2000

The genomic region encompassing the nephropathic cystinosis gene (CTNS): complete sequencing of a 200-kb segment and discovery of a novel gene within the common cystinosis-causing deletion.

Nephropathic cystinosis is an autosomal recessive disorder caused by the defective transport of cystine out of lysosomes. Recently, the causative gene (CTNS) was identified and presumed to encode an integral membrane protein called cystinosin. Many of the disease-associated mutations in CTNS are deletions, including one >55 kb in size that represents the most common cystinosis allele encountered to date. In an effort to determine the precise genomic organization of CTNS and to gain sequence-based insight about the DNA within and flanking cystinosis-associated deletions, we mapped and sequenced the region of human chromosome 17p13 encompassing CTNS. Specifically, a bacterial artificial chromosome (BAC)-based physical map spanning CTNS was constructed by sequence-tagged site (STS)-content mapping. The resulting BAC contig provided the relative order of 43 STSs. Two overlapping BACs, which together contain all of the CTNS exons as well as extensive amounts of flanking DNA, were selected and subjected to shotgun sequencing. A total of 200,237 bp of contiguous, high-accuracy sequence was generated. Analysis of the resulting data revealed a number of interesting features about this genomic region, including the long-range organization of CTNS, insight about the breakpoints and intervening DNA associated with the common cystinosis-causing deletion, and structural information about five genes neighboring CTNS (human ortholog of rat vanilloid receptor subtype 1 gene, CARKL, TIP-1, P2X5, and HUMINAE). In particular, sequence analysis detected the presence of a novel gene (CARKL) residing within the most common cystinosis-causing deletion. This gene encodes a previously unknown protein that is predicted to function as a carbohydrate kinase. Interestingly, both CTNS and CARKL are absent in nearly half of all cystinosis patients (i.e., those homozygous for the common deletion). [The sequence data described in this paper have been submitted to the GenBank data library under accession nos. AF168787 and AF163573.]

Amino Acid Transport Systems, Neutral↗
PubMed1995

Linkage of the gene for cystinosis to markers on the short arm of chromosome 17. The Cystinosis Collaborative Research Group.

Nephropathic cystinosis (MIM 21980) is an autosomal recessive disorder due to defective transport of the amino acid cystine out of lysosomes. Cystine storage leads to acidosis, dehydration, rickets and growth retardation in the first year of life, followed by renal glomerular failure at approximately ten years of age. Renal transplantation is highly successful, but cystine continues to accumulate in other tissues, resulting in complications such as corneal ulcerations and retinal blindness, a distal vacuolar myopathy, delayed puberty, swallowing difficulties, pancreatic deficiency and central nervous system involvement. Treatment with the cysteine-depleting agent, cysteamine (Cystagon), or phosphocysteamine, has proven successful in retarding glomerular deterioration and enhancing growth. Although cystinosis represents the prototypic disorder of lysosomal membrane transport, neither the cystinosis gene nor the lysosomal cystine carrier has been isolated. We now report linkage of the cystinosis gene to markers on the short arm of chromosome 17 (Zmax = 10.89, theta = 0.03) for marker D17S1584. Multipoint analysis and haplotypes in recombinant families suggest that the gene is located between markers D17S1583 and D17S796.

Chromosomes, Human, Pair 17↗
PubMed1998

Treatment with recombinant human growth hormone in short children with nephropathic cystinosis: no evidence for increased deterioration rate of renal function. The European Study Group on Growth Hormone Treatment in Short Children with Nephropathic Cystinosis.

To evaluate the effect of long-term treatment with recombinant human GH (rhGH) on renal function in short children with nephropathic cystinosis with and without concomitant cysteamine treatment, 36 growth-retarded children with nephropathic cystinosis (age 7.3+/-2.7 y; creatinine clearance [C(CR)] 50+/-27 mL (min x 1.73 m2)(-1) were treated with 1 IU rhGH/kg/wk for up to 5 y. The rise in serum creatinine before and during rhGH treatment was compared with that in a historical control group of cystinotic patients. The effect of concomitant cysteamine treatment on the evolution of renal function before and after the start of rhGH was evaluated separately in patients without (group A) and with cysteamine treatment (group B). The decline of C(CR) was also compared with that in noncystinotic patients with chronic renal failure with and without rhGH treatment. At study entry, serum creatinine values in group A were similar to those in the historical controls, whereas group B had significantly lower serum creatinine values. Treatment with rhGH did not accelerate the rise in creatinine independently of cysteamine treatment. There were no significant differences in the mean decline of C(CR) per year in cystinotic compared with noncystinotic patients with chronic renal failure with or without rhGH treatment. rhGH therapy for up to 5 y does not accelerate the deterioration of renal function. This justifies the continuation of controlled studies of rhGH treatment in these patients. The study also provides further evidence that cysteamine therapy reduces the progression of renal failure in children with cystinosis.

Child↗
PubMed1994

Progression of chronic renal failure in a historical group of patients with nephropathic cystinosis. European Collaborative Study on Cystinosis.

In a historical group of 205 patients with infantile or adolescent cystinosis treated without cysteamine, the rate of deterioration of renal function was analysed retrospectively. Patient survival curves and renal survival data are presented. Longitudinal data of serum creatinine values (n = 3280) in 157 patients were plotted for each patient, smoothed by the method of the running medians and grouped into 12 serum creatinine classes. In every patient the age at the last smoothed serum creatinine value observed in each serum creatinine class was determined. These virtual age values were then summarized per serum creatinine class, expressed as median and centiles and plotted, thus describing the "natural" course of the disease. In 9 pairs of affected siblings the rate of progression showed a median difference of about 12 months. Our data describe the "natural" course of nephropathic cystinosis and can be used as a prognostic aid for recently detected patients. The data can also be applied for the assessment of the influence of new therapeutic strategies on the rate of progression of renal failure in cystinotic patients.

Child, Preschool↗
PubMed1993

Pituitary-testicular function in nephropathic cystinosis.

OBJECTIVE: To evaluate reproductive function in patients with cystinosis and in renal transplant recipients without cystinosis. DESIGN: Cross-sectional study. SETTING: Clinical Center, National Institutes of Health. PATIENTS: Ten male patients, 15 to 28 years old, with nephropathic cystinosis and renal allografts formed the study group; 11 renal transplant recipients who had a primary renal disorder other than cystinosis and were matched with study patients for age and renal function served as the control group. MEASUREMENTS: Tanner staging, serum gonadotropin determinations, and testosterone and testosterone-binding globulin assessments. Selected patients also had a human chorionic gonadotropin (HCG) stimulation test, a gonadotropin-releasing hormone (GnRH) stimulation test, and serial sampling for luteinizing hormone (LH). MAIN RESULTS: Although testosterone levels were within normal limits in 7 of 10 patients with cystinosis, the mean testosterone level in patients with cystinosis was 11.5 +/- 2.0 nmol/L compared with 24.2 +/- 3.0 nmol/L in control patients (P < 0.005). No patient with cystinosis reached Tanner stage 5 (full pubertal development), whereas 9 of 11 control patients did. Seven of 10 patients with cystinosis had elevations in LH or follicle-stimulating hormone (FSH) levels, suggesting testicular failure. These patients also had normal LH and FSH responses after GnRH stimulation, increased LH pulse frequency, and reduced testosterone response after HCG stimulation. In comparison, only 3 of 11 control patients had minimally elevated gonadotropin levels, and all 11 had normal testosterone levels. Microscopic testicular examination in one patient showed cystine crystals, germinal dysplasia, increased fibrosis, and Leydig cell hyperplasia. CONCLUSIONS: Abnormalities in the pituitary-testicular axis are common in male patients with cystinosis. These changes appear to be related to the disease cystinosis and not to treated renal failure per se.

Adolescent↗
PubMed2000

Ocular nonnephropathic cystinosis: clinical, biochemical, and molecular correlations.

Ocular nonnephropathic cystinosis, a variant of the classic nephropathic type of cystinosis, is an autosomal recessive lysosomal storage disorder characterized by photophobia due to corneal cystine crystals but absence of renal disease. We determined the molecular basis for ocular cystinosis in four individuals. All had mutations in the cystinosis gene CTNS, indicating that ocular cystinosis is allelic with classic nephropathic cystinosis. The ocular cystinosis patients each had one severe mutation and one mild mutation, the latter consisting of either a 928 G-->A (G197R) mutation or an IVS10-3 C-->G splicing mutation resulting in the insertion of 182 bp of IVS10 into the CTNS mRNA. The mild mutations appear to allow for residual CTNS mRNA production, significant amounts of lysosomal cystine transport, and lower levels of cellular cystine compared with those in nephropathic cystinosis. The lack of kidney involvement in ocular cystinosis may be explained by two different mechanisms. On the one hand (e.g. the G197R mutation), significant residual cystinosin activity may be present in every tissue. On the other hand (e.g. the IVS 10-3 C-->G mutation), substantial cystinosin activity may exist in the kidney because of that tissue's specific expression of factors that promote splicing of a normal CTNS transcript. Each of these mechanisms could result in minimally reduced lysosomal cystine transport in the kidneys.

Amino Acid Transport Systems, Neutral↗
PubMed2005

Behavioral profiles of children with infantile nephropathic cystinosis.

Children with infantile nephropathic cystinosis have evidence of visuospatial and arithmetic deficits on a background of normal intellectual and verbal skills. This study aimed to define further their behavioral phenotype. The Achenbach Child Behavior Checklist was completed by parents of: 64 children and adolescents with cystinosis (33 females, 31 males; mean age 8 y 8 mo, range 4 to 16y, SD 2 y 11 mo); 101 healthy controls (47 females, 54 males; mean age 8 y 4 mo, range 4 to 16 y, SD 2 y 11 mo); 21 children and adolescents with cystic fibrosis (CF), termed chronic-disease controls (9 females, 12 males; mean age 11 y 3 mo, age range 4 to 17 y, SD 3 y 5 mo). Compared with healthy controls, individuals with cystinosis had evidence of a significantly higher incidence of behavioral problems, including social problems, somatic complaints, and attention problems. Compared with the chronic-disease control group, the cystinosis group differed only on the Social Problems scale, with 22% of participants with cystinosis scoring in the 'at risk' range whereas no participant with CF received an elevated score on this scale. We conclude that children and adolescents with cystinosis have evidence of a significant incidence of social difficulties compared with individuals with another chronic illness and healthy participants. The combination of visuospatial problems, difficulty with arithmetic, attention problems, and social difficulties seen in the cystinosis group constitutes a behavioral phenotype of this genetic disorder. This cluster of cognitive and behavioral symptoms is also seen in the nonverbal learning disabilities syndrome, and suggests a possible early difference in brain development in children with cystinosis compared with children who do not share this genetic disorder.

Chi-Square Distribution↗
PubMed1988

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

Cystinosis is an autosomal recessive disease in which three clinical forms are recognized: infantile nephropathic, with renal tubular damage by 1 year of age and progressive glomerular insufficiency; intermediate, with tubular and glomerular insufficiency beginning at a later age; benign, with no kidney damage. Skin fibroblasts cultured from patients with all types of cystinosis show increased intralysosomal free (nonprotein) cystine; however, fibroblasts from heterozygotes have normal free-cystine values. To determine whether genetic complementation occurs between the different forms, somatic cell hybrids were constructed between cells from a patient with infantile nephropathic cystinosis and cells from patients with other types of cystinosis. If complementation occurred, the hybrids would be expected to have normal cystine levels. To construct hybrid cells, a "universal parent" cell type (TG1-neo), which was hypoxanthine/aminopterin/thymidine (HAT) sensitive and G418 resistant was constructed from an infantile nephropathic cystinosis fibroblast strain. Polyethylene glycol fusion of TG1-neo with other cells that are not HAT sensitive or G418 resistant allowed for selection of hybrid cells in a medium containing HAT and the aminoglycoside G418. As indicated by elevated cystine levels, complementation did not occur between TG1-neo and two different benign cystinosis strains, an intermediate cystinosis strain, or another nephropathic cystinosis cell strain. When a normal fibroblast strain was fused with TG1-neo, all 15 hybrid clones studied contained normal amounts of intracellular free cystine.

Cells, Cultured↗
PubMed1999

Severity of phenotype in cystinosis varies with mutations in the CTNS gene: predicted effect on the model of cystinosin.

Infantile nephropathic cystinosis is a rare, autosomal recessive disease caused by a defect in the transport of cystine across the lysosomal membrane and characterized by early onset of renal proximal tubular dysfunction. Late-onset cystinosis, a rarer form of the disorder, is characterized by onset of symptoms between 12 and 15 years of age. We previously characterized the cystinosis gene, CTNS, and identified pathogenic mutations in patients with infantile nephropathic cystinosis, including a common, approximately 65 kb deletion which encompasses exons 1-10. Structure predictions suggested that the gene product, cystinosin, is a novel integral lysosomal membrane protein. We now examine the predicted effect of mutations on this model of cystinosin. In this study, we screened patients with infantile nephropathic cystinosis, those with late-onset cystinosis and patients whose phenotype does not fit the classical definitions. We found 23 different mutations in CTNS; 14 are novel mutations. Out of 25 patients with infantile nephropathic cystinosis, 12 have two severely truncating mutations, which is consistent with a loss of functional protein, and 13 have missense or in-frame deletions, which would result in disruption of transmembrane domains and loss of protein function. Mutations found in two late-onset patients affect functionally unimportant regions of cystinosin, which accounts for their milder phenotype. For three patients, the age of onset of cystinosis was <7 years but the course of the disease was milder than the infantile nephropathic form. This suggests that the missense mutations found in these individuals allow production of functional protein and may also indicate regions of cystinosin which are not functionally important.

Age of Onset↗
PubMed1996

Visuomotor performance in children with infantile nephropathic cystinosis.

Infantile nephropathic cystinosis is a genetic metabolic disorder in which the amino acid cystine accumulates in various organs, including the kidney, cornea, thyroid, and brain. Despite normal intellect, individuals with cystinosis may have specific impairments in the processing of visual information. To examine further the specific types of deficits in visual processing found in individuals with cystinosis, we administered the Development Test of Visual-motor Integration to 26 children with cystinosis (4 to 16 yr. old) and 26 matched controls. The cystinosis group achieved a significantly lower standard score, raw score, and mean ceiling than did the control group. Qualitative analyses showed that in the cystinosis group, size within errors and rotation errors were more prevalent than in the control group. Correlational analyses showed that with advancing age, the cystinosis subjects tended to fall further behind their chronological age. Our data, together with the findings of previous studies, suggest that the visuospatial difficulties in children with cystinosis may be due to inadequate perception or processing of visually presented information. Furthermore, the increasing discrepancy with age may reflect a progressive cognitive impairment, possibly as a result of cystine accumulation in the brain over time.

Adolescent↗
PubMed1997

Academic achievement in individuals with infantile nephropathic cystinosis.

The present study examined academic skills in children and young adults with infantile nephropathic cystinosis. Cystinosis is a genetic metabolic disorder in which the amino acid cystine accumulates in various tissues and organs, including the kidney, cornea, thyroid, and brain. Individuals with cystinosis have normal intelligence but subtle visual processing impairments. Subjects were 19 children and young adults with cystinosis and 19 age-, sex-, and IQ-matched controls. All subjects had IQs within the normal range. On a test of academic achievement, mean standard scores for cystinosis and control subjects, respectively, were as follows: arithmetic 89.95 +/- 13.77 vs. 102.16 +/- 9.62; spelling 90.68 +/- 18.81 vs. 98.00 +/- 10.96; reading 97.47 +/- 15.59 vs. 98.58 +/- 12.41. Multivariate analysis of variance revealed a significant main effect for Group (P = .009); there was no main effect for Sex, nor was there a Group x Sex interaction. Univariate follow-up tests indicated that the cystinosis group performed significantly more poorly than did controls on the arithmetic subtest (P = .001) and that there was a trend (P = .085) toward poorer performance by the cystinosis group on the spelling subtest. Regression analyses revealed no evidence of a developmental lag or deterioration of function with age. The visual processing deficits previously identified in these individuals may underlie the academic difficulties observed here. It is possible that both visual processing and academic difficulties may reflect a common mechanism of selective cortical damage by this genetic defect.

Achievement↗
PubMed1998

Clinical and molecular aspects of nephropathic cystinosis.

Nephropathic cystinosis, an autosomal recessively inherited lysosomal storage disease, results from impaired transport of the disulfide amino acid cystine out of cellular lysosomes. The consequent accumulation and crystallization of cystine destroys tissues, causing growth retardation in infancy, renal failure at 10 years of age, and a variety of other complications. Early oral therapy with the cystine-depleting agent cysteamine prevents renal deterioration and enhances growth. Although the lysosomal cystine carrier has been extensively studied, its molecular structure remains unknown. The lysosomal cystine transporter gene has been mapped by linkage analysis to human chromosome 17p between polymorphic microsatellite markers D17S1583 and D17S1584. Pertinent recombination events and homozygosity by descent has verified that the cystinosis gene lies in the 3.6 cM genetic interval between these two markers. The cystinosis region has been substantially reduced in size by the observation of recombination events in cystinosis patients between markers D17S1828 and D17S2167. According to radiation hybrid analysis, these two markers are separated by 10.2 cR8000 (centirad using 8000 rad radiation hybrids). Estimates of the physical size of this interval range from 187 to 510 kb. Four yeast artificial chromosomes have been identified which form a contig covering the original cystinosis region. Two P1 clones together may span the new, smaller interval, meaning that the cystinosis gene would lie on one of them. Current efforts are being directed toward using these P1 clones to isolate candidate cDNAs by a variety of methods. The ultimate cloning of the cystinosis gene will reveal how functional lysosomal porters are synthesized, targeted, processed, and integrated into the lysosomal membrane.

Carrier Proteins↗
PubMed2001

Pulmonary dysfunction in adults with nephropathic cystinosis.

OBJECTIVE: To characterize the pulmonary dysfunction in patients with nephropathic cystinosis after renal transplantation. DESIGN: Cross-sectional analysis of consecutive adult patients. PATIENTS: Twelve adult, nephropathic cystinosis patients and 3 adult, ocular, nonnephropathic cystinosis patients admitted to the National Institutes of Health Clinical Center. RESULTS: The 12 nephropathic cystinosis patients (age range, 21 to 40 years) showed an extraparenchymal pattern of restrictive lung disease, with inspiratory and expiratory dysfunction. Specifically, the mean FVC was 58% of predicted, the mean FEV(1) was 57% of predicted, and the mean total lung capacity was 66% of predicted, while the mean residual volume was normal. Furthermore, the mean maximal inspiratory pressure for the eight patients tested was 40% of predicted, and the mean maximal expiratory pressure was 26% of predicted. Two patients died of respiratory insufficiency. All the patients had lived at least 17 years, while lacking compliant cystine-depleting therapy with oral cysteamine. Seven patients had a conical chest, restricting excursion, and 10 of the 12 patients had evidence of the myopathy that typifies late cystinosis. In fact, the severity of pulmonary disease correlated directly with the severity of myopathy in our group of 12 patients. In contrast, the lung parenchyma was essentially normal, as gauged by chest radiographs and CT scans of the lung. The three patients with nonnephropathic cystinosis displayed entirely normal pulmonary function. CONCLUSION: The distal myopathy characteristic of nephropathic cystinosis results in an extraparenchymal pattern of restrictive lung disease in adults who have not received long-term cystine depletion. Whether or not oral cysteamine therapy can prevent this complication remains to be determined.

Adult↗
PubMed1999

CTNS mutations in patients with cystinosis.

Cystinosis is an autosomal recessive lysosomal storage disease caused by mutations in the gene CTNS. The CTNS gene product, cystinosin, has 367 amino acids and seven transmembrane domains and is thought to transport cystine out of lysosomes. The most common form of cystinosis, the nephropathic or infantile type, is characterized by renal failure at 10 years of age and other systemic complications. To date, 32 different CTNS mutations have been described in nephropathic cystinosis patients. Intermediate cystinosis, with later onset of renal disease, has been associated with three different CTNS mutations. Benign or nonnephropathic cystinosis, with symptoms related only to corneal crystals and photophobia, has been associated with two other CTNS mutations. In general, only certain splicing or missense mutations are associated with milder cystinosis phenotypes. Hum Mutat 14:454-458, 1999. Published 1999 Wiley-Liss, Inc.

Amino Acid Transport Systems, Neutral↗
PubMed1994

Global intellectual deficits in cystinosis.

Fourteen families of children with infantile nephropathic cystinosis were evaluated using the Stanford-Binet Intelligence Scale, Fourth Edition [Thorndike et al., 1986: Stanford-Binet Intelligence Scale, Fourth Ed.]. The IQs of 15 children with cystinosis, their 23 sibs and 24 parents were compared in order to evaluate a potential effect of cystinosis on intelligence. Children with cystinosis had a significantly lower mean IQ than their sibs and their parents (P = .001). Thus, even though the mean IQ of the children with cystinosis (94.4 +/- 10) was within the average range, there is evidence that these children have a mild global intellectual deficit relative to their expected IQ based upon the IQs of other relatives. In addition, to a subset of the subjects we administered a measure of scholastic ability, the Wide Range Achievement Test-Revised [Jastak and Wilkinson, 1984: The Wide Range Achievement Test-Revised], which consists of spelling, reading, and arithmetic subtests. The 11 cystinosis subjects scored significantly lower (P = .01) than their 16 sibs and their 14 parents in the area of spelling, whereas they did not significantly differ in their performance in the areas of reading and arithmetic.

Absenteeism↗
PubMed2002

Analysis of the CTNS gene in patients of German and Swiss origin with nephropathic cystinosis.

The autosomal recessive lysosomal storage disorder, nephropathic cystinosis is characterized by impaired transport of free cystine out of lysosomes. The gene responsible for cystinosis, CTNS, consists of 12 exons and encodes a 55 kDa putative lysosomal membrane protein, called cystinosin. Up to now more than 55 different CTNS mutations have been described in cystinosis. We have analyzed the mutation pattern in a population of 40 cystinosis patients from 35 families of German and Swiss origin. CTNS mutations in 68 out of 70 alleles were identified. The common 57-kb deletion accounted for 65% of the alleles. In five patients we found a known GACT deletion at position 18-21. In two patients we identified a nucleotide substitution at codon 339 and one patient showed a CG insertion at position 697-698. In five patients we observed a G insertion at position 926-927. Moreover, five novel mutations including two deletions involving exon 3 (61-61+2delGGT) and exon 6 (280delG), two insertions in exon 6 (292-293insA) and exon 7 (684insCACTT) and one nucleotide substitution in exon 11 (923G>T) have been identified. These data provide a basis for routine molecular diagnosis of cystinosis in the central European population, especially in cystinosis patients of German and Swiss origin.

Amino Acid Sequence↗