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PubMed1987

An evaluation of four methods for the detection of heterozygous cystinuria.

Heterozygotes for cystinuria (types II and III) may be detected on the basis of slight to moderate elevations in urinary cystine, lysine and sometimes arginine. This seems to be a common genetic trait, and there are indications of an increased risk of urinary stone disease. In order to test the sensitivity and reliability of the procedures normally used for screening and diagnosis of heterozygous cystinuria, we studied 32 heterozygotes previously diagnosed by ion-exchange chromatography of urinary amino acids, and 23 healthy individuals. A random urine sample from each subject was analysed using the cyanide-nitroprusside test, thin-layer amino acid chromatography, colorimetric estimations of cystine and lysine, and ion-exchange amino acid chromatography. Thin-layer chromatography provided the highest sensitivity. Thus the frequency of heterozygotes calculated in previous studies, based on screening by the cyanide-nitroprusside test, may be under-estimated. The colorimetric estimations of cystine and lysine provided low sensitivity as screening tests and, compared with the ion-exchange chromatography, were unreliable diagnostic methods.

Chromatography, Ion Exchange↗
PubMed1995

Oligomeric structure of a renal cystine transporter: implications in cystinuria.

Homologous proteins (NBAT) which mediate sodium-independent transport of neutral as well as basic amino acids and cystine when expressed in Xenopus oocytes were recently cloned from mammalian kidneys. Mutations in human NBAT have been implicated in cystinuria. Here, we show that rat kidney and jejunal brush border membrane NBAT (85 kDa) is found in association with a 50 kDa protein. The association involves one or more interprotein disulfide bonds. Rabbit kidney brush border membranes and membranes of NBAT cRNA-injected Xenopus oocytes also contain such heterodimers. Our data suggest that the heterodimer is the minimal functional unit of NBAT-mediated amino acid transport and that the NBAT-associated 50 kDa protein could play a role in cystinuria.

Amino Acid Transport Systems, Basic↗
PubMed1991

Liquid chromatographic-mass spectrometric analysis for screening of patients with cystinuria, and identification of cystine stone.

Analyses of amino acids in the urine of a normal human and of patients with heterozygous and homozygous cystinuria have been carried out, using liquid chromatography-mass spectrometry with an atmospheric pressure ionization interface system. A kidney cystine stone was also analysed by this system. Very intense quasi-molecular ions ([M + H]+) of standard cystine, arginine, lysine and ornithine were observed on mass chromatograms as base peaks. Mass chromatograms of the urine samples from a normal human and from patients with heterozygous and homozygous cystinuria were easily distinguishable. The retention times in the mass chromatogram and mass spectrum of kidney stone cystine was almost the same as that of authentic cystine.

Arginine↗
PubMedDate not supplied

Cystinuria with congenital myotonic dystrophy.

Two brothers with congenital myotonic dystrophy also had cystinuria with large renal stones. This report is the first to document the concurrence of cystinuria and congenital myotonic dystrophy. It is uncertain whether these two conditions are coincidental or share a common pathogenesis.

Child, Preschool↗
PubMed2003

Studies of urinary cystine precipitation in vitro: ontogeny of cystine nephrolithiasis and identification of meso-2,3-dimercaptosuccinic acid as a potential therapy for cystinuria.

Children with fully recessive (Type I/I) cystinuria have a high risk of stone formation in the first decade of life. To assess the tendency for cystine to precipitate in individual urine samples, we developed an in vitro assay in which radiolabelled cystine (4mM) was dissolved in urine at 37 degrees C after alkalization to pH 10. Samples were then brought to pH 5, cooled, and centrifuged. The % decrease in supernatant cpm was used as a measure of cystine precipitation (CP). CP varied widely among normal children (74%+/-34) whereas variability of repeated determinations on a single adult individual was modest (64%+/-3.3). The assay was used to compare various potential therapies for cystinuria. Precipitation of exogenous cystine from normal urine was strongly inhibited by addition of D-penicillamine (CP: 8%+/-3) or dimercaptosuccinic acid (DMSA) (CP: 5%+/-1), at urinary concentrations attained by standard oral doses of each drug. Mercaptopropionylglycine (MPG) was moderately effective (CP: 43%+/-9), whereas captopril was a weak inhibitor (CP: 63%+/-12). Precipitation of endogenous cystine (2191 micromol/L) from a cystinuric patient showed that DMSA and D-penicillamine were again highly effective compared to the other agents. In addition DMSA and penicillamine added to the same patient's urine reduced the free cystine by 50% (as measured by automated amino acid analyzer) whereas MPG and captopril had no effect. In conclusion, DMSA is comparable to D-penicillamine as an in vitro inhibitor.

Adolescent↗
PubMed1983

Heterozygous cystinuria and calcium oxalate urolithiasis.

To evaluate the incidence of heterozygous cystinuria in patients with primary and recurrent calcium oxalate stone disease 24-hour urine samples from 140 patients were examined. The frequency of heterozygous cystinuria in this study was only 1.4 per cent (2 patients). The frequency of other metabolic disorders was in accordance with other reports: hypercalciuria (32 per cent), hyperuricosuria (32 per cent) and hyperoxaluria (17 per cent).

Adult↗
PubMed1993

Successful treatment of cystinuria with captopril.

Cystinuria is an autosomal recessive hereditary disorder associated with nephrolithiasis and its attendant complications. Traditional management aimed at increasing urinary cystine solubility using oral alkali, D-penicillamine, or mercaptopropionyglycine is often unsuccessful due to intolerable side effects. Two cystinuric patients intolerant of traditional therapy were treated with captopril for 1 year, resulting in a marked decline in urinary cystine excretion. Neither patient experienced recurrent nephrolithiasis or adverse drug effects. Captopril should be considered an alternative to traditional drug management of cystinuria.

Adult↗
PubMed2001

The molecular bases of cystinuria and lysinuric protein intolerance.

Cystinuria and lysinuric protein intolerance are inherited aminoacidurias caused by defective amino-acid transport activities linked to a family of heteromeric amino-acid transporters (HATs). HATs comprise two subunits: co-expression of subunits 4F2hc and y(+)LAT-1 induces the efflux of dibasic amino acids from cells, whereas co-expression of subunits rBAT and b(o,+)AT induces the renal reabsorption and intestinal absorption of cystine and dibasic amino acids at the brush border of epithelial cells. Recently, the role of b(o,+)AT (SLC7A9) in cystinuria (non Type I) and the role of y(+)LAT-1 (SLC7A7) in lysinuric protein intolerance have been demonstrated.

Amino Acid Sequence↗
PubMed1994

Gyrate atrophy of the choroid and retina with hyperornithinaemia, cystinuria and lysinuria.

The case of a 45-year-old woman with gyrate atrophy of the choroid and retina is documented. Additional features in this case, to the authors' knowledge not previously described in gyrate atrophy, are massive cystinuria, massive lysinuria, axial hypermetropia and diabetes. Gyrate atrophy is a rare autosomal recessive degenerative disease of the choroid and retina and is accompanied by defective ornithine metabolism. Simell and Takki demonstrated the association with hyperornithinaemia in 1973. The main metabolic features are those of hyperornithinaemia and ornithuria caused by a deficiency of the mitochondrial matrix enzyme, ornithine aminotransferase (OAT). The responsible human gene has been localised to chromosome 10. Despite the generalised deficiency of OAT, the literature indicates significant pathological involvement of the eye only. Ophthalmological features of the disease are myopia (up to 10-20 dioptres), night blindness, constricted visual fields and complicated cataracts. The clinical picture has been detailed previously by various authors. The case of a 45-year-old woman with gyrate atrophy and hyperornithinaemia is documented here. She has been followed up for 12 years and fully investigated. Additional features in this case, to our knowledge not previously described in gyrate atrophy, are massive cystinuria, massive lysinuria, axial hypermetropia and diabetes.

Adult↗
PubMed2006

Urinary cystine excretion and capacity in patients with cystinuria.

The treatment of cystinuria is hampered by methods used to measure urinary lithogenicity. Most cystine assays cannot reliably distinguish cystine from soluble thiol drug-cysteine complexes. We used a solid-phase assay of urinary cystine capacity in a large sample of patients with cystinuria. A known amount of solid-phase cystine is added to urine. In supersaturated urine, cystine precipitates onto added crystals, so the solid phase recovered after incubation will be greater than that added. We studied the effect of cystine-binding thiol drugs (CBTD) to solubilize cystine and determined correlates of cystine capacity in patients who were and were not taking CBTD. Increasing concentrations of D-penicillamine, tiopronin and captopril dissolved cystine in urine with similar efficacy. A general linear model in which 24 h cystine excretion was the dependent variable showed that creatinine, urea nitrogen, and sodium excretions were associated with cystine excretion (P<0.02, all three). Urine volume, pH, and cystine excretion strongly correlated with cystine capacity (P<0.001). Tiopronin had no effect on supersaturation in a cross-sectional analysis. A subset of supersaturated samples, with negative cystine capacity, occurred mainly among women not taking CBTD. For this subset, capacity differed significantly between CBTD users and non-users; use of CBTD avoided extremes of supersaturation. Female enrichment in the supersaturated group was accounted for in part by underprescription of CBTD to women. This assay of cystine capacity was reliable in the presence of CBTD. It should be useful in monitoring patients' response to dietary interventions and administration of fluid, citrate, and CBTD.

Biological Assay↗
PubMed1995

Mutations of the basic amino acid transporter gene associated with cystinuria.

To investigate the function of a basic and neutral amino acid transporter-like protein (rBAT) which is a candidate gene for cystinuria, we analysed the rBAT gene in cystinuric patients. Patient 1 is a compound heterozygote with mutations in the rBAT gene causing a glutamine-to-lysine transition at amino acid 268, and a threonine-to-alanine transition at amino acid 341, who inherited these alleles from his mother (E268K) and father (T341A), respectively. Injection of T341A and E268K mutant cRNAs into oocytes decreased transport activity to 53.9% and 62.5% of control (L-cystine transport activity in oocytes injected with wild-type rBAT cRNA), respectively. Co-injection of E268K and T341A into oocytes strongly decreased amino acid transport activity to 28% of control. On the other hand, co-injection of wild-type and mutant rBAT did not decrease transport activity. Furthermore, immunological studies have demonstrated that the reduction of amino acid transport is not due to a decrease in the amount of rBAT protein expressed in oocyte membranes. These results indicate that mutations in the rBAT gene are crucial disease-causing lesions in cystinuria. In addition, co-injection experiments suggest that rBAT may function as a transport activator or regulatory subunit by homo- or hetero-multimer complex formation.

Adolescent↗
PubMed2003

[Cystinuria - Cystine Stones: Recommendations for Diagnosis, Therapy and Follow-up].

Cystinuria, an autosomal-recessive disorder, is the cause of 1 - 2 % of all kidney stones observed in adults and about 10 % of those observed in infants. Despite increasing understanding of underlying pathomechanisms, patients still form recurrent stones and have to undergo repeated interventions with increasing risk of renal insufficiency. Dietary and medical metaphylaxis may lower the frequency of recurrent stones but are often not practiced. Regular follow-up examinations and optimal therapy significantly enlarge stone-free intervals. This review offers an overview of the underlying pathogenetic mechanisms as well as guidance for diagnosis, monitoring, metaphylaxis and therapy of cystinuria following the recommendations of the Deutsche Gesellschaft für Urologie (DGU) and the European Association of Urology (EAU).

Adult↗
PubMed2001

A recessive contiguous gene deletion of chromosome 2p16 associated with cystinuria and a mitochondrial disease.

Deletions ranging from 100 Kb to 1 Mb--too small to be detected under the microscope--may still involve dozens of genes, thus causing microdeletion syndromes. The vast majority of these syndromes are caused by haploinsufficiency of one or several genes and are transmitted as dominant traits. We identified seven patients originating from an extended family and presenting with a unique syndrome, inherited in a recessive mode, consisting of cystinuria, neonatal seizures, hypotonia, severe somatic and developmental delay, facial dysmorphism, and lactic acidemia. Reduced activity of all the respiratory chain enzymatic complexes that are encoded in the mitochondria was found in muscle biopsy specimens of the patients examined. The molecular basis of this disorder is a homozygous deletion of 179,311 bp on chromosome 2p16, which includes the type I cystinuria gene (SLC3A1), the protein phosphatase 2Cbeta gene (PP2Cbeta), an unidentified gene (KIAA0436), and several expressed sequence tags. The extent of the deletion suggests that this unique syndrome is related to the complete absence of these genes' products, one of which may be essential for the synthesis of mitochondrial encoded proteins.

Abnormalities, Multiple↗
PubMed1997

Acalculous cystinuria.

We compared quantitative urinary cystine values in stone-forming family members and unaffected relatives based on an index stone-forming patient. A family pedigree of 39 members was identified. Quantitative urinalyses and serum biochemical profiles were collected with the subjects on similar diets over 72 hours. Detailed medical histories were obtained. Three family members are stone-forming cystinuric patients with a mean urinary cystine excretion of 496 mg/g of creatinine per day. Six persons without a history of stones (mean age 50) had a mean urinary cystine excretion of 364 mg/g of creatinine per day. Thirty-four family members had elevated urinary cystine concentrations (mean 151 mg/g of creatinine per day), and only two family members had normal urinary cystine excretion. Fifteen subjects with elevated urinary cystine values (> 150 mg/g of creatinine per day) had no history of urinary stones despite a mean age of 44 years. Urinary electrolytes and volumes were similar in the stone-forming and non-stone-forming groups. Thirty-nine per cent of the persons from this family pedigree had elevated quantitative urinary cystine concentrations and no history of urinary stones despite a mean age of 44 years. Acalculous cystinuria is an elevated urinary cystine concentration without evidence of urinary stone disease. Despite abnormal urinary cystine excretion, acalculous cystinuria does not necessarily culminate in clinical urinary stone disease.

Adolescent↗
PubMed1999

Luminal heterodimeric amino acid transporter defective in cystinuria.

Mutations of the glycoprotein rBAT cause cystinuria type I, an autosomal recessive failure of dibasic amino acid transport (b(0,+) type) across luminal membranes of intestine and kidney cells. Here we identify the permease-like protein b(0,+)AT as the catalytic subunit that associates by a disulfide bond with rBAT to form a hetero-oligomeric b(0,+) amino acid transporter complex. We demonstrate its b(0,+)-type amino acid transport kinetics using a heterodimeric fusion construct and show its luminal brush border localization in kidney proximal tubule. These biochemical, transport, and localization characteristics as well as the chromosomal localization on 19q support the notion that the b(0,+)AT protein is the product of the gene defective in non-type I cystinuria.

Amino Acid Sequence↗
PubMed2003

A mouse model for cystinuria type I.

Cystinuria, one of the most common inborn errors of metabolism in humans, accounts for 1-2% of all cases of renal lithiasis. It is caused by defects in the heterodimeric transporter system rBAT/b0,+AT, which lead to reduced reabsorption of cystine and dibasic amino acids through the epithelial cells of the renal tubules and the intestine. In an N-ethyl-N-nitrosourea mutagenesis screen for recessive mutations we identified a mutant mouse with elevated concentrations of lysine, arginine and ornithine in urine, displaying the clinical syndrome of urolithiasis and its complications. Positional cloning of the causative mutation identified a missense mutation in the solute carrier family 3 member 1 gene (Slc3a1) leading to an amino acid exchange D140G in the extracellular domain of the rBAT protein. The mouse model mimics the aetiology and clinical manifestations of human cystinuria type I, and is suitable for the study of its pathophysiology as well as the evaluation of therapeutic and metaphylactic approaches.

Amino Acid Sequence↗
PubMed1966

Cystinuria: genetic heterogeneity and allelism.

Studies of four stoneforming cystinuric subjects from three unrelated pedigrees indicated that each was heterozygous for two of the three described mutant genes producing cystinuria ( I, II, III). Their genotypes were I-II, II-III, I-III, and I-III, respectively. These doubly heterozygous patients were phenotypically indistinguishable from cystinuric homozygotes of genotype I-I, II-I, or III-III. The data provide the first direct evidence that all of the known mutations responsible for the genetic heterogeneity in cystinuria are allelic.

Adult↗
PubMed1976

Homozygous cystinuria and the oculo-cerebro-renal dystrophy of Lowe in same family.

The mother and daughter in a family had homozygous cystinuria and were also heterozygous carriers of the oculo-cerebro-renal dystrophy of Lowe. The daughter was also epileptic. The son had Lowe's syndrome and the father an increased urinary excretion of cystine and lysine. This evidence together with other case reports suggests that the defect in cystinuria and that of Lowe's syndrome may be connected.

Abnormalities, Multiple↗