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PubMed2000

Cystinuria at the turn of the millennium: clinical aspects and new molecular developments.

Cystinuria is caused by a defect in a transport molecule in the kidney and small intestine resulting in urinary excretion of cystine and the dibasic amino acids. Traditionally, three types have been recognized, but this classification correlates poorly with the findings of molecular analysis, and a new system is needed. Persons who are homozygous and heterozygous for non-Type I cystinuria can be distinguished by urinary amino acid excretion: the former secrete large amounts of cystine and all three dibasic amino acids, whereas the latter secrete more lysine and cystine than arginine and ornithine. The first gene found that is important in cystine transport is SLC3A1, located on chromosome 2p. More than 40 mutations have been identified, all associated with Type I cystinuria. The gene associated with non-Type I disease maps to chromosome 19, called SLC7A9, encodes a protein that apparently interacts with the product of the SLC3A1 gene. Almost 40 disease-associated mutations have been identified in SLC7A9, and there is some evidence that cystinuria in some patients reflects mutations in both genes. Mutations in other proteins with which the SLC3A1 and SLC7A9 products associated may be responsible for still other cases of cystinuria. Contemporary molecular knowledge has not offered any new treatment for the short term.

Amino Acid Transport Systems, Basic↗
PubMed2003

Genetic variations of the SLC7A9 gene: allele distribution of 13 polymorphic sites in German cystinuria patients and controls.

Cystinuria is a hereditary disorder of cystine and dibasic amino acid transport across the luminal membrane of renal tubules and intestine, resulting in recurrent nephrolithiasis. While mutations in the SLC3A1 gene cause type I cystinuria, patients with non-type I cystinuria carry mutations in the SLC7A9 gene. Both gene products form the renal amino acid transporter rBAT/b0,+AT affected in cystinuria. In the present study a total of 59 patients with different ethnic background were screened for sequence variations in SLC7A9, out of these 32 were of German origin. For determination of allele frequencies of detected polymorphisms, 58 healthy German controls were investigated. Molecular-genetic analysis was performed using single-strand conformation polymorphism analysis, restriction assays and sequencing. Allele frequencies were analyzed statistically for the detected polymorphisms. In addition to the 6 already known variants we identified 7 new polymorphisms. Statistical analyses showed a significantly different distribution of alleles between German patients and German controls in case of the polymorphisms c. 147C>T (exon 2), c.386C>T (exon 3), IVS3+22T>G, c.584C>T (exon 4), c.610T>C (exon 4), c.692C>T (exon 5), c.852C>A (exon 6) and c.872C>T (exon 6). In summary, our results show that cystinuria is a complex disease which is not only caused by mutations in SLC7A9 and SLC3A1, but also influenced by other modifying factors such as variants in SLC7A9.

Alleles↗
PubMed2004

Cystinuria: definition, epidemiology and clinical aspects.

Cystinuria ia an inheritable autosomal recessive disorder of amino acids transport affecting the epithelial cells of the renal tubules and gastrointestinal tract. It is characterized by abnormal concentrations of cystine and the other dibasic amino acids in the urine, resulting in a risk of renal stone formation because of the low solubility of cystine in urine. According to the recent advances in molecular genetics, two genes have been identified as responsible for this disease (SLC3A1 and SLC7A9), but other unknown genes may be involved in cystinuria. We assessed the presence of cystinuria in 2086 consecutive patients with renal stones by using cyanide-nitroprusside test (Brand's test). According to our experience, this screening test should be performed in all patients at the onset of renal stone disease in order to avoid a delay in the possible diagnosis of cystinuria. In fact cystinuric patients often have mixed calculi composed of substances other than cystine that can disguise the presence of cystininuria that is so diagnosed many years after the onset of the initial symptoms. Patients with positive cyanide-nitroprusside test were further studied for identification of urine amino acids by quantitative ion-exchange chromatography. Pathological cystinuria was confirmed in 39 (1.9%) out of 41 patients with positive Brand test. The mean age of cystine stone patients was 38.1 +/- 15.8 years, whereas the age at stone onset was 21.8 +/- 12.4. Renal stones were recurrent in 85% of cases, while other 6 patients were observed at their first stone. The male to female ratio was 1:0.62. The mean number of stone episodes for patient was 18.5 +/- 35.8 and the mean interval to first recurrence was 4.1 +/- 4.3 years. The recurrence rate 5 years after the first renal stone was 83%. Furthermore we studied 85 members from 24 families of patients with cystine stones. Twenty-four family members excreted excessive amounts of cystine, but only 5 of them (21%) had cystine calculi. Twenty-two patients were treated with 1-1.5 g alpha-mercaptopropionylglycine daily. Treatment reduced stone formation from 0.93 to 0.46 stones/patient/year. Only six patients had side effects of sufficient severity to require withdrawal.

Adult↗
PubMed1995

Mutations in the SLC3A1 transporter gene in cystinuria.

Cystinuria is an autosomal recessive disease characterized by the development of kidney stones. Guided by the identification of the SLC3A1 amino acid-transport gene on chromosome 2, we recently established genetic linkage of cystinuria to chromosome 2p in 17 families, without evidence for locus heterogeneity. Other authors have independently identified missense mutations in SLC3A1 in cystinuria patients. In this report we describe four additional cystinuria-associated mutations in this gene: a frameshift, a deletion, a transversion inducing a critical amino acid change, and a nonsense mutation. The latter stop codon was found in all of eight Ashkenazi Jewish carrier chromosomes examined. This report brings the number of disease-associated mutations in this gene to 10. We also assess the frequency of these mutations in our 17 cystinuria families.

Americas↗
PubMed1995

[Cystinuria and urolithiasis].

Cystinuria is a hereditary metabolic disorder which causes urinary lithiasis. Patients with cystinuria present at an earlier age (17 years), and with larger stones than patients with other types of urinary stones. As a result of frequent formation of new stones and multiple operations, many patients suffer from obstructive nephropathy and deterioration of kidney function. During the past decade we treated and followed 51 patients with cystine urolithiasis from 39 families. Screening disclosed another family member with cystinuria in 56% of the cases. The diagnosis of cystinuria was only made an average of 2 years after a patient first presented. In the group 12 kidneys had been removed due to various complications and in 7 kidneys there was significant deterioration of function. Each patient underwent a mean of 5.8 surgical interventions, including open operations, extra-corporeal shock wave lithotripsy (ESWL), percutaneous nephrolithotripsy (PCNL) and urethroscopy, but most still had residual stone fragments. To prevent complications from cystine urolithiasis every effort should be made to detect the disease early, including screening of families of patients with cystinuria and close follow-up of all family members. Early detection of stones, before they become large makes noninvasive treatment with ESWL possible, whereas large stones require PCNL. Patients should be urged to maintain high urine outputs and to continue uninterrupted treatment with penicillamine or tiopronin, and urinary alkalinization.

Cystinuria↗
PubMed1995

Assignment of the gene responsible for cystinuria (rBAT) and of markers D2S119 and D2S177 to 2p16 by fluorescence in situ hybridization.

We have established rBAT (named as SLC3A1 in the Genome Data Base) as a gene responsible for cystinuria, a heritable disorder of amino acid transport. The cystinuria locus has been mapped by linkage between microsatellite markers D2S119 and D2S177. Fluorescence in situ hybridization (FISH) either with Alu-polymerase-chain-reaction (PCR)-amplified sequences of a yeast artificial chromosome (YAC) containing the rBAT gene or with rBAT-specific PCR-amplified genomic fragments, and chromosome G-banding have cytogenetically mapped rBAT to 2p16.3. In order to correlate the physical and genetic information on cystinuria, we have performed FISH with combinations of Alu-PCR-amplified sequences from YACs containing rBAT or the D2S119 and D2S177 loci. In all cases, a fused signal is obtained that demonstrates their close physical location; this allows the assignment of rBAT, cystinuria and their linked markers, D2S119 and D2S177, to 2p16.

Amino Acid Transport Systems, Basic↗
PubMed1989

Cystinuria and its treatment: 25 years experience at St. Bartholomew's Hospital.

Cystinuria is an inherited condition affecting the active transport of the diamino acids cystine, ornithine, lysine and arginine across the renal tubule and the small intestine. The only clinical effect is the production of urinary tract stones and if these can be prevented the affected individuals can lead a normal life. In many people cystine stones can be dissolved and new stone formation prevented by a high fluid intake, but if this does not succeed regular treatment with penicillamine will do so. Although many side-effects have been described with penicillamine treatment it is rare for them to be severe enough to prevent its use in patients with cystinuria. Since the clinical effects of cystinuria can be prevented by either a high fluid intake or by penicillamine it is important to make the diagnosis in affected individuals as soon as possible and cystinuria should therefore be considered in all people (regardless of age) who form urinary stones.

Cystinuria↗
PubMed2003

Urinary excretion of total cystine and the dibasic amino acids arginine, lysine and ornithine in relation to genetic findings in patients with cystinuria treated with sulfhydryl compounds.

Advances in molecular genetics have brought a deeper understanding of cystinuria. This autosomal recessive disease, which is caused by a defective tubular reabsorption of cystine and the three dibasic amino acids arginine, lysine and ornithine, results in a lifelong risk of renal stone formation because of the low solubility of cystine in urine. Mutations detected within the two genes known to be associated with cystinuria, SLC3A1 (related to type I) and SLC7A9 (related to non-type I), cannot, however, in all cases explain the disease. Inasmuch as a high urinary concentration of cystine is the basis of stone formation in these patients, our aim was to measure urinary total cystine, arginine, lysine and ornithine, in patients currently lacking a full genetic explanation for their disease. Thirty-three patients with cystinuria who were on long-term treatment with tiopronin or D-penicillamine were divided into two groups. Group 1 comprised eight patients who carried mutation in one of the SLC3A1 alleles and two patients who completely lacked mutations both in the SLC3A1 and the SLC7A9 genes, that is genetic findings discordant with the increased urinary excretion of cystine and the dibasic amino acids in these patients. Group 2 comprised 23 patients homozygous for mutations within SLC3A1, that is genetic findings in accordance with the excretion pattern of classic type I cystinuria. When the two groups were compared, Group 1 had a significantly higher total urinary excretion of cystine ( p<0.01) as well as of arginine, lysine and ornithine ( p<0.05) than Group 2. Also, when the two patients without mutations were excluded from the calculations, there still was a significant difference in the urinary excretion of total cystine ( p<0.05). This suggests that the two patients without any detected mutations in the two known cystine transport genes also contributed to the difference. These unexpected findings indicate that an additional gene or genes participate in the urinary cystine reabsorption in the cystinuric patients who currently are without a full genetic explanation for their disease.

Adolescent↗
PubMed2026

Generation of a novel Slc7a9G105R mutant mouse identifies new biomarkers for cystinuria.

INTRODUCTION: Cystinuria is a rare inherited disease characterized by increased urinary cystine levels resulting in the formation of cystine stones in the urinary tract. Mutations in the genes encoding the cystine transporter complex, SLC3A1 and SLC7A9, are the primary drivers of the disease. Current mouse models used to study cystinuria rely on gene deficiency or spontaneous mutations in mice that do not accurately reflect the pathogenic mutations found in humans. METHODS: We generated a novel Slc7a9G105R knock-in mouse model in which glycine at position 105 is replaced by arginine, recapitulating the most common pathogenic mutation in human SLC7A9. Disease onset and progression were assessed using micro-CT imaging, fecal metagenomics, and urine and serum metabolomics and proteomics. RESULTS: Both male and female Slc7a9G105R mice developed a cystinuria phenotype by nine weeks of age, characterized by substantial cystine stone formation and increased urinary cystine, lysine, arginine, and ornithine. Slc7a9G105R mice displayed distinct serum and urinary metabolite profiles, mapped to dibasic amino acid pathways, and serum protein profiles, mapped to disease progression. Fecal metagenomics revealed that Slc7a9G105R mice had a heterogeneous microbiota with altered functional pathways, including increased L-cysteine biosynthesis. Antibiotic-induced depletion of the microbiota did not affect cystine stone burden but reduced urinary tract inflammation. Prophylactic or therapeutic dietary supplementation with alpha-lipoic acid reduced stone burden and inflammation, but it also caused urothelial damage. Untargeted metabolomics analysis following alpha-lipoic acid supplementation identified metabolites that can increase cystine solubility, reduce inflammation, and damage epithelial cells. Correlation analysis revealed novel serum metabolite biomarkers of stone burden, including 2-hydroxybutyric acid and 2-amino-2-thiazoline-4-carboxylic acid, which were also detected in human serum. CONCLUSIONS: Collectively, the Slc7a9G105R mutant mouse model offers a precise, rapid-onset, and translational platform for investigating cystinuria pathogenesis and evaluating potential therapeutic strategies.

SLC7A9↗
PubMed2005

Functional analysis of a new splice site mutation, c.605-3C>A, in the cystinuria gene SLC7A9 leading to exon skipping.

Cystinuria is a hereditary disorder of cystine and dibasic amino acid transport across the luminal membrane of renal tubules and intestine, resulting in recurrent nephrolithiasis. While mutations in the SLC3A1 gene cause type I cystinuria, patients with non-type I cystinuria carry mutations in the SLC7A9 gene. Up to now, more than 80 mutations in SLC3A1 and 50 in SLC7A9 have been reported in the literature. While deletions, duplications, and truncating mutations can often unambiguously classified to be pathogenic, the functional relevance of base pair substitutions is often difficult to predict. To determine the functional relevance of a new splice site mutation in intron 5 of SLC7A9, c.605-3C>A, we transfected COS7 cells with expression constructs containing the wild-type and mutant allele, respectively. cDNAs derived from the resulting SLC7A9 mRNAs were sequenced. By this approach we could demonstrate that the mutant allele c.605-3A causes exon skipping and therefore represents a splice site mutation. To the best of our knowledge, this is the first splice site mutation in a cystinuria gene with a proven functional consequence.

Amino Acid Transport Systems, Basic↗
PubMed1983

The incidence of cystinuria in Japan.

Screening tests for cystinuria were done in approximately 110,000 children and students. The rates of discovery were chemical cystinuria 920 to 1, cystine crystalluria 16,000 to 1 and homozygous cystinuria 18,000 to 1 (8,000 to 1 if a correction was made by the rates of performances of secondary screening and urinary amino acid assay). No stone formation was observed in a 7-year followup of 6 patients considered to be homozygotes. A correlation was observed between urinary cystine and urinary uric acid levels in 39 cases of chemical cystinuria.

Adolescent↗
PubMed2000

[Phenotypical manifestations of cystinuria: a study of 20 families in the Community of Valencia].

BACKGROUND: The aim of this study was to classify phenotypically cystinuria patients in the Comunidad Valenciana using their genealogy and to study the large heterogeneity of the disease expression. SUBJECTS AND METHOD: From 29 patients diagnosed of cystinuria, 20 families were enrolled in the study. An urine sample of every subject was collected to quantify urine amino acids using high pressure liquid chromatography. We also looked for the presence of cystine crystals. Genetic analyses were carried out using PCR (Polymerase Chain Reaction), and RFLPs (Restriction Fragment Length Polymorphisms). Demographic and clinical characteristics were recorded in a standard questionnaire. RESULTS: From 20 families, 4 were classified Type I, 10 as Type non I, and 6 as Type unknown. Type I cystinuria patients showed the highest urinary levels of cystine and ornithine. We also found an association of cystine crystals and M467T mutation in SLC3A1 gene with Type I. However, we did not find a higher risk of nephrolithiasis associated to any family type. CONCLUSIONS: Phenotypical characterization of patients with cystinuria has showed the wide variability of phenotypical traits indeed in the same transmission pattern. This variability could be due to the genetic and environmental heterogeneity which has developed this pathology and modulated its evolution.

Adolescent↗
PubMed1994

Localization of a gene causing cystinuria to chromosome 2p.

Cystinuria is an autosomal recessive disorder of amino acid transport. It is a common hereditary cause of kidney stones worldwide, and is associated with significant morbidity. In 17 affected families, we found linkage between cystinuria and three chromosome 2p markers. Maximal two-point lod scores between cystinuria and D2S119, D2S391 and D2S288 were 8.23 (theta = 0.07), 3.73 (theta = 0.15) and 3.03 (theta = 0.12), respectively. Analysis of recombinants and multipoint linkage data indicated that the most likely order is cen-D2S391-D2S119-cystinuria-D2S177-tel. We also observed high rates of homozygosity for markers in this chromosomal region among 11 affected offspring of consanguineous marriages. Based on its map position and function, the recently cloned SLC3A1 amino acid transporter gene is a primary candidate gene for this disease.

Amino Acid Transport Systems, Basic↗
PubMed1994

Cystinuria caused by mutations in rBAT, a gene involved in the transport of cystine.

Cystinuria is a classic heritable aminoaciduria that involves the defective transepithelial transport of cystine and dibasic amino acids in the kidney and intestine. Six missense mutations in the human rBAT gene, which is involved in high-affinity transport of cystine and dibasic amino acids in kidney and intestine, segregate with cystinuria. These mutations account for 30% of the cystinuria chromosomes studied. Homozygosity for the most common mutation (M467T) was detected in three cystinuric siblings. Mutation M467T nearly abolished the amino acid transport activity induced by rBAT in Xenopus oocytes. These results establish rBAT as a cystinuria gene.

Adolescent↗
PubMed2005

Urological intervention in patients with cystinuria is decreased with medical compliance.

PURPOSE: Theoretically patients with cystinuria compliant with medical treatment should undergo fewer surgical procedures than those noncompliant with treatment. We describe a single urologist's experience (SYN) with the effects of medical management on the number of surgical interventions required in patients with cystinuria treated at our metabolic stone clinic (MSC). MATERIALS AND METHODS: The records of 20 patients with cystine stones seen at our MSC (mean followup of 42.5 months) were evaluated. The number of surgical interventions (endourology or open surgery) during followup were recorded as surgical events. Patients were placed into a compliant or noncompliant category based on their attendance record at scheduled appointments at our MSC and whether they adhered to the prescribed medical regimen by report. Patients were classified in an active disease category if recent imaging revealed a clinically significant stone burden greater than 3 mm. Statistical analysis of the number of surgical events for stone-free patients compliant with treatment versus noncompliant was conducted (Student's t test). RESULTS: Of the 20 patients 11 were categorized as compliant and 9 as noncompliant. Of the compliant patients the average number of surgical events was 1.0 per patient versus 4.0 in the noncompliant group (p <0.05). Of the 11 compliant patients 8 (73%) were stone-free compared to 3 (33%) in the noncompliant group. CONCLUSIONS: The majority of our patients with cystinuria compliant with treatment underwent a significantly fewer number of surgical procedures per year than those noncompliant with treatment. Active medical management in patients with cystinuria compliant with treatment decreases the incidence of surgical interventions.

Adolescent↗
PubMed1993

Extracorporeal shock wave lithotripsy for treatment of ureterolithiasis in patients with cystinuria.

Ten of 42 patients with cystinuria admitted for extracorporeal shock wave lithotripsy (ESWL) treatment had ureterolithiasis. Of these, 3 had bilateral stones, 2 had only 1 functioning kidney, and 2 had stones in both the kidney and ureter on the same side. Only 1 patient was on medical treatment at the time of referral. After initiation of medical treatment for cystinuria, 2 patients were discharged without further intervention, 1 was discharged after placement of a ureteric stent and 10 were treated with ESWL. After an average of 1.5 ESWL treatment sessions per ureter, 8 patients became stone-free and in the remaining 2, ureteroscopy was required to complete the treatment. Problems associated with the ESWL treatment of cystine stones are discussed. It was concluded that ESWL is the treatment of choice for ureterolithiasis in patients with cystinuria because it is effective and is the least invasive procedure even in patients with cystinuria.

Adolescent↗
PubMed1979

Childhood cystinuria in New South Wales. Results in children who were followed up after being detected by urinary screening in infancy.

Homozygous cystinuria was diagnosed in 45 children and 19 of their siblings in the course of routine urine screening of 6-week-old infants in New South Wales. These children were followed for up to 14 years. During this time there were 5 clinical episodes of renal disease which could be ascribed to cystinuria. There was normal mental development in all the children except one. Of 49 children over 3 years, 4 had height centiles less than the midparent height centile, while 45 had height centiles equal to or above the midparent centiles. Family testing in these 45 cases showed that 60% were type I cystinurics, and 35% were of the mixed or compound type (5% were not classified). Data from the parents and grandparents showed that renal tract calculi had occurred in 14 of them. This study shows that children with homozygous cystinuria, detected by urinary screening in infancy, rarely have renal symptoms. Mental development was normal as was growth in height. There was an increased incidence of noncystine stone formation among the relatives of these children. The incidence of homozygous cystinuria in New South Wales in one in 17 286.

Adolescent↗
PubMed2005

New insights into cystinuria: 40 new mutations, genotype-phenotype correlation, and digenic inheritance causing partial phenotype.

OBJECTIVE: To clarify the genotype-phenotype correlation and elucidate the role of digenic inheritance in cystinuria. METHODS: 164 probands from the International Cystinuria Consortium were screened for mutations in SLC3A1 (type A) and SLC7A9 (type B) and classified on the basis of urine excretion of cystine and dibasic amino acids by obligate heterozygotes into 37 type I (silent heterozygotes), 46 type non-I (hyperexcretor heterozygotes), 14 mixed, and 67 untyped probands. RESULTS: Mutations were identified in 97% of the probands, representing 282 alleles (86.8%). Forty new mutations were identified: 24 in SLC3A1 and 16 in SLC7A9. Type A heterozygotes showed phenotype I, but mutation DupE5-E9 showed phenotype non-I in some heterozygotes. Type B heterozygotes showed phenotype non-I, with the exception of 10 type B mutations which showed phenotype I in some heterozygotes. Thus most type I probands carried type A mutations and all type non-I probands carried type B mutations. Types B and A mutations contributed to mixed type, BB being the most representative genotype. Two mixed cystinuria families transmitted mutations in both genes: double compound heterozygotes (type AB) had greater aminoaciduria than single heterozygotes in their family. CONCLUSIONS: Digenic inheritance is an exception (two of 164 families), with a limited contribution to the aminoaciduria values (partial phenotype) in cystinuria. Further mutational analysis could focus on one of the two genes (SLC3A1 preferentially for type I and SLC7A9 for type non-I probands), while for mixed probands analysis of both genes might be required, with priority given to SLC7A9.

Amino Acid Transport Systems, Basic↗