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Background: Cystinuria is a rare inherited renal stone disease caused by mutations in the SLC3A1 and SLC7A9 genes. The Chinese cystinuria phenotype and genotype have rarely been reported in the literature., Methods: For this research, the clinical features and genetic etiology were analyzed in seven children, and the clinical characteristics were summarized. The blood and urine amino acids and acylcarnitine were analyzed. Additionally, the whole coding sequence and exon-intron junctions of the SLC3A1 and SLC7A9 genes were analyzed., Results: These seven patients with cystinuria were from seven unrelated Chinese families, and they were diagnosed between the ages of 1 month and 16 years old. The urinary amino acids, including ornithine, arginine, and threonine, were elevated in these patients. A homozygous c.325G>A mutation in SLC7A9 was identified in two patients, and six SLC3A1 mutations were found in five patients., Conclusions: The core pedigree analysis showed that most of the parents carried mutations; however, there was no association between the clinical course and the genotype.

Cystinuria is reportedly a rare condition affecting the stone patients in India. This paper presents the occurrence of cystine-related abnormality in the population of stone patients reporting to the hospitals in South India. Two thousand and eight hundred urine samples from 1,300 patients attending the urinary stone clinic during the period 2004-2008 were assessed for cystinuria by performing the nitroprusside test on the early morning urine and random samples on the day of attendance. Urinary deposits were also studied in all the patients. Stones retrieved from 800 stone patients were analysed qualitatively and by Fourier Transform infra red (FTIR) spectroscopy. Cystinuria was identified in only three patients. None of these patients showed cystine crystals. Three other patients out of the 1,300 showed presence of cystine crystals in the urine deposit. FTIR spectroscopy of the stones retrieved from the patients showed presence of cystine in 19 out of the 800 stones analysed (2.375%). None of the patients with cystine in the stones had either cystine crystals in the urine or positive nitroprusside test for cystine. All the patients who had positive cystine, cystine crystals or cystine in stone analysis had other biochemical abnormalities. They were medically managed with appropriate biochemical corrective chemotherapy and had control of stone disease process. All the patients were advised purine restriction in the diet. It is concluded from the study that cystinuria is a rare entity in South India. It, however, exists in a small percentage of stone patients. Specific treatment with D-penicillamine was not administered to the patients in view of the high cost, nonavailability and possible toxicity. The patients considered above did not have intractable stone disease which was not amenable to usual modalities of directed medical therapy.

Cystinuria is a common inherited aminoaciduria resulting in nephrolithiasis. Mutations in two genes, SLC3A1 and SLC7A9, have been identified in cystinuric patients. Considering the population-specific distribution of genetic variants in the SLC3A1 gene, we focused our study on mutations in SLC3A1 and SLC7A9 described more than once in the literature. We evaluated the usefulness of this restricted analysis as a diagnostic approach. Furthermore, the data obtained were used to estimate the frequency of heterozygote carriers of SLC3A1 mutations in the general European population. A total of 22 unclassified cystinuric patients were screened for genetic variants in four exons of both SLC3A1 and SLC7A9 in which the most common mutations have been identified. For screening, we used single strand conformation polymorphism analysis (SSCP), restriction assays, real-time PCR and direct sequencing. In total, we identified mutations in 17 of our 22 patients, including a new mutation (R365Q) as well as a novel polymorphism (c.1035G/A) within the SLC3A1 gene. An ethnic influence on the distribution of mutations was confirmed: T216M in SLC3A1 is the major mutation in south-eastern Europe, whereas M467T in SLC3A1 is mainly found in western Europe. A complex duplication in SLC3A1 is restricted to German patients. Generally, we could show that a stepwise analysis directed to the most common mutations in the two cystinuria genes is sufficient to detect variants in more than 75% of patients of European origin. The test consists of nine different PCR-based approaches and therefore represents a low-cost, reliable and timesaving diagnostic tool.

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.

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.

Unlabelled: Identification of five novel SLC3A1 (rBAT) gene mutations in Japanese cystinuria., Background: Cystinuria is an inheritable amino aciduria and has been classified into three subtypes: I, II, and III. One of the genes responsible for cystinuria has recently been identified as SLC3A1 or rBAT, but only type I cystinuria seems to be caused by genetic alterations in rBAT. To our knowledge, thus far 38 mutations in rBAT gene have been described. In this study, we investigated rBAT mutations in Japanese patients and compared the results with the previously reported mutations in other races., Methods: We investigated 36 Japanese cystinuria patients by mutational analysis of rBAT gene. To identify newly mutated alleles, genomic DNA was analyzed by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP). When an abnormal migration was observed on SSCP, a nucleotide sequence determination was performed., Results: Five novel mutations were identified in five patients, three with missense mutations (L346P, I445T, C673R), one with a 1 bp deletion (1820delT), and one with a 2 bp insertion (1898insTA), and we detected three previously reported polymorphisms. Three of the mutations were homozygous, in whom parents had intermarried, and two were heterozygous for each mutations. Analysis of rBAT in family of the 1898insTA patient revealed that the patient had inherited the mutated allele from his parents., Conclusion: Five novel mutations in the rBAT gene have been identified in Japanese patients with cystinuria. A racial difference was not apparent in the position and frequency of the mutations.

Cystinuria (MIM 220100) is a common recessive disorder of renal reabsorption of cystine and dibasic amino acids. Mutations in SLC3A1, encoding rBAT, cause cystinuria type I (ref. 1), but not other types of cystinuria (ref. 2). A gene whose mutation causes non-type I cystinuria has been mapped by linkage analysis to 19q12-13.1 (Refs 3,4). We have identified a new transcript, encoding a protein (bo, +AT, for bo,+ amino acid transporter) belonging to a family of light subunits of amino acid transporters, expressed in kidney, liver, small intestine and placenta, and localized its gene (SLC7A9) to the non-type I cystinuria 19q locus. Co-transfection of bo,+AT and rBAT brings the latter to the plasma membrane, and results in the uptake of L-arginine in COS cells. We have found SLC7A9 mutations in Libyan-Jews, North American, Italian and Spanish non-type I cystinuria patients. The Libyan Jewish patients are homozygous for a founder missense mutation (V170M) that abolishes b o,+AT amino-acid uptake activity when co-transfected with rBAT in COS cells. We identified four missense mutations (G105R, A182T, G195R and G295R) and two frameshift (520insT and 596delTG) mutations in other patients. Our data establish that mutations in SLC7A9 cause non-type I cystinuria, and suggest that bo,+AT is the light subunit of rBAT.

Cystinuria is a hereditary disorder manifested by the development of kidney stones. Three subtypes of the disease have been described, based on urinary excretion of cystine and the dibasic amino acids in heterozygotes, and oral loading tests in homozygotes. Cystinuria is very common among Libyan Jews living in Israel. Recently, we mapped the disease-causing gene in Libyan Jews to 19q, and have shown a very strong founder effect. In this report we present the results of biochemical and clinical studies performed on Libyan Jewish cystinuria patients and members of their families. High levels of cystine and the dibasic amino acids in heterozygotes support previous data that cystinuria in Libyan Jews is a non-type I disease. Oral loading tests performed with lysine showed some degree of intestinal absorption, but less than in normal controls. Previous criteria for determining the disease type, based solely on urinary amino acid levels, proved useless due to a very wide range of cystine and the dibasic amino acids excreted by the heterozygotes. Urinary cystine levels were useful in distinguishing between unaffected relatives and heterozygotes, but were unhelpful in differentiating between heterozygotes and homozygotes. Urinary levels of ornithine or arginine, and the sum of urinary cystine and the dibasic amino acids, could distinguish between the last two groups. Among stone formers, 90% were homozygotes and 10% were heterozygotes; 15% of the homozygotes were asymptomatic.

Cystinuria is a hereditary disorder of amino acid transport and is manifested by the development of kidney stones. In some patients the disease is caused by mutations in the SLC3A1 gene, which is located on the short arm of chromosome 2 and encodes a renal/intestinal transporter for cystine and the dibasic amino acids. In Israel cystinuria is especially common among Jews of Libyan origin. After excluding SLC3A1 as the disease-causing gene in Libyan Jewish patients, we performed a genomewide search that shows that the Libyan Jewish cystinuria gene maps to the long arm of chromosome 19. Significant linkage was obtained for seven chromosome 19 markers. A maximal LOD score of 9.22 was obtained with the marker D19S882. Multipoint data and recombination analysis placed the gene in an 8-cM interval between the markers D19S409 and D19S208. Significant linkage disequilibrium was observed for alleles of four markers, and a specific haplotype comprising the markers D19S225, D19S208, D19S220, and D19S422 was found in 11 of 17 carrier chromosomes, versus 1 of 58 Libyan Jewish noncarrier chromosomes.