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PubMed2004

The molecular basis of cystinuria.

Cystinuria is an inherited form of nephrolithiasis due to failure of reabsorptive transport in the proximal tubule. Patients with classical recessive cystinuria have inherited two mutations of the SLC3A1 gene, encoding a subunit of the transport mechanism. Patients with the dominant form of cystinuria have inherited two mutations of the SLC7A9 gene, encoding the transport channel itself. A smaller subset of patients have mixed-type cystinuria, combining recessive and dominant mutant alleles. Children at risk for nephrolithiasis can be identified by the level of urinary cystine only after tubular transport has matured (age 2 years). Conservative therapy with high urine volume and urinary alkalinization is sufficient for some, but recurrent stone formation may cause renal damage and warrants prophylaxis with agents that form mixed disulfides with cystine.

Amino Acid Transport Systems, Basic↗
PubMed1971

Biochemical and genetic studies in cystinuria: observations on double heterozygotes of genotype I-II.

10 families with cystinuria were investigated by measuring: (a) quantitative 24 hr urinary excretion of amino acids by column chromatography; (b) endogenous renal clearances of amino acids and creatinine; (c) intestinal uptake of (34)C-labeled L-cystine, L-lysine, and L-arginine using jejunal mucosal biopsies; (d) oral cystine loading tests. All four of these were studied in the probands and the first two in a large number of the family members.49 members of 8 families were found to have a regular genetic pattern as described previously by Harris, Rosenberg, and their coworkers. Clinical or biochemical differences between the homozygotes type I (recessive cystinuria) and homozygotes type II (incompletely recessive cystinuria) have not been found. Both types excreted similarly excessive amounts of cystine, lysine, arginine, and ornithine, and had high endogenous renal clearances for these four amino acids. Some homozygotes of both types had a cystine clearance higher than the glomerular filtration rate. Jejunal mucosa from both types of homozygotes exhibited near complete inability to concentrate cystine and lysine in vitro. This was also documented in vivo with oral cystine loads. The heterozygotes type I were phenotypically normal with respect to the above four measurements. The heterozygotes type II showed moderate but definite abnormalities in their urinary excretion and their renal clearances of dibasic amino acids. Of the four amino acids concerned, cystine was the most reliable marker to differentiate between the heterozygotes type II and the homozygous normals. In this study, type III cystinuria, as described by Rosenberg, was not encountered. In two additional families, double heterozygotes of genotype I/II were found. The disease affecting these is clinically and biochemically less severe than that affecting homozygotes of either type I or type II. With respect to the four parameters used in this study, the double heterozygotes type I/II have results which are intermediate between those of the homozygotes type I and II and those of the heterozygotes type II.

Adolescent↗
PubMed1992

Bardet-Biedl syndrome and cystinuria.

An unusual association of Bardet-Biedl syndrome with cystinuria was described in one patient. A 21-year-old male was admitted to hospital because of renal failure, severe deterioration of visual acuity, polydactyly, brachydactyly, and mental retardation. Laboratory investigations revealed a serum creatinine of 292 mumol/L (3.3 mg/dL) and a GFR of 25 mL/min per 1.73 m2. Quantitative ion exchange chromatography demonstrated an increased urinary excretion rate of cystine, lysine, arginine, and ornithine. The ophthalmologic examination showed a severe atypical retinal dystrophy. Visual acuity was severely deteriorated and the patient could only count the examining physician's fingers. The patient had been previously evaluated at the age of 7 years for polyuria, polydipsia, and growth failure. His workup at that time demonstrated nephrogenic diabetes insipidus, normal GFR, and a urinary amino acid pattern consistent with the cystinuric phenotype. There was mental retardation notwithstanding the normal ophthalmologic examination. Intravenous pyelography showed calyceal clubbing, calyceal cysts, and lobulated renal outlines of the fetal type. The patient was evaluated again at the age of 13 years for deterioration of visual acuity and the ophthalmologic examination showed an atypical retinal dystrophy, with sparse pigmentation, central and peripheral atrophy, attenuated vessels, and marked optic disk pallor. To our knowledge the association of Bardet-Biedl syndrome with cystinuria has never been reported. It is unlikely that cystinuria may have contributed to the kidney damage. The possibility that mental retardation has been induced or aggravated by cystinuria cannot be excluded.

Adult↗
PubMed2003

[From gene to disease; SLC3A1, SLC7A9 and cystinuria].

In total, 1-2% of adults and 6-8% of children suffering from kidney stones have cystinuria, a defect in the transport of amino acids, which leads to high concentrations of cystine in the urine. Two genes have been implicated, solute carrier family 3 (cystine, basic and) neutral amino acid transporter, member 1 (SLC3A1) coding for the protein related to the system bo,+ amino-acid transporter, and solute carrier family 7, member 9 (SLC7A9), coding for the protein bo,+AT. There are three clinically defined types of cystinuria. Type I (autosomal recessive) is characterised by mutations in the SLC3A1 gene; carriers have normal cystine levels in urine. In total 80% of non-type-I patients have a detectable mutation in the SLC7A9 gene. First-degree relatives of a patient with type 2 (dominant) or type 3 (incomplete recessive) cystinuria may have slightly elevated cystine levels in the urine. The early recognition and treatment of cystinuria is important because recurrent stone formation may lead to urinary tract infection and, eventually, renal failure.

Amino Acid Transport Systems, Basic↗
PubMed1990

A case of nephrotic syndrome due to alpha-mercaptopropionyl glycine in a patient with familial cystinuria.

A 26-year-old male with nephrotic syndrome (NS) due to alpha-mercaptopropionyl glycine (MPG) is described. In March, 1988, he was diagnosed as having familial cystinuria after receiving urolithiasis treatment since December, 1985. Massive proteinuria and slight pedal edema were noted. Nephrotic syndrome was suggested and renal biopsy was performed. The renal pathological finding demonstrated membranous glomerulonephritis (MN) at stage I. This case was defined as NS clinically associated with MPG, and glucocorticoid intake was initiated. The response to the glucocorticoids was fairly good with no clinical problems after discontinuation of MPG, and the cystinuria was maintained with alkaline medication. The patient's parents and younger brother were suggested and confirmed to have cystinuria based on urinary aminogram analysis, but displayed no symptoms. We present a rare case of NS due to MPG therapy in a patient with familial cystinuria. However, the mechanism of onset remains unclear.

Adult↗
PubMed1988

[Distribution of cystinuria subtypes in the Democratic Republic of Germany].

The classic cystinuria is a hereditary disorder characterized by a defective transport of cystine and the dibasic amino acids arginine, lysine and ornithine in the epithelial cells of the renale tubule and the gastrointestinal tract. The excretion patterns of cystine and the dibasic amino acids in 24-hour urine samples from heterozygotes can be used to the differentiation between the genetic subtypes. 120 probands in the age range from 3 to 70 years from 22 families with cystinuria were investigated by thin-layer chromatography and by ion exchange chromatography. In patients with cystinuria the genotype I-I has a frequency of 50%. These results and the distribution of the other subtypes are in accordance with published data. From 98 persons investigated in 22 families with cystinuria 14 run the risk to form cystine stones. Therefore, the knowledge of the subtypes is relevant for practice.

Adolescent↗
PubMedDate not supplied

The use of D-penicillamine in cystinuria: efficacy and untoward reactions.

A retrospective study was conducted to assess the efficacy of D-penicillamine in the management of cystinuria, as well as to define the frequency and nature of untoward reactions to this drug. Fifty-six individuals were identified who, by stone analysis and/or biochemical studies, met the accepted diagnostic criteria for phenotypic cystinuria. The majority of these patients presented in the second decade of life with evidence of stone formation: renal colic, hematuria, and/or stone passage. Thirty-five individuals were considered to have clinically advanced cystinuria because they had required at least one urinary tract lithotomy. In these advanced cases, frequency of subsequent lithotomies and episodes of renal colic per 100 patient-years of observation were used as indices to measure the efficacy of D-penicillamine treatment. By both measurements, D-penicillamine significantly improved the clinical course of patients. The incidence of acute drug sensitivity reactions (rash, fever, and/or arthropathy) was in excess of 40 percent. Delayed drug-induced proteinuria occurred in 34 percent of treated patients. We conclude that D-penicillamine is useful in the treatment of cystinuria. Because of the significant number of untoward drug reactions, however, we believe the drug should be instituted only in selected, high-risk patients.

Adolescent↗
PubMed1995

Inheritance of cystinuria and renal defect in Newfoundlands.

OBJECTIVE: To describe clinical features, characterize metabolic renal abnormalities, and evaluate mode of inheritance of cystinuria in Newfoundlands. DESIGN: Prospective study. ANIMALS: Two families of Newfoundlands including 11 dogs with dysuria, stranguria, or obstruction attributable to cystine calculi. PROCEDURE: Urinalysis and nitroprusside spot tests were performed to evaluate cystinuria in the affected dogs. All calculi were analyzed by crystallography. Amino acid concentrations in urine and plasma of affected dogs were compared with those in clinically normal related dogs. Renal fractional excretion and reabsorption of amino acids were determined in 5 affected Newfoundlands. RESULTS: Nine dogs had pure cystine calculi in the bladder, and 4 of these had renal cystine calculi. Affected dogs persistently excreted excessive amounts of cystine (> 500 nmol/mg of creatinine; reference = 54 +/- 38 nmol/mg of creatinine) and had typical cystine crystals in acidic urine. Urinary excretion of ornithine, lysine, and arginine was also high. Dogs with cystinuria had complete lack of reabsorption and active secretion of cystine, and reabsorption of lysine, ornithine, and arginine was moderately impaired. Although clinical signs of urinary obstruction were observed only in males, cystinuric male and female offspring were produced from noncystinuric parents, consistent with an autosomal recessive mode of inheritance. Obligate heterozygotes did not have clinical signs, and had normal urinary cystine content and renal amino acid reabsorption. CLINICAL IMPLICATIONS: Because detection of carriers by routine urinalysis is currently not possible, Newfoundlands with cystinuria and their parents and offspring should be excluded from breeding.

Animals↗
PubMed1995

Molecular genetics of cystinuria: identification of four new mutations and seven polymorphisms, and evidence for genetic heterogeneity.

A cystinuria disease gene (rBAT) has been recently identified, and some mutations causing the disease have been described. The frequency of these mutations has been investigated in a large sample of 51 Italian and Spanish cystinuric patients. In addition, to identify new mutated alleles, genomic DNA has been analyzed by an accurate and sensitive method able to detect nucleotide changes. Because of the lack of information available on the genomic structure of rBAT gene, the study was carried out using the sequence data so far obtained by us. More than 70% of the entire coding sequence and 8 intron-exon boundaries have been analyzed. Four new mutations and seven intragenic polymorphisms have been detected. All mutations so far identified in rBAT belong only to cystinuria type I alleles, accounting for approximately 44% of all type I cystinuric chromosomes. Mutation M467T is the most common mutated allele in the Italian and Spanish populations. After analysis of 70% of the rBAT coding region, we have detected normal sequences in cystinuria type II and type III chromosomes. The presence of rBAT mutated alleles only in type I chromosomes of homozygous (type I/I) and heterozygous (type I/III) patients provides evidence for genetic heterogeneity where rBAT would be responsible only for type I cystinuria and suggests a complementation mechanism to explain the intermediate type I/type III phenotype.

Alleles↗
PubMed1996

Recent advances in the biochemical and molecular biological basis of cystinuria.

PURPOSE: We reviewed the literature describing recent advances in the understanding of the nature of the transport proteins involved in the renal transport of cystine, properties of the solute carrier family 3, member 1 (SLC3A1) gene, which is involved in renal cystine transport, and the mutations reported in this gene, which have been shown to be the causative factor in approximately half of the cases of type I cystinuria studied. MATERIALS AND METHODS: The MEDLINE data base from 1966 to date and the internet online mendelian inheritance in man were searched using cystinuria, cystine crossed with biological transporters and cystine transporter as key words. Selected citations within these references were also reviewed. RESULTS: The SLC3A1 gene has been shown to code for a protein that, when expressed in Xenopus oocytes, confers on these cells the ability to transport cystine, arginine, lysine and ornithine. To date 21 different mutations and 9 polymorphisms have been reported in the SLC3A1 gene isolated from cystinuric patients. CONCLUSIONS: Type I cystinuria appears to be due to mutations in the SLC3A1 gene, while the molecular genetic determinants of types II and III cystinuria remain to be delineated.

Amino Acid Transport Systems, Basic↗
PubMed1998

Biochemical and clinical studies in Libyan Jewish cystinuria patients and their relatives.

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.

Chromosome Mapping↗
PubMed1977

CNS lesions in cystinuria.

A man with cystinuria developed, at the age of 23, a neurological disorder with relapses and remissions similar to multiple sclerosis. This is the third documented case of cystinuria with central neuraxis lesions, and it is suggested that neurological complications may occur in cystinuria more frequently than is generally recognized.

Adult↗
PubMed1985

Heterozygous cystinuria and urinary lithiasis.

Cystinuria is a recessively inherited transport disorder, with at least three mutant alleles (I, II, and III) demonstrable. I/I, II/II, and III/III homozygotes and I/II, I/III, and II/III compound heterozygotes (cystinuric patients) have high urinary concentrations of cystine, lysine, arginine, and ornithine and frequently form cystine stones. +/I heterozygotes (nondetectable) are phenotypically normal, whereas +/II and +/III heterozygotes (detectable) show variable increases in urinary cystine and lysine concentration and at times increases in urinary arginine levels. The objectives of the present study were to determine the frequency of +/II heterozygotes among stone-forming and nonstone-forming individuals from the same region of Brazil and to evaluate the possible relationship between heterozygous cystinuria and urinary lithiasis. When urine samples from 5,150 individuals (5,000 nonstone-forming individuals and 150 stone-forming individuals) were screened by the qualitative cyanide-nitroprusside cystine test, by thin-layer amino acid chromatography, and by quantitative amino acid determination by ion-exchange chromatography, 32 +/II or +/III heterozygotes (26 nonstone-forming and six stone-forming individuals) were detected. The frequency of detectable heterozygotes among the stone-forming individuals (1:25) was significantly higher than that among nonstone-forming individuals (1:104), which provides additional evidence that heterozygosity for +/II and +/III cystinuria is a risk factor in the formation of urinary stones. No significant difference was detected in urinary cystine concentration or in terms of the various characteristics of urolithiasis when stone-forming heterozygotes were compared to nonstone-forming heterozygotes. These data suggest that the tendency towards stone-forming among heterozygotes is probably owing to a complex and multifactorial mechanism.

Arginine↗
PubMed1999

Refined mapping of the CSNU3 gene to a 1.8-Mb region on chromosome 19q13.1 using historical recombinants in Libyan Jewish cystinuria patients.

Cystinuria is a genetic disease manifested by the development of kidney stones. In some patients, the disease is caused by mutations in the SLC3A1 gene located on chromosome 2p. In others, the disease is caused by a gene that maps to chromosome 19q, but has not yet been cloned. Cystinuria is very common among Jews of Libyan ancestry living in Israel. Previously we have shown that the disease-causing gene in Libyan Jews maps to an 8-cM interval on chromosome 19q between the markers D19S409 and D19S208. Several markers from chromosome 19q showed strong linkage disequilibrium, and a specific haplotype was found in more than half of the carrier chromosomes. In this study we have analyzed Libyan Jewish cystinuria families with eight markers from within the interval containing the gene. Seven of these markers showed significant linkage disequilibrium. A common haplotype was found in 16 of the 17 carrier chromosomes. Analysis of historical recombinants placed the gene in a 1.8-Mb interval between the markers D19S430 and D19S874. Two segments of the historical carrier chromosome used to calculate the mutation's age revealed that the disease-causing mutation was introduced into this population 7-16 generations ago.

Alleles↗
PubMed1999

Recombinant families locate the gene for non-type I cystinuria between markers C13 and D19S587 on chromosome 19q13.1.

Cystinuria is an autosomal recessive aminoaciduria in which three urinary phenotypes have been described. The gene responsible for type I, SLC3A1, encodes the amino acid transporter rBAT. This gene is not responsible for types II or III. Recently the type III locus (CSNU3) was mapped by two groups to overlapping 6-Mb regions on chromosome 19q. In the present study, we restrict the critical region for non-type I cystinuria to 2.4 Mb by recombination analysis in Italian, German, and Spanish families. For this purpose, we have used the microsatellite markers described in the region plus new microsatellites that we have developed. Our results locate the non-type I cystinuria gene in an interval flanked by the markers C13 and D19S587, which are about 2.8 cM apart.

Chromosome Mapping↗
PubMed1983

Familial cystinuria in Ioannina District (Greece). Diagnosis and treatment.

The "Urocystin Test" has been used as a screening procedure for the diagnosis of the incidence of cystinuria in Ioannina District (Northwest Greece). From the 210 investigated urine samples, eight were positive and four of them were also L-cystine stone formers. All positive cases belong to two cystinuric families. The pedigree in village "Kato-Lapsista" is a genetic type of a "completely recessive cystinuria" while the other one in "Marmara" is the type of an "incompletely recessive cystinuria". All patients with L-cystine urolithiasis, except one child, were treated with the drug Thiola.

Adolescent↗
PubMed1975

Phenylketonuria in a patient with cystinuria.

During routine screening procedures for amino-acid disorders by thin-layer chromatography, a 16-year-old boy was found to have phenylketonuria and cystinuria. A phenylalanine and a cystine loading were carried out. The patient was found to be homozygous for phenylketonuria and heterozygous for cystinuria type II. His father was heterozygous for phenylketonuria and cystinuria, while his mother proved to be heterozygous only for phenylketonuria.

Adolescent↗
PubMed2006

Evidence for association of SLC7A9 gene haplotypes with cystinuria manifestation in SLC7A9 mutation carriers.

Cystinuria is a complex genetic disorder. In the present study, we report on the strict linkage disequilibrium of SLC7A9 mutations with the wild type SLC7A9 haplotype of 15 single nucleotide polymorphisms (SNPs) and their effect on cystinuria manifestation and classification. Specifically, screening for mutations and polymorphisms was performed in the family members of ten cystinuric patients with SLC7A9 gene mutations. The molecular genetic and clinical data of cystinuric patients and their relatives were combined to construct the SLC7A9 SNP haplotypes and evaluate the manifestation of the disorder in carriers for a SLC7A9 gene mutation. It was found that all carriers of a SLC7A9 mutation manifested cystinuria if their normal allele had non-wild type nucleotides in two or more of the identified polymorphic sites. Subsequently, the polymorphic background of the SLC7A9 gene probably affects the expression of the disorder in SLC7A9 mutation carriers and points to a revised genetic classification of cystinuric patients.

Amino Acid Transport Systems, Basic↗