2007 JASN IMPACT FACTOR 7.111	HOME   AUTHOR INFO   EDITORIAL BOARD   SUBSCRIBE   FEEDBACK   ALERTS   HELP
advanced	CURRENT ISSUE	ARCHIVES	JASN Express	ONLINE SUBMISSION

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Strologo, L. D. Articles by Rizzoni, G. Search for Related Content PubMed PubMed Citation Articles by Strologo, L. D. Articles by Rizzoni, G.

Comparison between SLC3A1 and SLC7A9 Cystinuria Patients and Carriers: A Need for a New Classification

Luca Dello Strologo^*, Elon Pras, Claudia Pontesilli^*, Ercole Beccia, Vittorino Ricci-Barbini, Luisa de Sanctis, Alberto Ponzone, Michele Gallucci^¶, Luigi Bisceglia^||, Leopoldo Zelante^||, Maite Jimenez-Vidal^#, Mariona Font^#, Antonio Zorzano^**, Ferran Rousaud, Virginia Nunes^#, Paolo Gasparini, Manuel Palacín^** and Gianfranco Rizzoni^*

*Division of Nephrology and Dialysis, Bambino Gesù Children’s Hospital and Research Institute, Rome, Italy; Danek Gartner Institute, Sheba Medical Center, Israel; Urology Department, IRCCS CSS, S. Giovanni Rotondo Hospital, Italy; Pediatrics Department, Turin University, Turin, Italy; ^¶Urology Department, Campus Biomedico University, Rome Italy; ^||Medical Genetics Service, IRCCS CSS, S. Giovanni Rotondo Hospital, Italy; ^#Medical and Molecular Genetics, Duran y Reinals Hospital, Barcelona, Spain; **Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain; Nephrology Service, Fundació Puigvert, Barcelona, Spain; and Tigem Medical Genetic, Second University of Naples, Naples, Italy.

Correspondence to Dr. Luca Dello Strologo, Nephrology and Dialysis Dept., Bambino Gesù Children’s Hospital and Research Institute, Piazza S. Onofrio 4, 00165 Rome, Italy. Phone: 39-06-68592393; Fax: +39-06-68592602;

	Abstract

Top Abstract Introduction Material and Methods Results Discussion References

 
ABSTRACT. Recent developments in the genetics and physiology of cystinuria do not support the traditional classification, which is based on the excretion of cystine and dibasic amino acids in obligate heterozygotes. Mutations of only two genes (SLC3A1 and SLC7A9), identified by the International Cystinuria Consortium (ICC), have been found to be responsible for all three types of the disease. The ICC set up a multinational database and collected genetic and clinical data from 224 patients affected by cystinuria, 125 with full genotype definition. Amino acid urinary excretion patterns of 189 heterozygotes with genetic definition and of 83 healthy controls were also included. All SLC3A1 carriers and 14% of SLC7A9 carriers showed a normal amino acid urinary pattern (i.e., type I phenotype). The rest of the SLC7A9 carriers showed phenotype non-I (type III, 80.5%; type II, 5.5%). This makes the traditional classification imprecise. A new classification is needed: type A, due to two mutations of SLC3A1 (rBAT) on chromosome 2 (45.2% in our database); type B, due to two mutations of SLC7A9 on chromosome 19 (53.2% in this series); and a possible third type, AB (1.6%), with one mutation on each of the above-mentioned genes. Clinical data show that cystinuria is more severe in males than in females. The two types of cystinuria (A and B) had a similar outcome in this retrospective study, but the effect of the treatment could not be analyzed. Stone events do not correlate with amino acid urinary excretion. Renal function was clearly impaired in 17% of the patients. E-mail: dellostrologo@opbg.net

	Introduction

Top Abstract Introduction Material and Methods Results Discussion References

 
Cystinuria is an autosomal recessive disorder that is characterized by an impaired transport of cystine, lysine, ornithine, and arginine in the proximal renal tubule and in the epithelial cells of the gastrointestinal tract. High cystine concentration in the urinary tract most often causes the formation of recurring renal stones that are resistant to medical treatment. Urine acidification and concentration facilitate stone formation (1).

Traditionally, cystinuria has been divided into three subtypes: types I, II, and III (2). Type I heterozygotes show a normal amino acid urinary pattern, whereas type II and III are characterized by an increase of cystine, lysine, ornithine, and arginine urinary excretion. Type II has been described as having a more severe impairment of intestinal transport than type III, as demonstrated by a lack of increase in plasma level after an oral load of cystine or lysine (2,3). Subtype non-I grouped previous subtypes II and III (4).

In 1994 a first gene, SLC3A1 in chromosome 2 (5,6) encoding rBAT, the mutations of which are responsible for type I cystinuria, was identified (7–9). Thereafter, the defect associated with the most common cystinuria-specific SLC3A1 mutation was described (10) and over 50 mutations in SLC3A1 were reported (11). A second locus gene that is responsible for type non-I cystinuria was mapped on chromosome 19 (12–15). In 1999, the gene responsible for type non-I cystinuria, SLC7A9 encoding for bo,+AT, was identified (15,16). This second gene encodes a subunit that associates with rBAT to form the active transporter (17,18). This gene appears to cause both type II and III cystinuria (13), supporting the grouping of these subtypes in type non-I (16,19). Over 30 mutations in SLC7A9 have been described so far (19).

Despite the increasing knowledge of the genetic and physiologic characteristics of the carriers involved in cystinuria, clinical data in homozygotes are very scanty. Large series are not available in the literature. In this study, we present clinical data combined with mutation analysis of 224 patients and the amino acid urinary patterns of 47 and 142 SLC3A1 and SLC7A9 heterozygotes, respectively, compared with those of 83 healthy control relatives of the affected subjects in whom the mutation identified in the proband was not detected. Excretion patterns in heterozygotes with known mutations do not fully correspond to the classification used up to now. We propose a new cystinuria classification based on molecular analysis and not on urinary cystine and dibasic amino acid excretion patterns.

	Material and Methods

Top Abstract Introduction Material and Methods Results Discussion References

 
The Institutional Review Board at each of the participating centers approved the study and participants gave informed consent.

All subjects meeting the following criteria were reported to the database:

• Cystine urinary excretion higher than 1040 µmol/g creatinine in a single urine sample or in a 24-h collection and at least one identified cystine stone (emitted or surgically removed).
  
• Siblings of cystinuric patients defined as above in whom the same genetic mutations were identified or with an amino acid urinary pattern compatible with the diagnosis of cystinuria, even in the absence of stone identification.
  

Two classifications were attempted:

1. On the basis of parents’ amino acid urinary excretion, as previously published (19). Patients were classified as type I when both parents showed a normal urine amino acid pattern, type non-I when urinary excretion of both parents was above normal, and mixed type when urinary excretion was above normal in one of the parents and normal in the other. If urinary excretion in one or both parents was not available, they were defined as unclassified.
   Type non-I patients were classified as type II or III according to Kelly (20). Patients were therefore classified as type II when obligate heterozygotes in their families had urine excretion of cystine over 750 µmol/g of creatinine, lysine over 4000 µmol/g of creatinine, and the sum of cystine and the three dibasic amino acids over 4500 µmol/g of creatinine. Patients were classified as type III when obligate heterozygotes in their families had urine excretion of amino acids above normal but below the above-mentioned limits.

2. On the basis of genetic findings. Patients with two mutations in SLC3A1 (one on each allele) were defined as type A, whereas patients with two mutations in SLC7A9 were defined as type B. Patients with one mutation on SLC3A1 and one on SLC7A9 were defined as type AB. The remaining patients with only one or zero mutations detected were not considered for this classification.

The database includes the following entries: personal data (gender, age, and presence of siblings), anamnestic data (age at first stone emission, number of emitted stones, type and number of surgical interventions [extracorporeal shock wave lithotripsy being excluded due to its low efficacy in treating the stones]), laboratory data (including creatinine plasma levels and amino acid urinary excretion), and genetic data (screening for mutations in SLC3A1 and SLC7A9). To compare patients of different ages, number of emitted stones and surgical interventions were considered as events per year of life.

Heterozygotes
The urinary levels of cystine and dibasic amino acids of the parents of the patients (obligated heterozygotes) and of siblings whose carrier status was genetically proven were also introduced when available in the database.

Controls
Amino acid urinary excretions were measured in 83 healthy subjects, relatives of the affected patients, who agreed to undergo genetic analysis and who were found not to carry the mutations of the probands and/or the affected chromosome.

Genetic Analysis
All patients included in the database agreed to undergo genetic analysis. So far, 210 patients have been analyzed by means of single strand conformation polimorphism (SSCP) analysis and/or direct sequencing, as described previously (16,19).

Statistical Analyses
Comparisons between proportion of males and females have been performed through the binomial test. Comparison between groups was performed by means of Mann-Whitney or with t test as appropriate. ANOVA for multiple comparisons (Bonferroni test) was used when needed. Correlation between amino acid urinary excretion and stone events was evaluated with Spearman rank correlation coefficient. Each test was considered significant if P < 0.05.

	Results

Top Abstract Introduction Material and Methods Results Discussion References

 
Database
Data on 224 patients from 150 families were collected in the database; 125 were male patients, and 99 were female patients. Most were from Italy (69.6%); 16.5% were from Spain, and 13.9% were from Israel.

According to the parents’ urinary amino acids, classification was as follows: 31% of the patients where type I, 30% where type non-I, 10% were mixed type, and the remaining 29% were unclassified. In 125 patients, a complete genetic classification was possible: 45.2% were type A, 53.2% were type B, and only 1.6% were type AB (i.e., two patients from one family).

Clinical symptoms were almost identically represented in the groups when either the clinical or genetic classification was considered; to provide data from a larger series, the figures concerning clinical aspects of the disease refer to the urinary amino acid–based classification. Clinical manifestations of cystinuria were early events in all patients. Average age at detection of first renal stone was 13.1 yr (median, 15; SD, ± 9.3) for type I and 11.7 yr (median, 14; SD, ± 8) for type non-I (P = NS). Male and female patients had a similar average age at onset (13.6 yr for type I in male patients [median, 15] and 12.4 yr for type I in female patients [median, 12]; 12.1 yr for type non-I in male patients [median, 14] and 11.08 yr for type non-I in female patients [median, 10.5]), but if we look at the gender distribution in the first 3 yr of life, 35 male patients and only 14 female patients reported having had disease-related symptoms (P = 0.003). All patients except one had their first renal stone detected before the age of 40 (Figure 1). Twelve siblings of affected patients with increased urinary excretion of cystine and dibasic amino acids who did not develop renal stones were also included in the database. Two of them are over 40 yr of age (one is 43 and the other is 65). In 10 of the 12 patients, full genetic confirmation of the disease was obtained (i.e., two mutations were identified in SLC3A1 or SLC7A9). In two patients, a single mutation was identified in SLC3A1 in one and in SLC7A9 in the other.

View larger version (29K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 1. Age at fist stone discovery.

View larger version (25K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 2. Stone emission rates in male and female patients: cystinuria types classified according to parents urinary excretion.

View larger version (16K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 3. Plasma creatinine in patients over 15 yr of age. One patient, in renal replacement therapy, is not reported in the figure.

Unexplained alleles in the 188 studied patients could be due to mutations outside the coding region or mutations that escape SSCP analysis. Linkage studies of the families with an incomplete genotype do not exclude the SLC3A1 and SLC7A9 loci (data not shown). Therefore, additional cystinuria loci for these families is unlikely. A manuscript with a complete report of the newly identified mutations is in preparation.

Controls
Amino acid urinary excretion of the controls is reported in Table 3.

View larger version (26K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 4. Sum of cystine, lysine, ornithine, arginine in parents of probands (obligated heterozygotes), with a precise genetic characterization and in controls (relatives of the affected, without the mutation of the probands).

View larger version (23K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 5. Distribution of genetically confirmed heterozygotes according to log plotting of cystinuria and lysinuria.

	Discussion

Top Abstract Introduction Material and Methods Results Discussion References

The relative rarity of this condition accounts for the absence of large series reports in the literature. Most of the available clinical data concerning cystinuria deal with specific problems: surgical techniques, the effect of medical or surgical treatment on the occurrence of stone relapses, and the effect of diet (25–30). Our multinational database presently collects data on 224 patients, most of whom have been screened for genetic mutations, allowing a complete genetic definition of the two alleles in 60%. This represents the largest series reported so far. It is not a Registry, as we are not collecting all possible cases; therefore, it cannot provide a disease prevalence. Moreover, it is possible that subjects exist with mutations on both alleles of either chromosome 2 or 19 but without renal stone formation or detection. These patients would not be reported to the database, as it has not been set up as a screening program. Twelve such patients were indeed detected when the siblings of symptomatic patients were being studied.

Our data show that renal stones occur early in life when cystinuria is symptomatic; the great majority of the patients had their first stone identified before the age of 30 yr (82.9% in the first two decades). Only one patient was diagnosed after the age of 40; however, two other patients included in the database with a negative history for renal stones are older than that. The proportion of the two subtypes of cystinuria (I and non-I) is almost identically represented in the database. The age at onset, the clinical outcome and the severity of the disease do not differ in the two subtypes. Indeed, no difference in stone emissions or number of interventions per year is evident between the two subtypes. We may not, however, exclude that the treatment received by the patients might have influenced the outcome, blunting differences between patients. Severe cases may indeed have received a stronger treatment.

No differences in the age of onset could be detected between male and female patients, but an early appearance of the stones was more likely to occur in male patients than in female patients. Male patients are more severely affected than female patients. In fact, male patients produce significantly more renal stones. The differences in severity between the genders, in addition to marked intrafamilial differences between siblings sharing the same mutations (31) suggest that other lithogenic factors, both genetic and environmental, play a role in determining the final phenotype.

Amino acid urine excretion was also similar for patients with mutations in SLC3A1 and those with mutations in SLC7A9. Stone event frequency did not correlate with urinary excretion of any of the considered amino acids or with the sum of urinary dibasic amino acid and cystinuria. As urinary excretion of cystine is always well above the solubility threshold, mild differences in urinary excretion of cystine and/or dibasic amino acid might not induce significant differences in stone formation and, again, other factors and/or treatment, may play a determinant role.

Type B female patients (i.e., bearing two mutated SLC7A9 alleles) excreted a higher amount of cystine than did the male patients. We have no explanation for this finding.

Renal insufficiency, defined as plasma creatinine higher than 120 µmol/L, was identified in 17% of our patients. It is important to note that renal function was only studied by measuring plasma creatinine, which is a rather imprecise method, but it is reliable enough to obtain a picture of the occurrence of chronic renal failure in this disease. Renal function was previously studied in 40 patients (19 female and 21 male) (32) by means of a gamma camera renography (indicators were ⁵¹Cr-EDTA in 29 cases, ^99mTC-DTPA in 5, and iohexol in 1). The conclusion of the authors was that renal function was impaired in 70% of the patients after a mean follow-up of 25.9 yr (range, 1 to 52 yr).

In previous studies, mutations in SLC3A1 have been associated with type I disease, and type II and III disease (type no-I) have been attributed to mutations in SLC7A9. However, in this study an analysis of the urinary amino acid excretion patterns in heterozygotes demonstrated that a SLC7A9 carrier status was compatible with a normal amino acid urinary pattern in 14% of the cases. This makes the classification of cystinuria used so far imprecise. Genetic classification would, therefore, be a more appropriate way to classify patients with cystinuria. The classification we propose is therefore as follows:

TYPE A:Cystinuria caused by mutations in both alleles of SLC3A1 (chromosome 2). In this type, heterozygotes show a normal amino acid urinary pattern.

TYPE B:Cystinuria caused by mutations in both alleles of SLC7A9 (chromosome 19). In this type heterozygotes usually (but not always) show an increase of cystine and dibasic amino acid urinary excretion but may also have a normal pattern as demonstrated in 14% of our cases.

TYPE AB:Cystinuria caused by one mutation in SLC3A1 and one mutation in SLC7A9. This type would involve the offspring of one parent carrier of a mutation on chromosome 2 and of another parent with a mutation on chromosome 19. Interestingly, the observed prevalence of AB patients was much lower than expected. Considering a similar frequency of mutations in SLC7A9 and SLC3A1, we would expect one third of the patients to suffer from type A disease, one third from B disease, and one third from AB disease. Indeed, the prevalence of type A disease is similar to that of type B disease; however, type AB is extremely rare (only two patients from one family in our database). Two explanations could account for this low prevalence. The first, type AB patients may suffer from a mild phenotype and therefore, in most cases, escape detection. Alternatively, these patients may actually represent type B disease (two mutations in SLC7A9, one of which was detected, the other yet to be defined) and a coincidental carrier state for an SLC3A1 mutation. Indeed, one patient from our database has three mutations, M467T in SLC3A1 and two missense mutations in SLC7A9, one in each allele.

In conclusion, no clinical differences were evident in this retrospective study between cystinuria type A (due to SLC3A1 mutations) and B (due to SLC7A9 mutations). Male patients are more severely affected than female patients. Renal function is clearly impaired in 17% of patients. Renal stone formation cannot be directly correlated with amino acid urinary excretion, suggesting the importance of cofactors of lithogenesis. A type B carrier status was compatible with a normal amino acid urinary pattern in 14% of cases. A reliable classification of cystinuria requires the identification of the mutations in both alleles. The existence of type AB cystinuria is possible but needs to be confirmed.

	Acknowledgments

 
Part of these data were presented at the 2001 Congress of the International Society of Nephrology, San Francisco, October 10 to 17, 2001. We thank Lidia Feliubadaló for her critical reading of the article and Vincenzo Maria Di Ciommo for his help with statistical procedure. This research was supported in part by BIOMED BMH4 CT 98–3514 to V Nunes, M Palacín, and G Rizzoni, by La Marató de TV3 Grant N° 981932 to F Rousaud, V Nunes, and M Palacín, and by the support of the Comissionat per a Universitats I Recerca de la Generalitat de Catalunya (Spain) to M Palacín. M Font is the recipient of a fellowship from the Comissiò Interdepartamental de Recerca i Innovaciò Tecnologica, Catalonia, Spain.

	References

Top Abstract Introduction Material and Methods Results Discussion References

 

1. Segal S, Thier SO: Cystinuria,In: The Metabolic Basis of Inherited Disease, 6th edition, edited by Scriver CR, Beaudet AL, Sly WS, Valle D, New York, McGraw-Hill Book Co, 1989, pp 2479–2496
2. Rosenberg LE, Downing S, Durant JL, Segal S: Cystinuria: Biochemical evidence for three genetically distinct diseases. J Clin Invest 45: 365–371, 1966
3. Rosenberg LE, Crawhall JC, Segal S: Intestinal transport of cystine and cysteine in man: Evidence for separate mechanisms. J Clin Invest 46: 30–34, 1967
4. Palacín M, Goodyer P, Nunes V, Gasparini P. Cystinuria,In: The Molecular and Metabolic Bases of Inherited Disease, 8th edition, Edited by Scriver CR, Beaudet AL, Sly SW, Valle D, Childs B, Kinzler KW, Vogelstein B, McGraw-Hill. New York, 2001, pp 4909–4932
5. Calonge MJ, Nadal M, Calvano S, Testar X, Zelante L, Zorzano A, Estivill X, Gasparini P, Palacin M, Nunes V: Assignment of the gene responsible for cystinuria (rBAT) and of markers D2S119 and D2S177 to 2p16 by fluorescence in situ hybridization. Hum Genet 95: 633–636, 1995[Medline]
6. Zhang XX, Rozen R, Hediger MA, Goodyer P, Eydoux P: Assignment of the gene for cystinuria (SLC3A1) to human chromosome 2p21 by fluorescence in situ hybridization. Genomics 24: 413–414, 1994[CrossRef][Medline]
7. Calonge MJ, Gasparini P, Chillaron J, Chillon M, Gallucci M, Rousaud F, Zelante L, Testar X, Dallapiccola B, Di Silverio F: Cystinuria caused by mutations in rBAT, a gene involved in the transport of cystine. Nat Genet 6: 420–425, 1994[CrossRef][Medline]
8. Calonge MJ, Volpini V, Bisceglia L, Rousaud F, de Sanctis L, Beccia E, Zelante L, Testar X, Zorzano A, Estivill X: Genetic heterogeneity in cystinuria: The SLC3A1 gene is linked to type I but not to type III cystinuria. Proc Natl Acad Sci USA 92: 9667–9671, 1995[Abstract/Free Full Text]
9. Gasparini P, Calonge MJ, Bisceglia L, Purroy J, Dianzani I, Notarangelo A, Rousaud F, Gallucci M, Testar X, Ponzone A: Molecular genetics of cystinuria: Identification of four new mutations and seven polymorphisms, and evidence for genetic heterogeneity. Am J Hum Genet 57: 781–788, 1995[Medline]
10. Chillaron J, Estevez R, Samarzija I, Waldegger S, Testar X, Lang F, Zorzano A, Busch A, Palacin M: An intracellular trafficking defect in type I cystinuria rBAT mutants M467T and M467K. J Biol Chem 272: 9543–9549, 1997[Abstract/Free Full Text]
11. Palacin M, Borsani G, Sebastio G: The molecular bases of cystinuria and lysinuric protein intolerance. Curr Opin Genet Dev 11: 328–335, 2001[CrossRef][Medline]
12. Feliubadalo L, Bisceglia L, Font M, Dello Strologo L, Beccia E, Arslan-Kirchner M, Steinmann B, Zelante L, Estivill X, Zorzano A, Palacin M, Gasparini P, Nunes V: Recombinant families locate the gene for non-type I cystinuria between markers C13 and D19S587 on chromosome 19q13.1. Genomics 60: 362–365, 1999[CrossRef][Medline]
13. Bisceglia L, Calonge MJ, Totaro A, Feliubadalo L, Melchionda S, Garcia J, Testar X, Gallucci M, Ponzone A, Zelante L, Zorzano A, Estivill X, Gasparini P, Nunes V, Palacin M: Localization, by linkage analysis, of the cystinuria type III gene to chromosome 19q13.1. Am J Hum Genet 60: 611–616, 1997[Medline]
14. Wartenfeld R, Golomb E, Katz G, Bale SJ, Goldman B, Pras M, Kastner DL, Pras E: Molecular analysis of cystinuria in Libyan Jews: Exclusion of the SLC3A1 gene and mapping of a new locus on 19q. Am J Hum Genet 60: 617–624, 1997[Medline]
15. Pras E, Kreiss Y, Frishberg Y, Prosen L, Aksentijevich I, Kastner DL: Refined mapping of the CSNU3 gene to a 1.8-Mb region on chromosome 19q13.1 using historical recombinants in Libyan Jewish cystinuria patients. Genomics 60: 248–250, 1999[CrossRef][Medline]
16. Feliubadalo L, Font M, Purroy J, Rousaud F, Estivill X, Nunes V, Golomb E, Centola M, Aksentijevich I, Kreiss Y, Goldman B, Pras M, Kastner DL, Pras E, Gasparini P, Bisceglia L, Beccia E, Gallucci M, de Sanctis L, Ponzone A, Rizzoni GF, Zelante L, Bassi MT, George AL Jr, Palacin M: Non-type I cystinuria caused by mutations in SLC7A9, encoding a subunit (bo,+AT) of rBAT. International Cystinuria Consortium. Nat Genet 23: 52–57, 1999[Medline]
17. Chillaron J, Roca R, Valencia A, Zorzano A, Palacin M: Heteromeric amino acid transporters: Biochemistry, genetics, and physiology. Am J Physiol Renal Physiol 281: F995–F1018, 2001[Abstract/Free Full Text]
18. Fernández E, Carrascal M, Rousaud F, Abián J, Zorzano A, Palacín M, Chillarón J: The rBAT-bo,+AT heterodimer is the main apical reapsorption system for cystine in kidney. Am J Physiol Renal Physiol DOI 10.1152/ajprenal.00071.2002 (online ahead of publication), 2002
19. Font MA, Feliubadalo L, Estivill X, Nunes V, Golomb E, Kreiss Y, Pras E, Bisceglia L, d’Adamo AP, Zelante L, Gasparini P, Bassi MT, George AL Jr, Manzoni M, Riboni M, Ballabio A, Borsani G, Reig N, Fernandez E, Zorzano A, Bertran J, Palacin M: Functional analysis of mutations in SLC7A9, and genotype-phenotype correlation in non-Type I cystinuria. Hum Mol Genet 10: 305–316, 2001[Abstract/Free Full Text]
20. Kelly S: Cystinuria genotypes predicted from excretion patterns. Am J Med Genet 2: 175–190, 1978[CrossRef][Medline]
21. Rosenberg LE: Cystinuria: Genetic heterogeneity and allelism. Science 154: 1341–1343, 1966[Abstract/Free Full Text]
22. Ito H, Murakami M, Miyauchi T, Mori I, Yamaguchi K, Usui T, Shimazaki J: The incidence of cystinuria in Japan. J Urol 129: 1012–1014, 1983[Medline]
23. Goodyer PR, Clow C, Reade T, Girardin C: Prospective analysis and classification of patients with cystinuria identified in a newborn screening program. J Pediatr 122: 568–572, 1993[Medline]
24. Goodyer P, Saadi I, Ong P, Elkas G, Rozen R: Cystinuria subtype and the risk of nephrolithiasis [see comments]. Kidney Int 54: 56–61, 1998[CrossRef][Medline]
25. Salas SM, Martin X, Gelet A, Sanseverino R, Marechal JM, Michel DJ: [Long-term results of endourological treatment with and without ESWL in cystine lithiasis]. Arch Esp Urol 44: 273–280, 1991[Medline]
26. Singer A, Das S: Therapeutic dilemmas in management of cystine calculi. Urology 37: 322–326, 1991[CrossRef][Medline]
27. Perazella MA, Buller GK: Successful treatment of cystinuria with captopril [see comments]. Am J Kidney Dis 21: 504–507, 1993[Medline]
28. Norman RW, Manette WA: Dietary restriction of sodium as a means of reducing urinary cystine. J Urol 143: 1193–1195, 1990[Medline]
29. Chow GK, Streem SB: Contemporary urological intervention for cystinuric patients: immediate and long-term impact and implications. J Urol 160: 341–344, 1998[CrossRef][Medline]
30. Joly D, Rieu P, Mejean A, Gagnadoux MF, Daudon M, Jungers P: Treatment of cystinuria. Pediatr Nephrol 13: 945–950, 1999[CrossRef][Medline]
31. Dello Strologo L, Carbonari D, Gallucci M, Gasparini P, Bisceglia L, Zelante L, Rosaud F, Nunes V, Palacin M, Rizzoni G: Inter and intrafamilial clinical variability in patients with cystinuria type I and identified mutation. J Am Soc Nephrol 8: 388A, 1997
32. Lindell A, Denneberg T, Granerus G: Studies on renal function in patients with cystinuria. Nephron 77: 76–85, 1997[Medline]

This article has been cited by other articles:

				S. Broer Amino Acid Transport Across Mammalian Intestinal and Renal Epithelia Physiol Rev, January 1, 2008; 88(1): 249 - 286. [Abstract] [Full Text] [PDF]

				M. Font-Llitjos, L. Feliubadalo, M. Espino, R. Cleries, S. Manas, I. M. Frey, S. Puertas, G. Colell, S. Palomo, J. Aranda, et al. Slc7a9 knockout mouse is a good cystinuria model for antilithiasic pharmacological studies Am J Physiol Renal Physiol, September 1, 2007; 293(3): F732 - F740. [Abstract] [Full Text] [PDF]

				M. Palacin, V. Nunes, M. Font-Llitjos, M. Jimenez-Vidal, J. Fort, E. Gasol, M. Pineda, L. Feliubadalo, J. Chillaron, and A. Zorzano The Genetics of Heteromeric Amino Acid Transporters Physiology, April 1, 2005; 20(2): 112 - 124. [Abstract] [Full Text] [PDF]

				M Font-Llitjos, M Jimenez-Vidal, L Bisceglia, M Di Perna, L de Sanctis, F Rousaud, L Zelante, M Palacin, and V Nunes New insights into cystinuria: 40 new mutations, genotype-phenotype correlation, and digenic inheritance causing partial phenotype J. Med. Genet., January 1, 2005; 42(1): 58 - 68. [Abstract] [Full Text] [PDF]

				T. Peters, C. Thaete, S. Wolf, A. Popp, R. Sedlmeier, J. Grosse, M.C. Nehls, A. Russ, and V. Schlueter A mouse model for cystinuria type I Hum. Mol. Genet., September 1, 2003; 12(17): 2109 - 2120. [Abstract] [Full Text] [PDF]

				L. Feliubadalo, M. L. Arbones, S. Manas, J. Chillaron, J. Visa, M. Rodes, F. Rousaud, A. Zorzano, M. Palacin, and V. Nunes Slc7a9-deficient mice develop cystinuria non-I and cystine urolithiasis Hum. Mol. Genet., September 1, 2003; 12(17): 2097 - 2108. [Abstract] [Full Text] [PDF]

				E. Fernandez, D. Torrents, J. Chillaron, R. Martin del Rio, A. Zorzano, and M. Palacin Basolateral LAT-2 Has a Major Role in the Transepithelial Flux of L-Cystine in the Renal Proximal Tubule Cell Line OK J. Am. Soc. Nephrol., April 1, 2003; 14(4): 837 - 847. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Strologo, L. D. Articles by Rizzoni, G. Search for Related Content PubMed PubMed Citation Articles by Strologo, L. D. Articles by Rizzoni, G.