Advertisement

Urological Research

, Volume 31, Issue 6, pp 417–425 | Cite as

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

  • Erik Fjellstedt
  • Lotta Harnevik
  • Jan-Olof Jeppsson
  • Hans-Göran Tiselius
  • Peter Söderkvist
  • Torsten Denneberg
Original Paper

Abstract

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.

Keywords

Cystinuria Urinary cystine Amino acid transport SLC3A1 SLC7A9 Inherited disease 

Notes

Acknowledgements

We thank all patients for their participation in this study. This investigation was supported by grants from FORSS (The Health Research Council in the South-East of Sweden), MFR (the Swedish Medical Research Council), Lisa and Johan Grönberg’s Research Fund and Skane County Council Research and Development Foundation. We wish to thank the late Mats Ekberg MD, Department of Internal Medicine, Hässleholm Hospital, Birger Lindergård MD, Department of Nephrology, Lund University Hospital, and Anders Christensson MD, Department of Nephrology and Transplantation, Malmö University Hospital, for valuable help in making the patients medical records available for this study. Ms Iréne Eriksson at the Renal Stone Unit, Division of Urology, Linköping University Hospital is acknowledged for managing patients and blood sampling. We also want to thank Mats Fredriksson, Department of Environmental Medicine, Linköping University Hospital for valuable statistical advice.

References

  1. 1.
    Albers A, Lahme S, Wagner C, Kaiser P, Zerres K, Capasso G, Pica A, Palacin M, Lang F, Bichler KH, Eggermann T (1999) Mutations in the SLC3A1 gene in cystinuric patients: frequencies and identification of a novel mutation. Genet Test 3:227PubMedGoogle Scholar
  2. 2.
    BertranJ, Werner A, Moore ML, Stange G, Markovich D, Biber J, Testar X, Zorzano A, Palacin M, Murer H (1992) Expression cloning of a cDNA from rabbit kidney cortex that induces a single transport system for cystine and dibasic amino acids. Proc Natl Acad Sci USA 89:5601PubMedGoogle Scholar
  3. 3.
    Bisceglia L, Calonge MJ, Dello Strologo L, Rizzoni G, de Sanctis L, Gallucci M, Beccia E, Testar X, Zorzano A, Estivill X, Zelante L, Palacin M, Gasparini P, Nunes V (1996) Molecular analysis of the cystinuria disease gene: identification of four new mutations, one large deletion, and one polymorphism. Hum Genet 98:447PubMedGoogle Scholar
  4. 4.
    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 (1997) Localization, by linkage analysis, of the cystinuria type III gene to chromosome 19q13.1. Am J Hum Genet 60:611PubMedGoogle Scholar
  5. 5.
    Bisceglia L, Purroy J, Jimenez-Vidal M, d’Adamo AP, Rousaud F, Beccia E, Penza R, Rizzoni G, Gallucci M, Palacin M, Gasparini P, Nunes V, Zelante L (2001) Cystinuria type I: identification of eight new mutations in SLC3A1. Kidney Int 59:1250CrossRefPubMedGoogle Scholar
  6. 6.
    Botzenhart E, Vester E, Scmidt C, Hesse A, Halber M, Wagner C, Lang F, Hoyer P, Zerres K, Eggermann T and members of the Arbeitsgemeinschaft fur Pädiatrische Nephrologie (APN) (2002) Cystinuria in children: distribution and frequencies of mutations in the SLC3A1 and SLC7A9 genes. Kidney Int 62:1136CrossRefPubMedGoogle Scholar
  7. 7.
    Calonge MJ, Gasparini P, Chillaron J, Chillon M, Gallucci M, Rousaud F, Zelante L, Testar X, Dallapiccola B, Di Silverio F et al (1994) Cystinuria caused by mutations in rBAT, a gene involved in the transport of cystine. Nat Genet 6:420PubMedGoogle Scholar
  8. 8.
    Chairoungdua A, Segawa H, Kim JY, Miyamoto K, Haga H, Fukui Y, Mizoguchi K, Ito H, Takeda E, Endou H, Kanai Y (1999) Identification of an amino acid transporter associated with the cystinuria-related type II membrane glycoprotein. J Biol Chem 274:28845CrossRefGoogle Scholar
  9. 9.
    Crawhall JC (1987) Cystinuria—an experience in management over 18 years. Min Elec Met 13:286Google Scholar
  10. 10.
    Crawhall JC, Scowen EF, Watts RWE (1963) Effect of penicillamine on cystinuria. Br Med J 1:588Google Scholar
  11. 11.
    Dahlberg PJ, van den Berg CJ, Kurtz SB, Wilson DM, Smith LH (1977) Clinical features and management of cystinuria. Mayo Clin Proc 52:533PubMedGoogle Scholar
  12. 12.
    Denneberg T, Jeppsson J-O, Stenberg P (1983) Alternative treatment of cystinuria with alpha-mercaptopropionylglycine, Thiola. Proc EDTA 20:427Google Scholar
  13. 13.
    Dent CE, Senior B (1955) Studies on the treatment of cystinuria. Br J Urol 27:317PubMedGoogle Scholar
  14. 14.
    Dent CE, Friedman M, Green H, Watson LCA (1965) Treatment of cystinuria. Br Med J 1:403Google Scholar
  15. 15.
    Egoshi KI, Akakura K, Kodama T, Ito H (2000) Identification of five novel SLC3A1 (rBAT) gene mutations in Japanese cystinuria. Kidney Int 57:25Google Scholar
  16. 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 et al (1999) Non-type I cystinuria caused by mutations in SLC7A9, encoding a subunit (bo,+AT) of rBAT. International Cystinuria Consortium. Nat Genet 23:52PubMedGoogle Scholar
  17. 17.
    Fernandez E, Carrascal M, Rousad F, Abian J, Zorzano A, Palacin M, Chillaron J (2002) rBAT-b(o,+)AT heterodimer is the main apical reabsorption system for cystine in the kidney. Am J Physiol Renal Physiol 283:F540PubMedGoogle Scholar
  18. 18.
    Fjellstedt E, Denneberg T, Jeppsson JO, Christensson A, Tiselius HG (2001) Cystine analyses of separate day and night urine as a basis for the management of patients with homozygous cystinuria. Urol Res 29:303CrossRefPubMedGoogle Scholar
  19. 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, International Cystinuria Consortium (2001) Functional analysis of mutations in SLC7A9, and genotype-phenotype correlation in non-type I cystinuria. Hum Mol Genet 10:305CrossRefGoogle Scholar
  20. 20.
    Gasparini P, Calonge MJ, Bisceglia L, Purroy J, Dianzani I, Notarangelo A, Rousaud F, Gallucci M, Testar X, Ponzone A et al (1995) Molecular genetics of cystinuria: identification of four new mutations and seven polymorphisms, and evidence for genetic heterogeneity. Am J Hum Genet 57:781PubMedGoogle Scholar
  21. 21.
    Gitomer WL, Reed BY, Ruml LA, Sakhaee K, Pak CY (1998) Mutations in the genomic deoxyribonucleic acid for SLC3A1 in patients with cystinuria. J Clin Endocrinol Metab 83:3688PubMedGoogle Scholar
  22. 22.
    Goodyer P, Saadi I, Ong P, Elkas G, Rozen R (1998) Cystinuria subtype and the risk of nephrolithiasis. Kidney Int 54:56PubMedGoogle Scholar
  23. 23.
    Harnevik L, Fjellstedt E, Molbaek A, Tiselius HG, Denneberg T, Söderkvist P (2001) Identification of 12 novel mutations in the SLC3A1 gene in Swedish cystinuria patients. Hum Mutat 18:516CrossRefPubMedGoogle Scholar
  24. 24.
    Harnevik L, Fjellstedt E, Molbaek A, Denneberg T, Söderkvist P (2003) Mutation analysis of SLC7A9 in cystinuria in Sweden: implications for involvement of additional cystinuria genes. Genet Test 7:13CrossRefPubMedGoogle Scholar
  25. 25.
    Horsford J, Saadi I, Raelson J, Goodyer PR, Rozen R (1996) Molecular genetics of cystinuria in French Canadians: identification of four novel mutations in type I patients. Kidney Int 49:1401PubMedGoogle Scholar
  26. 26.
    Jeppsson J-O, Karlsson IM (1972) Ion-exchange chromatography of physiological sulphur amino acids on a highly crosslinked resin. J Chromat 72:93PubMedGoogle Scholar
  27. 27.
    Kallistratos G, Timmerman A (1968) Uber die wirkung von Thiola. Naturvissenschaften 55:648Google Scholar
  28. 28.
    Kanai Y, Stelzner MG, Lee WS, Wells RG, Brown D, Hediger MA (1992) Expression of mRNA (D2) encoding a protein involved in amino acid transport in S3 proximal tubule. Am J Physiol 263:F1087PubMedGoogle Scholar
  29. 29.
    Langen H, von Kietzell D, Byrd D, Aslan-Kirchner, Vester U, Stuhrmann M, Dörk T, Saar K, Reis A, Schmidtke J, Brodehl J (2000) Renal polyamine excretion, tubular amino acid reabsorption and molecular genetics in cystinuria. Pediatr Nephrol 14:376CrossRefPubMedGoogle Scholar
  30. 30.
    Leclerc D, Butrous M, Suh D, Wu Q, Palacin M, Ellis JR, Goodyer P, Rozen R (2002) SLC7A9 mutations in all three cystinuria subtypes. Kidney Int 62:1550CrossRefPubMedGoogle Scholar
  31. 31.
    Lee W-S, Wells RG, Sabbag RV, Mohandas TK, Hediger MA (1993) Cloning and chromosomal localization of a human kidney cDNA involved in cystine, dibasic and neutral amino acid transport. J Clin Invest 91:1959PubMedGoogle Scholar
  32. 32.
    Levy HL, Shih VE, Madiga PM (1971) Massachusetts metabolic disorders screening program. I. Techniques and results of urine screening. Pediatrics 49:825Google Scholar
  33. 33.
    Linari F, Marangella M, Fruttero B, Bruno M (1980) The natural history of cystinuria: a 15-year follow-up in 106 patients. In: Smith LH, Robertson G, Finlayson B, (eds). Urolithiasis, clinical and basic research. Plenum Press, New York, p 145Google Scholar
  34. 34.
    Lindell A, Denneberg T, Jeppsson JO (1995) Urinary excretion of free cystine and the tiopronin-cysteine-mixed disulfide during long term tiopronin treatment of cystinuria. Nephron 71:328PubMedGoogle Scholar
  35. 35.
    Lotz M, Potts JT Jr, Holland JM, Kiser WS, Bartter FC (1966) D-penicillamine therapy in cystinuria. J Urol 95:257PubMedGoogle Scholar
  36. 36.
    Miyamoto K, Katai K, Tatsumi S, Sone K, Segawa H, Yamamoto H, Taketani Y, Takada K, Morita K, Kanayama H et al (1995) Mutations of the basic amino acid transporter gene associated with cystinuria. Biochem J 310:951PubMedGoogle Scholar
  37. 37.
    Mosckovitz R, Yan N, Heimer E, Felix A, Tate SS, Udenfriend S (1993) Characterization of the rat neutral and basic amino acid transporter utilizing anti-peptide antibodies. Proc Natl Acad Sci U S A 90:4022Google Scholar
  38. 38.
    Pak CYC, Fuller CJ, Sakhaee K, Zerwekh JE, Adams BV (1986) Management of cystine nephrolithiasis with alpha-mercaptopropionylglycine. J Urol 136:1003PubMedGoogle Scholar
  39. 39.
    Palacin M (1994) A new family of proteins (rBAT and 4F2hc) involved in cationic and zwitterionic amino acid transport: a tale of two proteins in search of a transport function. J Exp Biol 196:123PubMedGoogle Scholar
  40. 40.
    Pfeiffer R, Loffing J, Rossier G, Bauch C, Meier C, Eggermann T, Loffing-Cueni D, Kuhn LC, Verrey F (1999) Luminal heterodimeric amino acid transporter defective in cystinuria. Mol Biol Cell 10:4135PubMedGoogle Scholar
  41. 41.
    Pickel VM, Nirenberg MJ, Chan J, Mosckovitz R, Udenfriend S, Tate SS (1993) Ultrastructural localization of a neutral and basic amino acid transporter in rat kidney and intestine. Proc Natl Acad Sci U S A 90:7779Google Scholar
  42. 42.
    Pras E, Arber N, Askentijevich I, Katz G, Schapiro JM, Prosen L, Gruberg L, Harel D, Liberman U, Weissenbach J et al (1994) Localization of a gene causing cystinuria to chromosome 2p. Nat Genet 6:415PubMedGoogle Scholar
  43. 43.
    Pras E, Raben N, Golomb E, Arber N, Aksentijevich I, Schapiro JM, Harel D, Katz G, Liberman U, Pras M et al (1995) Mutations in the SLC3A1 transporter gene in cystinuria. Am J Hum Genet 56:1297PubMedGoogle Scholar
  44. 44.
    Rajan DP, Huang W, Kekuda R, George RL, Wang J, Conway SJ, Devoe LD, Leibach FH, Prasad PD, Ganapathy V (2000) Differential influence of the 4F2 heavy chain and the protein related to b(0,+) amino acid transport on substrate affinity of the heteromeric b(0,+) amino acid transporter. J Biol Chem 275:14331CrossRefPubMedGoogle Scholar
  45. 45.
    Reig N, Chillaron J, Bartoccion P, Fernandez E, Bendahan A, Zorzano A, Kanner D, Palacin M, Bertran J (2002) The light subunit of system b(0,+) is fully functional in the absence of the heavy subunit. EMBO J 16:4906CrossRefGoogle Scholar
  46. 46.
    Rosenberg LE, Downing SJ, Durant JL, Segal S (1966) Cystinuria: biochemical evidence of three genetically distinct diseases. J Clin Invest 45:365PubMedGoogle Scholar
  47. 47.
    Saadi I, Chen XZ, Hediger M, Ong P, Pereira P, Goodyer P, Rozen R (1998) Molecular genetics of cystinuria: mutation analysis of SLC3A1 and evidence for another gene in type I (silent) phenotype. Kidney Int 54:48PubMedGoogle Scholar
  48. 48.
    Schmidt C, Albers A, Tomiuk J, Eggerman K, Wagner C, Capasso G, Lahme S, Hesse A, Lang F, Zerres K, Eggermann T (2002) Analysis of the genes SLC7A9 and SLC3A1 in unclassified cystinurics: mutation detection rates and association between variants in SLC7A9 and the disease. Clin Nephrol 57:342Google Scholar
  49. 49.
    Stephens AD (1989) Cystinuria and its treatment. 25 years experience at St Bartholomew’s Hospital. J Inher Metab Dis 12:197PubMedGoogle Scholar
  50. 50.
    Strologo LD, Pras E, Pontesilli C, Beccia E, Ricci-Barbini V, De Sanctis L, Ponzone A, Gallucci M, Bisceglia L, Zelante L, Jimenez-Vidal M, Font M, Zorzano A, Rousaud F, Nunes V, Gasparini P, Palacin M, Rizzoni G (2002) Comparison between SLC3A1 and SCL7A9 cystinuria patients and carriers: a need for a new classification. J Am Soc Nephrol 13:2547PubMedGoogle Scholar
  51. 51.
    Tate SS, Yan N, Udenfriend S (1992) Expression cloning of a Na+-independent neutral amino acid transporter from rat kidney. Proc Natl Acad Sci U S A 89:1Google Scholar
  52. 52.
    Wartenfeld R, Golomb E, Katz G, Bale SJ, Goldman B, Pras M, Kastner DL, Pras E (1997) Molecular analysis of cystinuria in Libyan Jews: exclusion of the SLC3A1 gene and mapping of a new locus on 19q. Am J Hum Genet 60:617PubMedGoogle Scholar
  53. 53.
    Weinberger A, Sperling O, Rabinovitz M, Brosh S, Adam A, De Vries A (1974) High frequency of cystinuria among Jews of Libyan origin. Hum Hered 24:568PubMedGoogle Scholar
  54. 54.
    Wells RG, Hediger MA (1992) Cloning of a rat kidney cDNA that stimulates dibasic and neutral amino acid transport and has sequence similarity to glucosidases. Proc Natl Acad Sci USA 89:5596PubMedGoogle Scholar
  55. 55.
    Zhang XX, Rozen R, Hediger MA, Gooyer P, Eydoux P (1994) Assignment of the gene for cystinuria (SLC3A1) to human chromosome 2p21 by fluorescence in situ hybridisation. Genomics 24:413CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Erik Fjellstedt
    • 1
  • Lotta Harnevik
    • 2
  • Jan-Olof Jeppsson
    • 3
  • Hans-Göran Tiselius
    • 4
  • Peter Söderkvist
    • 2
  • Torsten Denneberg
    • 5
  1. 1.Department of Nephrology and TransplantationMalmö University HospitalMalmöSweden
  2. 2.Division of Cell Biology, Department of Biomedicine and SurgeryFaculty of Health SciencesLinköpingSweden
  3. 3.Department of Clinical ChemistryMalmö University HospitalMalmöSweden
  4. 4.Department of Urology, Huddinge University Hospital and Centre for Surgical SciencesKarolinska InstitutetStockholmSweden
  5. 5.Division of Urology, Department of Biomedicine and SurgeryFaculty of Health SciencesLinköpingSweden

Personalised recommendations