Heteromeric amino acid transporters: cystinuria and lysinuric protein intolerance

  • Josep Chillarón
  • Joan Bertran
  • Manuel Palacín

Abstract

Six families of plasma membrane amino acid transporters have been described in mammals, one of which has a heteromeric structure (Palacón et al. 1998; Chillarón et al. 2001). These heteromeric amino acid transporters (HATs) are composed of a heavy subunit and a ligh t subunit, linked by a disulfide bridge (Table 1, Figure 1). Two homologous heavy subunits (HSHATs) are known, rBAT (re lated to system bO,+ amino acid transport) and 4F2hc (heavy chain of the surface antigen 4F2, also referred to as CD98). Nine light subunits (LSHATs) have been identified. Six of them are partners of 4F2hc (LAT-l, LAT-2, y+LAT-l, y+LAT-2, asc-I, and xCT), one assembles with rBAT (bo,+AT), and two (asc-2 and AGT-l) seem to interact with as yet unknown heavy subunits (Kanai et al. 1998; Mastroberardi no et al. 1998; Torrents et al. 1998; Feliubadalo et al. 1999; Pineda et al. 1999; Rossier et al. 1999; Sato et al. 1999; Bröer et al. 2000; Fukasawa et al. 2000; Chairoungdua et al. 2000; Matsuo et al. 2002).

Keywords

Osteoporosis Glycine Cysteine Proline Glutamine 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Adibi, SA (1971). Intestinal Transport of Dipcptides in Man: Relative Importance of Hydrolysis and Intact Absorption. J, Clin. Invest., 50, 2266.CrossRefGoogle Scholar
  2. Angelo, S. and Devés, R. (1994). Amino Acid Transport System y+L of Human Erythrocytes: Specificity and Cation Dependence of the Translocation Step. J. Membr. Biol., 141, 183–192.PubMedGoogle Scholar
  3. Asatoor, A.M., Groughman, M.R., Harrison, A.R., Light, F.W., Loughridge, L.w., Milne, M.D., et al. (1971). Intestinal Absorption of Oligopeptides in Cystinuria. Clin. Sci., 41, 23.PubMedGoogle Scholar
  4. Awrich, A.E., Stackhouse, J., Cantrell, J.E., Patterson, J.H., and Rudman, D. (1975). Hyperdibasicaminoaciduri a, Hyperammonemia, and Growth Retardation: Treatment with Arginine, Lysine, and Citrulline. J. Pediatr., 87, 731.PubMedCrossRefGoogle Scholar
  5. Bauch, C., Forster, N., Loffing-Cueni, D., Summa, V., and Verrey, F. (2003). Functional Cooperation of Epithelial Heteromeric Amino Acid Transporters Expressed in Madin-Darby Canine Kidney Cells. J. Biol. Chem. 278,1316–1322.PubMedCrossRefGoogle Scholar
  6. Bertran, J., Magagnin, S., Werner, A., Markovich, D., Biber, J., Testar, X., et al. (1992a). Stimulation of System y(+)-Like Amino Acid Transport by the Heavy Chain of Human 4F2 Surface Antigen in Xenopuslaevis Oocytes. Proc. Natl Acad. Sci. USA. 89, 5606–5610.PubMedCrossRefGoogle Scholar
  7. Bertran, J., Werner, A., Moore, M.L., Stange, G., Markovich, D., Biber, J., et al. (1992b). Express ion Cloning of a cDNA from Rabbit Kidney Cortex that Induces a Single Transport System for Cystine and Dibasic and Neutral Amino Acids. Proc. Natl Acad. Sci. USA. 89, 5601–5605.PubMedCrossRefGoogle Scholar
  8. Bertran, J., Werner, A., Chillarón, J., Nunes, V., Biber, J., Testar, X., et al. (1993). Expression Cloning of a Human Renal cDNA that Induces High Affinity Transport of L-Cystine Shared with Dibasic Amino Acids in Xenopus Oocytes. J. Biol. Chem., 268, 14842–14849.PubMedGoogle Scholar
  9. Bisaccia, E, Zara, V., Capobianco, L., lacobazzi, V., Mazzeo, M., and Palmieri, F. (1996). The Formation of a Disulfide Cross-Link between the Two Subunits Demonstrates the Dimeric Structure of the Mitochondrial Oxoglutarate Carrier. Biochim. Biophys. Acta. 1292, 281–288.PubMedCrossRefGoogle Scholar
  10. Bisceglia, L., Calonge, M.J., Totaro, A., Feliubadalo, L., Melchionda, S., Garcia, J., et al. (1997). Localization, by Linkage Analysis, of the Cystinuria Type III Gene to Chromosome 19q1 3. 1. Am. J. Hum. Genet., 60, 611–616.PubMedGoogle Scholar
  11. Boll, M., Markovich, D., Weber, W.M., Korte. H., Daniel, H., and Murer, H. (1994). Expression Cloning of a cDNA from Rabbit Small Intestine Related to ProtonCoupled Transport of Peptides, Beta-Lactam Antibiotics and ACE-Inhibitors. Pflügers Arch., 429, 146–149.PubMedCrossRefGoogle Scholar
  12. Boll, M., Herget, M., Wagener, M., Weber, W.M., Markovich, D., Biber, J., et al. (1996). Expression Cloning and Functional Characterization of the Kidney Cortex High-Affinity Proton-Coupled Peptide Transporter. Proc. Natl Acad. Sci. USA. 93, 284–289.PubMedCrossRefGoogle Scholar
  13. Borsani, G., Bassi, M.T., Sperandeo, M.P., De Grandi, A., Buoninconti, A., Riboni, M., et al. (1999). SLC7A 7, Encoding a Putative Permease-Related Protein, is Mutated in Patien ts with Lysinuric Protein Intolerance. Nat. Genet., 21, 297–301.PubMedCrossRefGoogle Scholar
  14. Boyd, C.A., Devés, R., Laynes, R., Kudo. Y, and Sebastio, G. (2000). Cat ionic Amino Acid Transport Through System y+L in Erythrocytes of Patients with Lysinuric Protein Intolerance. Pflügers Arch., 439, 513–516.PubMedCrossRefGoogle Scholar
  15. Bröer, S. and Wagner, C.A. (2002). Structure-Function Relationships of Heterodimeric Amino Acid Transporters. Cell Biochem. Biophys., 36, 155–168.PubMedCrossRefGoogle Scholar
  16. Bröer, A., Wagner, C.A., Lang, F, and Bröer, S. (2000). The Heterodimeric Amino Acid Transporter 4F2hc/y+LAT2 Mediates Arginine Efflux in Exchange with Glutamine. Biochem. J., 349, 787–795.PubMedGoogle Scholar
  17. Busch, A.E., Herzer. T., Wald egger, S., Schmidt, E, Palacín, M., Biber. J., et al. (1994). Opposite Direct ed Currents Induced by the Tran sport of Dibasic and Neutral Amino Acids in Xenopus Oocytes Expressing the Protein rBAT. J. Biol. Chem., 269, 25581–25586.PubMedGoogle Scholar
  18. Calonge, MJ., Gasparini, P., Chillarón, J., Chillon, M., Gallucci, M., Rousaud, F., et al. (1994). Cystinuria Caused by Mutations in rBAT, a Gene involved in the Transport of Cystine. Nat. Genet., 6, 420–425.PubMedCrossRefGoogle Scholar
  19. Calonge, MJ., Volpini, V., Bisceglia. L., Rousaud, F., DeSantis. L., Brescia, E., et al. (1995). Genetic Heterogeneity in Cystinuria: The rBAT Gene is Linked to Type I but not to Type III Cystinuria. Proc. Natl Acad. Sci. USA. 92, 9667–9671.PubMedCrossRefGoogle Scholar
  20. Carpenter, T.O., Levy, H.L., Holtrop, M.E., Shih, VE., and Anast, C.S. (1985). Lysinuric Protein Intolerance Presenting as Childhood Osteoporosis. Clinical and Skeletal Response to Citrulline Therapy. N. Engl. J. Med. 312, 290–294.PubMedCrossRefGoogle Scholar
  21. Chairoungdua, A., Segawa, H., Kim, J.Y., Miyamoto, K., Haga, H., Fukui, Y, et al. (1999). Identification of an Amino Acid Transporter Associated with the Cystinuria Related Type II Membrane Glycoprotein. J. Biol. Chem., 274, 28845–28848.PubMedCrossRefGoogle Scholar
  22. Chairoungdua, A., Kanai, Y, Matsuo, H., Inatomi, J., Kim. D.K., and Endou, H. (2001). Identification and Characterization of a Novel Member of the Heterodimeric Amino Acid Transporter Family Presumed to be Associated with an Unknown Heavy Chain. J. Biol. Chem., 276, 49390–49399.PubMedCrossRefGoogle Scholar
  23. Cheeseman, C.I. (1983). Characteristics of Lysine Transport Across the Serosal Pole of the Anuran Small Intestine. J. Physiol., 338, 87–97.PubMedGoogle Scholar
  24. Chillarón, J., Estévez, R., Mora, C., Wagner. C.A., Suessbrich, H., Lang, E, et al. (1996). Obligatory Amino Acid Exchange via Systems bO,+-Like and y+L Like. A Tertiary Active Transport Mechanism for Renal Reabsorption of Cystine and Dibasic Amino Acids. J. Biol. Chem., 271, 17761–17770.PubMedCrossRefGoogle Scholar
  25. Chillarón, J., Estévez, R., Samarzija, I., Waldegger, S., Testar, X., Lang, E, et al. (1997). An Intracellular Trafficking Defect in Type I Cystinuria rBAT Mutants M467T and M467K. J. Biol. Chem., 272, 9543–9549.PubMedCrossRefGoogle Scholar
  26. Chillarón, J., Roca, R., Valencia, A., Zorzano, A., and Palacín, M. (2001). Heteromeric Amino Acid Transporters: Biochemistry, Genetics. and Physiology. Am. J. Physiol. Renal Phvsiol., 281, F995–10 18.Google Scholar
  27. Christensen. H.N. (1984). Organic Ion Transport during Seven Decades. The Amino Acids. Biochim. Biophys. Acta, 779, 255–269.PubMedCrossRefGoogle Scholar
  28. Christensen, H.N. (1990). Role of Amino Acid Transport and Countertransport in Nutrition and Metabolism. Physiol. Rev., 70, 43–77.PubMedGoogle Scholar
  29. Coady. MJ., Chen, X.Z., and Lapointe, J.Y (1996). rBAT is an Amino Acid Exchanger with Variable Stoichiometry. J. Membr: Biol., 149, 1–8.CrossRefGoogle Scholar
  30. Crawhall, J.C., Scowen, E.F., Thompson. CJ., and Watts, R.W.E. (1967). The Renal Clearance of Amino Acids in Cystinuria. J. Clin. Invest., 46, 1162–1171.PubMedCrossRefGoogle Scholar
  31. Dall’ Asta, V, Bussolati, O., Sala, R., Rotoli, B.M., Sebastio, G., Sperandeo, M.P., et al. (2000). Arginine Transport through System y(+ )L in Cultured Human Fibroblasts: Normal Phenotype of Cells from LPI Subjects. Am. J. Physiol. Cell Physiol., 279, C1829–C1837.Google Scholar
  32. Dello Strologo, L., Carbonari, D., Gallucci, M., Gasparini, P., Bisceglia, L., Zelante, L., et al. (1997). Inter and Intrafamilial Clinical Variability in Patients with Cystinuria Type I and Identified Mutation. J. Am. Soc. Nephrol., 8, 388A.Google Scholar
  33. Dello Strologo, L., Pras, E., Pontesilli, C., Beccia, E., Ricci-Barbini, V. deSanctis, L., et al. (2002). Comparison between SLC3A I and SLC7A9 Cystinuria Patients and Carriers: A Need for a New Classification. J. Am. Soc. Nephrol., 13, 2547–2553.CrossRefGoogle Scholar
  34. de Sanctis, L., Bonetti, G., Bruno, M., De Luca, E, Bisceglia, L., Palacín, M., et al. (2001). Cystinuria Phenotyping by Oral Lysine and Arginine Loading. Clin. Nephrol., 56, 467–474.PubMedGoogle Scholar
  35. Desjeux, J.-F., Rajantie, J., Sirnell, O., Dumontier, A.-M., and Perheentupa, J. (1980). Lysine Fluxe s across the Jejunal Epithelium in Lysinuric Protein Intolerance. J. Clin. Invest., 65, 1382–1387.PubMedCrossRefGoogle Scholar
  36. Dovés, R. and Boyd, C.A. (1998). Transporter s for Cationic Amino Acid s in Animal Cell s: Discover y, Structure, and Function. Physiol. Rev., 78, 487–545.Google Scholar
  37. Devés, R. and Boyd, C.A. (2000). Surface Antigen CD98(4F2): Not a Single Membrane Protein, but a Family of Proteins with Multiple Functions. J. Membr. Biol., 173, 165–177.PubMedCrossRefGoogle Scholar
  38. Devés, R., Chavez, P., and Boyd, C.A.R. (1992). Identification of a New Transport System (y+L) in Human Erythrocytes that Recognizes Lysine and Leucine with High Affinity. J. Physiol., 454, 491–501.PubMedGoogle Scholar
  39. Devés, R., Ange lo, S., and Chavez, P. (1993). Nethylmaleimide Discriminates between Two Lysine Transport System s in Human Erythrocytes. J. Physiol., 468, 753–766.PubMedGoogle Scholar
  40. Dierks, T., Riemer. E., and Kramer, R. (1988). Reaction Mechanism of the Reconstituted Aspartate/Glutamate Carrier from Bovine Heart Mitochondria. Biochim. Biophys. Acta, 943, 231–244.PubMedCrossRefGoogle Scholar
  41. DiRocco, M., Garibotto, G., Rossi, G.A., Caruso, U., Taccone, A., Picco, P., et al. (1993). Role of Haema-tological, Pulmonary and Renal Complications in the Long-Term Prognosis of Patients with Lysinuric Protein Intolerance. Eur. J. Pediatr., 152, 437.PubMedCrossRefGoogle Scholar
  42. Eleno, N., Devés, R., and Boyd, CAR. (1994). Membrane Potential Dependence of the Kinetics of Cationic Amino Acid Tran sport Systems in Hum an Placenta. J. Physiol., 479, 291–300.PubMedGoogle Scholar
  43. Estevez, R., Camps, M., Rojas, A.M., Testar, X., Devés, R., Hediger, M.A., et al. (1998). The Amino Acid Transport System y+L/4F2hc Is a Heteromultimeric Complex. FASEB J., 12, 1319–1329.PubMedGoogle Scholar
  44. Fei, YJ., Kanai, Y., Nussberger, S., Ganapathy, Y., Leibach, EH., Romero, M.E, et al. (1994). Expression Cloning of a Mammalian Proton-Coupled Oligopeptide Tran sporter. Nature, 368, 563–566.PubMedCrossRefGoogle Scholar
  45. Feliubadalo, L., Font, M., Purroy, J., Rousaud, E., Estivill, X., Nunes, Y., et al. (1999). Non-Type I Cystinuria Caused by Mutations in SLC7A9, Encoding a Subunit (bo,+AT) of rBAT. Nat. Genet., 23, 52–57.PubMedGoogle Scholar
  46. Fene zik, C.A., Zent, R., Dellos, M., Calderwood, D.A., Satriano, J., Kelly, C., et al. (2001). Distinct domains of CD98hc Regulate Integrins and Amino Acid Transport. J. Biol. Chem., 276, 8746–8752.CrossRefGoogle Scholar
  47. Fernández, E., Carraseal, M., Rousaud, E., Abian, J., Zorzano, A., Palaciń, M., et al. (2002). rBAT-b(O,+)AT Heterodimer is the Main Apical Reabsorption System for Cystine in the Kidney. Am. J. Physiol. Renal Physiol., 283, F540–F5488.PubMedGoogle Scholar
  48. Fernández, E., Torrents, D., Chillarón, J., Martín del Río, R., Zorzano, A., and Palacín, M. (2003). Basolateral LAT-2 Has a Major Role in the Transepithelial Flux of L-Cystine in the Renal Proximal Tubule Cell Line, O.K. J. Am. Soc. Nephrol., 14, 837–847.PubMedCrossRefGoogle Scholar
  49. Font, M.A., Feliubadalo, L., Estivill, X., Nunes, Y., Golomb, E., Kreiss, Y., et al. (2001). Functional Analysis of Mutations in SLC7A9, and Genotype/Phenotype Correlation in Non-Type I Cystinuria. Hum. Mol. Genet., 10, 305–316.PubMedCrossRefGoogle Scholar
  50. Frimpter, G.w., Horwith, M., Furth, E., Fellows, R.E., and Thompson, D.D. (1962). Inulin and Endogenous Amino Acid Renal Clearances in Cystinuria: Evidence for Tubular Secretion. J. Clin. Invest., 41, 281–288.PubMedCrossRefGoogle Scholar
  51. Fukasawa, Y., Segawa, H., Kim, J.Y., Chairoungdua, A., Kim, DK, Matsuo, H., et al. (2000). Identification and Characterization of a Na+-Independent Neutral Amino Acid Transporter that Associates with the 4F2 Heavy Chain and Exhibits Substrate Selectivity for Small Neutral D-and L-Amino Acids. J. Biol. Chem., 275, 9690–9698.PubMedCrossRefGoogle Scholar
  52. Furriols, M., Chillarón, J., Mora, C., Castello, A., Bertran, J., Camps, M., et al. (1993). rBAT, Related to L-Cysteine Transport, is Localized to the Microvilli of Proximal Straight Tubules, and its Expression is Regulated in Kidney by Development. J. Biol. Chem., 268, 27060–27068.PubMedGoogle Scholar
  53. Garrod, A.E. (1908). Inborn Errors of Metabolism (Lectures I-IV). Lancet, ii, 1–214.CrossRefGoogle Scholar
  54. Goodyer, P.R., Clow, C. Reade, T., and Girardin, C. (1993). Prospective Analysis and Classification of Patients with Cystinuria Identified in a Newborn Screening Program. J. Pediatr., 122, 568–572.PubMedCrossRefGoogle Scholar
  55. Groneberg, D.A., Doring, E, Eynott, P.R., Fischer, A., and Daniel, H. (2001). Intestinal Peptide Transport: Ex Vivo Uptake Studies and Localization of Peptide Carrier PEPT1. Am. J. Physiol. Gastrointest. Liver Physiol., 281, G697–704.PubMedGoogle Scholar
  56. Henthorn, P.S., Liu, J., Gidalevich, T., Fang, J., Casal, M.L., Patterson, D.F., et al. (2000). Canine Cystinuria: Polymorphism in the Canine SLC3A1 Gene and Identification of a Nonsense Mutation in Cystinuric Newfoundland Dogs. Hum. Genet., 107, 295–303.PubMedCrossRefGoogle Scholar
  57. Iida, S., Peck, A.B., Jonson-Tardieu, J., Moriyama, M., Glenton, P.A., Byer, K.J., et al. (1999). Temporal Changes in mRNA Expresi6n for Bikunin in the Kidneys of Rats during Calcium Oxalate Nephrolithiasis. J. Am. Soc. Nephrol., 10, 986–996.PubMedGoogle Scholar
  58. Janecek, S., Svensson, B., and Henrissat, B. (1997). Domain Evolution in the Alpha-Amylase Family. J. Moi. Eval., 45, 322–331.CrossRefGoogle Scholar
  59. Kanai, Y., Segawa, H., Miyamoto, K., Uchino, H., Takeda, E., and Endou, H. (1998). Expression Cloning and Characterization of a Transporter for Large Neutral Amino Acids Activated by the Heavy Chain of 4F2 Antigen (CD98). J. Biol. Chem., 273, 23629–23632.PubMedCrossRefGoogle Scholar
  60. Kanai, Y., Fukasawa, Y., Cha, S.H., Segawa, H., Chairoungdua, A., Kim, D.K., et al. (2000). Transport Properties of a System y+L Neutral and Basic Amino Acid Transporter. Insights into the Mechanisms of Substrate Recognition. J. Bio. Chem., 275, 20787–20793.CrossRefGoogle Scholar
  61. Kekomaki, M., Visakorpi, J.K., Perheentupa, J., and Saxen, L. (1967). Familial Protein Intolerance with Deficient Tran sport of Basic Amino Acids. An Analysis of 10 Patients. Acta Paediatr. Scand., 56, 617.PubMedCrossRefGoogle Scholar
  62. Kim, J.W, Closs, E.I., Albritton, L.M., and Cunningham, J.M. (1991). Transport of Cationic Amino Acids by the Mouse Ecotropic Retrovirus Receptor. Nature, 352, 725–728.PubMedCrossRefGoogle Scholar
  63. Lauteala, T., Sistonen, P., Savontaus, M.-L., Mykkänen, J., Simell, J., Lukkarinen, M., et al. (1997). Lysinuric Protein Intolerance (LPI) Gene Maps to the Long Arm of Chromosome 14. Am. J. Hum. Genet., 60, 1479.PubMedCrossRefGoogle Scholar
  64. Lauteala, T., Mykkanen, J., Sperandeo, M.P., Gasparini, P., Savontaus, M.L., et al. (1998). Genetic Homogeneity of Lysinuric Protein Intolerance. Eur.J. Hum. Genet., 6, 612.PubMedCrossRefGoogle Scholar
  65. Lee, W.S., Wells, R.G., Sabbag, R.Y., Mohandas, T.K., and Hediger, M.A. (1993). Cloning and Chromosomal Localization of a Human Kidney cDNA Involved in Cystine, Dibas ic, and Neutral Amino Acid Transport. J. Clin. Invest., 91, 1959–1963.PubMedCrossRefGoogle Scholar
  66. Mannion, B.A., Kolesnikova, T.V, Lin, S.H., Wang, S., Thompson, N.L., and Hemler, M.E. (1998). The Light Chain of CD98 Is Identified as E16/TA I Protein. J. Biol. Chem., 273, 33127–33129.PubMedCrossRefGoogle Scholar
  67. Mastroberardino, L., Spindler, B., Pfeiffer, R., Skelly, P.J., Loffing, J., Shoemaker, C.B., et al. (1998). Amino-Acid Tran sport by Heterodimers of 4F2hc/ CD98 and Members of a Permease Family. Nature, 395, 288–291.PubMedCrossRefGoogle Scholar
  68. Matsuo, H., Kanai, Y., Kim, J.Y., Chairoungdua, A., Kim D.K., Inatomi, J., et al. (2002). Identification of a Novel Na+-Independent Acidic Amino Acid Tran sporter with Structural Similarity to the Member of a Heterodimeric Amino Ac id Transporter Family Associated with Unknown Heavy Chains. J. Biol. Chern., 277, 21017–21026.CrossRefGoogle Scholar
  69. Matthews, D.M. and Adib i, S.A. (1976). Peptide Absorption. Gastroenterology, 71, 151.Google Scholar
  70. Meier, C. Ristic, Z., Klauser, S., and Verrey, F. (2002). Activation of System L Heterodimeric Amino Acid Exchangers by Intracellular Substrates. EMBO J., 21, 580–589.PubMedCrossRefGoogle Scholar
  71. Mizoguchi, K., Cha, S.H., Chairoungdua, A., Kim, D.K., Shigeta, Y., Matsuo, H., et al. (2001). Human Cystinuria-Related Transporter: Localization and Functional Characterization. Kidney Int., 59, 1821–1833.PubMedCrossRefGoogle Scholar
  72. Mora, C., Chillarón, J., Calonge, M.J., Forgo, J., Testar, X., Nunes, V., et al. (1996). The rBAT Gene Is Responsible for L-Cystine Uptake via the b0,(+)-Like Amino Acid Transport System in a “Renal Proximal Tubular” Cell Line (OK Cell s). J. Biol. Chem., 271, 10569–10576.PubMedCrossRefGoogle Scholar
  73. Mosckovitz, R., Udenfriend, S., Felix, A., Heimer, E., and Tate, S.S. (1994). Membrane Topology of the Rat Kidney Neutral and Basic Amino Acid Transporter. FASEB J., 8, 1069–1074.PubMedGoogle Scholar
  74. Mykkanen, J., Torrents, D., Pineda, M., Camps, M., Yoldi, M.E., Horelli-Kuitunen, N., et al. (2000). Functional Analysis of Novel Mutations in y(+)LAT-1 Amino Acid Transporter Gene Causing Lysinuric Protein Intolerance (LPI). Hum. Mol. Genet., 9, 431–438.PubMedCrossRefGoogle Scholar
  75. Nagata, M., Suzuki, M., Kawamura, G., Kono, S., Koda, N., Yamaguchi, S., et al. (1987). Immunological Abnormalities in a Patient with Lysinuric Protein Intolerance. Eur. J. Pediatr., 146, 427.PubMedCrossRefGoogle Scholar
  76. Nozaki, J., Dakcishi, M., Ohura, T, Inoue, K., Manabe, M., Wada, Y., et al. (2001). Homozygosity Mapping to Chromo some 5pl5 of a Gene Responsible for Hartnup Disorder. Biochem. Biophys. Res. Commun., 284, 255–260.PubMedCrossRefGoogle Scholar
  77. Oyanagi, K., Miura, R., and Yamanouchi, T (1970). Congenital Lysinuria: A New Inherit ed Tran sport Disorder of Dibasic Amino Acids. J. Pediatr., 77, 259.CrossRefGoogle Scholar
  78. Alacín, M., Estévez, R., Bertran, J., and Zorzano, A. (1998). Molecular Biology of Mammalian Plasma lembrane Amino Acid Transporters. Physiol. Rev., 78, 1–1054.Google Scholar
  79. Palacín, M., Bertran, J., and Zorzano, A. (2000). Heteromeric Amino Acid Transporters Explain Inherited Aminoacidurias. Curr. Opin. Nephrol. Hypertens., 9, 547–553.PubMedCrossRefGoogle Scholar
  80. Palacín, M., Borsani, G., and Sebastio, G. (2001a). The Molecular Bases of Cystinuria and Lysinuric Protein Intolerance. Curr. Opin. Genet. Dev., 11, 328–335.PubMedCrossRefGoogle Scholar
  81. Palacín, M., Goodyer, P., Nunes, V., and Gasparini, P. (2001b). Cystinuria. In C.R. Scriver, A.L. Beaudet, S.w. Sly, and D. Valle (eds), Metabolic and Molecular Bases of Inherited Diseases (8th edn), New York: McGraw-Hill, pp. 4909–4932.Google Scholar
  82. Parto, K., Svedstrom, E., Maju rin, M.L., Harkonen, R., and Simell, O. (1993). Pulmonary Manifestations in Lysinuric Protein Intolerance. Chest, 104, 1176.PubMedCrossRefGoogle Scholar
  83. Perheentupa, J. and Visakorpi, J.K. (1965). Protein Intolerance with Deficient Transport of Basic Amino Acids. Lancet, ii, 813.CrossRefGoogle Scholar
  84. Pfeiffer, R., Spindler, B., Lofting, J., Skelly, P.J., Shoemaker, C.B., and Verrey, F. (1998). Functional Heterodimeric Amino Acid Transporters Lacking Cystine Residues Involved in Disulfide Bond. FEBS Lett., 439, 157–162.PubMedCrossRefGoogle Scholar
  85. Pfeiffer, R., Lofting, J., Rossier, G., Bauch, C., Meier, C., Eggermann, T, et al. (1999a). Luminal Heterodimeric Amino Acid Transporter Defective in Cystinuria. Mol. Biol. Cell., 10, 4135–4147.PubMedGoogle Scholar
  86. Pfeiffer, R., Rossier, G., Spindler, B., Meier, C., Kuhn, L., and Verrey F. (1999b). Amino Acid Transport of y+L-Type by Heterodimers of 4F2hc/CD98 and Members of the Glycoprotein-Associated Amino Acid Transporter Family. EMBO J., 18, 49–57.PubMedCrossRefGoogle Scholar
  87. Pickel, VM., Nirenberg, M.J., Chan, J., Mosckovitz, R., Udenfriend, S., and Tate, S.S. (1993). Ultra structural Localizati on of a Neutral and Basic Amino Acid Tran sporter in Rat Kidney and Intestine. Proc. Natl Acad. Sci. USA. 90, 7779–7783.PubMedCrossRefGoogle Scholar
  88. Pineda, M., Fernández, E., Torrents, D., Estévez, R., Lopez, C., Camps, M., et al. (1999). Identification of a Membrane Protein, LAT-2, that Co-expresses with 4F2 Heavy Chain, an L-Type Amino Acid Transport Acti vity with Broad Specificity for Small and Large Zwitterionic Amino Acids. J. Biol. Chem., 274, 19738–19744.PubMedCrossRefGoogle Scholar
  89. Rajantie, J., Simell, O., and Perheentupa, J. (1980a). Basolateral Membrane Transport Defect for Lysine in Lysinuric Protein Intolerance. Lancet, i, 1219–1221.CrossRefGoogle Scholar
  90. Rajantie, J., Simell, O., and Perheentupa. J. (1980b). Intestinal Absorption in Lysinuric Protein Intolerance: Impaired for Diamino Acid s, Normal for Citrulline. Gut, 21, 519.PubMedCrossRefGoogle Scholar
  91. Rajantie, J., Simell, O., Rapola, J., and Perheentupa, J. (1980c). Lysinuric Protein Intolerance: A Two-Year Trial of Dietary Supplementation Therapy with Citrulline and Lysine. J. Pediatr., 97, 927.PubMedCrossRefGoogle Scholar
  92. Rajantie, J. and Sirnell, O. (1981). Lysinuric Protein Intolerance. Basolateral Membrane Transport Defect in Renal Tubuli. J. Clin. Invest., 67, 1078–1082.PubMedCrossRefGoogle Scholar
  93. Rajantie, J., Sirnell, O., and Perheentupa, J. (1983a). Oral admini stration of e-N-acetyllysine and Homocitrulline for Lysinuric Protein Intolerance. J. Pediatr., 102, 388.PubMedCrossRefGoogle Scholar
  94. Rajantie, J., Sirnell, O., and Perheentupa, J. (1983b). Oral Administration of Urea Cycle Intermediates in Lysinuric Protein Intolerance: Effect on Plasma and Urinary Arginine and Ornithine. Metabolism, 32, 49.PubMedCrossRefGoogle Scholar
  95. Reig, N., Chillarón, J., Bartoccioni. P., Fernández, E., Bendahan, A., Zorzano, A., et al. (2002). The Light Subunit of System bO,+ is Fully Functional in the Absence of the Heavy Subunit. EMBO J., 21, 4906–4914.PubMedCrossRefGoogle Scholar
  96. Rosenberg, L.E., Downing, S., Durant, J.L., and Segal, S. (1967). Cystinuria: Biochemical Evidence of Three Genetically Distinct Diseases. J. Clin. Invest., 46, 30.PubMedCrossRefGoogle Scholar
  97. Rossier, G., Meier, C, Bauch, C., Summa, V., Sordat, B., Verrey, F., et al. (1999). LAT2, a New Basolateral 4F2hc/CD98-Associated Amino Acid Transporter of Kidney and Intestine. J. Biol. Chem., 274, 34948–34954.PubMedCrossRefGoogle Scholar
  98. Saadi, I., Chen, X.Z., Hediger, M., Ong, P., Pereira, P., Goodyer, P., et al. (1998). Molecular Genetics of Cystinuria: Mutation Analysis of SLC3A I and Evidence for Another Gene in Type I (Silent) Phenotype. Kidney Int., 54, 48–55.CrossRefGoogle Scholar
  99. Saier, M.H., Jr, Beatty, J.T., Goffeau, A., Harley, K.T., Heijne, W.H., Huang, S.C., et al. (1999). The Major Facilitator Superfamily. J. Mol. Microbiol. Biotechnol., 1, 257–279.PubMedGoogle Scholar
  100. Sato, H., Tarnba, M., Ishii, T., and Bannai, S. (1999). Cloning and Expression of a Plasma Membrane Cystine/Glutamate Exchange Transporter Composed of Two Distinct Proteins. J. Biol. Chem., 274, 11455–11448.PubMedCrossRefGoogle Scholar
  101. Schroers, A., Burkovski, A., Wohlrab, H., and Kramer, R. (1998). The Phosphate Carrier from Yeast Mitochondria. Dimerization is a Prerequisite for Function. J. Biol. Chem., 273, 14269–14276.PubMedCrossRefGoogle Scholar
  102. Segal, S. and Thier, S.O. (1995). Cystinuria. In C.H. Scriver, A.L. Beaudet, W.S. Sly, and D. Valle (eds), Metabolic and Molecular Bases of Inherited Diseases, New York: McGraw-Hill, pp. 2479–2496.Google Scholar
  103. Shoji, Y., Noguchi, A., Shoji, Y., Matsumori, M., Takasago, Y., Takayanagi, M., et al. (2002). Five Novel SLC7A7 Variants and y+ L Gene-Expression Pattern in Cultured Lymphoblasts from Japanese Patients with Lysinuric Protein Intolerance. Hum. Mutat., 20, 375–381.PubMedCrossRefGoogle Scholar
  104. Silbernagl, S. (1988). The Renal Handling of Amino Acids and Oligopeptides. Physiol. Rev., 68, 911–1007.PubMedGoogle Scholar
  105. Silk, D.B., Perrett, D., and Clark, M.L. (1975). Jejunal and Ileal Absorption of Dibasic Amino Acids and an Arginine-Containing Dipeptide in Cystinuria. Gastroenterology, 68, 1426–1432.PubMedGoogle Scholar
  106. Simell, O. (2002). In /ldThe Metabolic and Molecular Bases of Inherited Disease”; Part 21 (Membrane Transport Disorders) Chapter 192 (Lysinuric Protein Intolerance and other Cat ionic Aminoacidurias). Available at http://genetics.acce ssmedicine.com.Google Scholar
  107. Simell, O. and Perheentupa, J. (1974). Renal Handling of Diamino Acids in Lysinuric Protein Intolerance. J. Clin. Invest., 54, 9–17.PubMedCrossRefGoogle Scholar
  108. Simell, O., Perheentupa, L Rapola, J., Visakorpi, J.K., and Eskelin, L.-E. (1975). Lysinuric Protein Intolerance. Am. J. Med., 59, 229.PubMedCrossRefGoogle Scholar
  109. Smith, D.W., Scriver, C.R., and Simell, O. (1988). Lysinuric Protein Intolerance Mutation is not Expressed in the Plasma Membrane of Erythrocytes. Hum. Genet., 80, 395–396.PubMedCrossRefGoogle Scholar
  110. Sperandeo, M.P., Bassi, M.T., Riboni, M., Parenti, G., Buoninconti, A., Manzoni, M., et al. (2000). Structure of the SLC7A7 Gene and Mutational Analysis of Patient s Affec ted by Lysinuric Protein Intolerance. Am. J. Hum. Genet., 66, 92–99.PubMedCrossRefGoogle Scholar
  111. Stoller, M.L., Bruce, J.E., Bruc e, C.A., Foroud, T., Kirkwo od, S.C., and Stambrook, PJ. (1999). Linkage of Type II and Type III Cystinuria to 19q13.1: Codominant Inheritance of Two Cystinuric Alleles at 19q 13.1 Produces an Extreme Stone-Forming Phenotype. Am. J. Med. Genet., 86, 134–139.PubMedCrossRefGoogle Scholar
  112. Tate, S.S., Yan, N., and Udenfriend, S. (1992). Expression Cloning of a Na+-Independent Neutral Amino Acid Tran sporter from Rat Kidne y. Proc. Natl Acad. Sci. USA, 89, 1–5.PubMedCrossRefGoogle Scholar
  113. Toivonen, M., Mykkanen, J., Aula, P., Sirnell, O., Savontaus, M.L., and Huoponen, K. (2002). Expression of Normal and Mutant GFP-Tagged y+L Amino Acid Transporter-l in Mammalian Cells. Biochem. Biophys. Res. Commun., 291, 1173–1179.PubMedCrossRefGoogle Scholar
  114. Torras-Llort, M., Torrents, D., Soriano-Garcia, J.E., Gelpi, J.L., Estévez, R., Ferrer, R., et al. (2001). Sequential Amino Acid Exchange Across bO,+-Like System in Chicken Brush Border Jejunum. J. Membr. Biol., 180, 213–220.PubMedCrossRefGoogle Scholar
  115. Torrents, D., Estévez, R., Pineda, M., Fernandez, E., Lloberas, J., Shi, Y.B., et al. (1998). Identification and Characterization of a Membrane Protein (y+ L Amino Acid Tran sporter-l) that Associates with 4F2hc to Encode the Am ino Acid Transport Activity y+ L. A Candidate Gene for Lysinuric Protein Intolerance. J. Biol. Chem., 273, 32437–32445.PubMedCrossRefGoogle Scholar
  116. Torrents, D., Mykkanen, J., Pineda, M., Feliubadalo, L., Estevez, R., de Cid, R., et al. (1999). Identification of SLC7A7, Encoding y+LAT-1, as the Lysinuric Protein Intolerance Gene. Nat. Genet., 21, 293–296.PubMedCrossRefGoogle Scholar
  117. Van Winkle, L.J. (1988). Amino Acid Tran sport in Developing Animal Oocyte s and Early Conceptuses. Biochim. Biophys. Acta, 947, 173–208.PubMedCrossRefGoogle Scholar
  118. Vecnhoff, L.M., Heuberger, E.H.M.L., and Poolman, B. (2002). Quaternary Structure and Function of Tran sport Protein s. Trends Biochem. Sci., 27, 242–249.CrossRefGoogle Scholar
  119. Verrey, E, Jack, D.L., Paulsen, LT., Saier, M.H., Jr, and Pfeiffer, R. (1999). New Glycoprotein-Associated Amino Acid Transporters. J. Membr. Biol., 172, 181–192.PubMedCrossRefGoogle Scholar
  120. Verrey, E., Meier, C., Rossier, G., and Kuhn, L.C. (2000). Glycoprotein-Associated Amino Acid Exchangers: Broadening the Range of Transport Specificity. Pflügers Arch., 440, 503–512.PubMedGoogle Scholar
  121. Völkl, H. and Silbernagl, S. (1982). Mutual Inhibition of t-Cystine/l-Cysteine and Other Neutral Amino Acids during Tubular Reabsorption. A Microperfusion Study in Rat Kidney. Pflügers Arch., 395. 190–195.PubMedCrossRefGoogle Scholar
  122. Wang, H., Kavanaugh, M.P., North, R.A., and Kabat, D. (1991). Cell-Surface Recept or for Ecotropic Murine Retroviruses is a Basic Amino-Acid Transporter. Nature, 352, 729–731.PubMedCrossRefGoogle Scholar
  123. Wartenfeld, R., Golomb, E., Katz, G., Bale, S.J., Goldman, B., Pras, M., et al. (1997). Molecular Analysis of Cystinuria in Libyan Jews: Exclusion of the SLC3AJ Gene and Mapping of a New Locus on 19q. Am. J. Hum. Genet., 60, 617–624.PubMedGoogle Scholar
  124. Watanabe, K., Hata, Y., Kizaki, H., Katsube, Y., and Suzuki, Y. (1997). The Refined Crystal Structure of Bacillus cereus Oligo-1,6-Glucosidase at 2.0 Å Resolution: Structural Characterization of Proline-Substitution Sites for Protein Thermostabilization. J. Mol. Biol., 269, 142–153.PubMedCrossRefGoogle Scholar
  125. Wells, R.G. and Hediger, M.A. (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. 5596–5600.PubMedCrossRefGoogle Scholar
  126. Wells. R.G., Lee, W.S., Kanai, Y., Leiden, J.M., and Hediger, M.A. (1992). The 4F2 Antigen Heavy Chain Induces Uptake of Neutral and Dibasic Amino Acids in Xenopus Oocytes. J. Biol. Chem., 267, 15285–15288.PubMedGoogle Scholar
  127. White, M.F. (1985). The Transport of Cationic Amino Acid sacross the Plasma Membrane of Mammalian Cells. Biochim. Biophys. Acta. 822, 355–374.PubMedCrossRefGoogle Scholar
  128. Xie, Y., Sakatsume, M., Nishi, S., Narita, I., Arakawa, M., and Gejyo, F. (2001). Expression. Roles, Receptors. and Regulation of Osteopontin in the Kidney. Kidney Int., 60, 1645–1657.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2003

Authors and Affiliations

  • Josep Chillarón
  • Joan Bertran
  • Manuel Palacín
    • 1
  1. 1.Dept. Bioquimica i Biologia MolecularUniversidad BarcelonaBarcelonaSpain

Personalised recommendations