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Transport Defects of Amino Acids at the Cell Membrane: Cystinuria, Lysinuric Protein Intolerance and Hartnup Disorder

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Inborn Metabolic Diseases

Abstract

Inherited defects in amino acid transport at the cell membrane are usually expressed as selective renal aminoaciduria, i.e. the concentration of the affected amino acids is high in the urine while it is normal or low in plasma. Intestinal absorption of the affected amino acids is also almost always impaired. The clinical symptoms thus result from excess of certain amino acids in urine or lack of them in tissues. Consequently, in cystinuria renal stones may be formed because of high urinary concentration of poorly soluble cystine. In lysinuric protein intolerance (LPI), the transporter defect for the dibasic cationic amino acids leads to poor intestinal absorption and urinary loss of arginine, ornithine and lysine.

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References

  1. Chillaron J, Roca R, Valencia A et al. (2001) Heteromeric amino acid transporters: biochemistry, genetics, and physiology. Am J Physiol Renal Physiol 281:F995-F1018

    PubMed  CAS  Google Scholar 

  2. Lindell A, Denneberg T, Granerus G (1997) Studies on renal function in patients with cystinuria. Nephron 77:76–85

    Article  PubMed  CAS  Google Scholar 

  3. Purohit RS, Stoller ML (2004) Stone clustering of patients with cystine urinary stone formation. Urology 63:630–635

    Article  PubMed  Google Scholar 

  4. Parvari R, Brodyansky I, Elpeleg O et al. (2001) A recessive contiguous gene deletion of chromosome 2p16 associated with cystinuria and a mitochondrial disease. Am J Hum Genet 69:869–875

    Article  PubMed  CAS  Google Scholar 

  5. Jaeken J, Martens K, François I et al. (2006) Deletion of PREPL; a gene encoding a putative serine oligopeptidase, in patients with hypotonia-cystinuria syndrome. Am J Hum Genet 78:38–51

    Article  PubMed  CAS  Google Scholar 

  6. Calonge MJ, Gasparini P, Chillaron J et al. (1994) Cystinuria caused by mutations in RBAT, a gene involved in the transport of cystine. Nat Genet 6:420–425

    Article  PubMed  CAS  Google Scholar 

  7. Feliubadalo L, Font M, Purroy J et al. (1999) Non-type I cystinuria caused by mutations in SLCA9, encoding a subunit (b0,002B;)AT of rBAT. International Cystinuria Consortium. Nat Genet 23:52–57

    PubMed  CAS  Google Scholar 

  8. Leclerc D, Boutros M, Suh D et al. (2002) SLC7A mutations in all three cystinuria subtypes. Kidney Int 62:1550–1559

    Article  PubMed  CAS  Google Scholar 

  9. Dello-Strogolo L, Pras E, Pontesilli C et al. (2002) Comparison between SLC3A1 and SLC7A9 cystinuria patients and carriers: a need for a new classification. J Am Soc Nephrol 13:2547–2553

    Article  Google Scholar 

  10. Bisceglia L, Fischetti L, De Bonis P et al. (2010) Large rearrangements detected by MLPA, point mutations, and survey of the frequency of mutations within the SLC3A1 and SLC7A9 genes in a cohort of 172 cystinuric Italian patients. Mol Genet Metab 99:42–52

    Article  PubMed  CAS  Google Scholar 

  11. Schmidt C, Vester U, Wagner CA et al. (2003) Significant contribution of genomic rearrangements in SLC3A1 and SLC7A9 to the etiology of cystinuria. Kidney Int 64:1564–1573

    Article  PubMed  CAS  Google Scholar 

  12. Barbey F, Joly D, Rieu P et al. (2000) Medical treatment of cystinuria: critical reappraisal of long-term results. Clin Urol 163:1419–1423

    CAS  Google Scholar 

  13. Fjellstedt E, Denneberg T, Jeppsson JO, Tiselius HG (2001) A comparison of the effects of potassium citrate and sodium bicarbonate in the alkalinization of urine in homozygous cystinuria. Urol Res 29:295–302

    Article  PubMed  CAS  Google Scholar 

  14. Barbey F, Joly D, Rieu P et al. (2000) Medical treatment of cystinuria: critical reappraisal of long-term results. Clin Urol 163:1419–1423

    CAS  Google Scholar 

  15. DeBernardinis RJ, Coughlin CR, Kaplan P (2008) Penicillamine therapy for pediatric cystinuria: experience from a cohort of American children. J Urol 180:2620–2623

    Article  Google Scholar 

  16. Dello Strologo L, Laurenzi C, Legato A, Pastore A (2007) Cystinuria in children and young adults: success of monitoring free-cystine urine levels. Pediatr Nephrol 22:1869–1873

    Article  PubMed  Google Scholar 

  17. Berio A, Piazzi A (1998) Prophylaxis of cystine calculi by low dose of alpha mercaptopropionylglycine administered every other day. Panminerva Med 40:244–246

    PubMed  CAS  Google Scholar 

  18. Sterrett SP, Penniston KL, Wolf JS, Nakada SY (2008) Acetazolamide is an effective adjunct for urinary alkalization in patients with uric acid and cystine stone formation recalcitrant to potassium citrate. Urology 72:278–281

    Article  PubMed  Google Scholar 

  19. Chow GK, Streem SB (1996) Medical treatment of cystinuria: results of contemporary clinical practice. J Urol 156:1576–1578

    Article  PubMed  CAS  Google Scholar 

  20. Tiselius HG (2010) New horizons in the management of patients with cystinuria. Curr Opin Urol 20;169–173

    Article  PubMed  Google Scholar 

  21. Romanowsky I, Lismer L, Asali M, Rosenberg E, Kaneti J (2008) Percutaneous nephrolithotomy for pediatric renal calculus disease: 5 years of local experience. Arch Ital Urol Androl 80:56–58

    PubMed  Google Scholar 

  22. Daudon M, Cohen-Solail F, Barbey F et al (2003) Cystine crystal volume determination: a useful tool in the management of cystinuric patients. Urol Res 31:207–211

    Article  PubMed  CAS  Google Scholar 

  23. Coe FL, Clark C, Parks JH, Asplin JR (2001) Solid phase assay of urine cystine supersaturation in the presence of cystine binding drugs. J Urol 166:688–693

    Article  PubMed  CAS  Google Scholar 

  24. Goodyer P, Saadi I, Ong P et al. (1998) Cystinuria subtype and the risk of nephrolithiasis. Kidney Int 54:56–61

    Article  PubMed  CAS  Google Scholar 

  25. Perheentupa J, Visakorpi JK (1965) Protein intolerance with deficient transport of basic amino acids: another inborn error of metabolism. Lancet 2:813–816

    Article  PubMed  CAS  Google Scholar 

  26. Simell O, Perheentupa J, Rapola J et al. (1975) Lysinuric protein intolerance. Am J Med 59:229–240

    Article  PubMed  CAS  Google Scholar 

  27. Carpenter TO, Levy HL, Holtrop ME et al. (1985) Lysinuric protein intolerance presenting as childhood osteoporosis. Clinical and skeletal response to citrulline therapy. N Engl J Med 312:290–294

    Article  PubMed  CAS  Google Scholar 

  28. Svedström E, Parto K, Marttinen M et al. (1993) Skeletal manifestations of lysinuric protein intolerance. A follow-up study of 29 patients. Skeletal Radiol 22:11–16

    Article  PubMed  Google Scholar 

  29. Parto K, Svedström E, Majurin M-L et al. (1993) Pulmonary manifestations in lysinuric protein intolerance. Chest 104:1176–1182

    Article  PubMed  CAS  Google Scholar 

  30. Rajantie J, Simell O, Perheentupa J, Siimes MA (1980) Changes in peripheral blood cells and serum ferritin in lysinuric protein intolerance. Acta Paediatr Scand 69:741–745

    Article  PubMed  CAS  Google Scholar 

  31. Tanner LM, Niinikoski H, Näntö-Salonen K, Simell O (2010) Combined hyperlipidemia in patients with lysinuric protein intolerance. J Inherit Metab Dis, EPub ahead of print

    Google Scholar 

  32. Yoshida Y, Machigashira K, Suehara M et al. (1995) Immunological abnormality in patients with lysinuric protein intolerance. J Neurol Sci 134:178–182

    Article  PubMed  CAS  Google Scholar 

  33. Lukkarinen M, Parto K, Ruuskanen O et al. (1999) B and T cell immunity in patients with lysinuric protein intolerance. Clin Exp Immunol 116:430–434

    Article  PubMed  CAS  Google Scholar 

  34. Lukkarinen M, Näntö-Salonen K, Ruuskanen O et al. (1998) Varicella and varicella immunity in patients with lysinuric protein intolerance. J Inherit Metab Dis 21:103–111

    Article  PubMed  CAS  Google Scholar 

  35. Dionisi-Vici C, De Felice L, el Hachem M et al. (1998) Intravenous immunoglobulin in lysinuric protein intolerance. J Inherit Metab Dis 21:95–102

    Article  PubMed  CAS  Google Scholar 

  36. Kamoda T, Nagai Y, Shigeta M et al. (1998) Lysinuric protein intolerance and systemic lupus erythematosus. Eur J Pediatr 157:130–131

    Article  PubMed  CAS  Google Scholar 

  37. Aoki M, Fukao T, Fujita Y et al. (2001) Lysinuric protein intolerance in siblings: complication of systemic lupus erythematosus in the elder sister. Eur J Pediatr 160:522–523

    Article  PubMed  CAS  Google Scholar 

  38. Kerem E, Elpelg ON, Shalev RS et al. (1993) Lysinuric protein intolerance with chronic interstitial lung disease and pulmonary cholesterol granulomas at onset. J Pediatr 123:275–278

    Article  PubMed  CAS  Google Scholar 

  39. DiRocco M, Garibotto G, Rossi GA et al. (1993) Role of haematological, pulmonary and renal complications in the long-term prognosis of patients with lysinuric protein intolerance. Eur J Pediatr 152:437–440

    Article  PubMed  CAS  Google Scholar 

  40. Parto K, Kallajoki M, Aho H, Simell O (1994) Pulmonary alveolar proteinosis and glomerulonephritis in lysinuric protein intolerance: case reports and autopsy findings of four pediatric patients. Hum Pathol 25:400–407

    Article  PubMed  CAS  Google Scholar 

  41. Santamaria F, Parenti G, Guidi G et al. (1996) Early detection of lung involvement in lysinuric protein intolerance: role of high-resolution computed tomography and radioisotopic methods. Am J Respir Crit Care Med 153:731–735

    PubMed  CAS  Google Scholar 

  42. Duval M, Fenneteau O, Doireau V et al. (1999) Intermittent hemophagocytic lymphohistiocytosis is a regular feature of lysinuric protein intolerance. J Pediatr 134:236–239

    Article  PubMed  CAS  Google Scholar 

  43. Parenti G, Sebastio G, Strisciuglio P et al. (1995) Lysinuric protein intolerance characterised by bone marrow abnormalities and severe clinical course. J Pediatr 126:246–251

    Article  PubMed  CAS  Google Scholar 

  44. Tanner L, Näntö-Salonen K, Niinikoski H et al. (2007) Nephropathy leading to end-stage renal disease – a novel complication of lysinuric protein intolerance. J Pediatr 150:631–634

    Article  PubMed  Google Scholar 

  45. Santamaria F, Brancaccio G, Parenti G et al. (2004) Recurrent fatal pulmonary alveolar proteinosis after heart-lung transplantation in a child with lysinuric protein intolerance. J Pediatr 145:268–272

    Article  PubMed  Google Scholar 

  46. Tanner L, Näntö-Salonen K, Niinikoski H et al. (2006) Hazards associated with pregnancies and deliveries in lysinuric protein intolerance. Metabolism 55:224–231

    Article  PubMed  CAS  Google Scholar 

  47. Rajantie J, Simell O, Perheentupa J (1980) Basolateral membrane transport defect for lysine in lysinuric protein intolerance. Lancet 1:1219–1221

    Article  PubMed  CAS  Google Scholar 

  48. Rajantie J, Simell O, Perheentupa J (1981) Lysinuric protein intolerance. Basolateral transport defect in renal tubuli. J Clin Invest 67:1078–1082

    Article  PubMed  CAS  Google Scholar 

  49. Smith DW, Scriver CR, Tenenhouse HS, Simell O (1987) Lysinuric protein intolerance mutation is expressed in the plasma membrane of cultured skin fibroblasts. Proc Natl Acad Sci USA 84:7711–7715

    Article  PubMed  CAS  Google Scholar 

  50. Dall’Asta V, Bussolati O, Sala R et al. (2000) Arginine transport through system y002B;L in cultured human fibroblasts: normal phenotype of cells from LPI subjects. Am J Physiol Cell Physiol 279:C1829–1837

    PubMed  Google Scholar 

  51. Smith DW, Scriver CR, Simell O (1988) Lysinuric protein intolerance mutation is not expressed in the plasma membrane of erythrocytes. Hum Genet 80:395–396

    Article  PubMed  CAS  Google Scholar 

  52. Boyd CA, Deves R, Laynes R, Kudo Y et al. (2000) Cationic amino acid transport through system y002B;L in erythrocytes of patients with lysinuric protein intolerance. Pflugers Arch 459:513–516

    Article  Google Scholar 

  53. Rajantie J, Simell O, Perheentupa J (1983) ‘Basolateral’ and mitochondrial membrane transport defect in the hepatocytes in lysinuric protein intolerance. Acta Paediatr Scand 72:65–70

    Article  PubMed  Google Scholar 

  54. Kayanoki Y, Kawata S, Kiso S et al. (1999) Reduced nitric acid production by l-arginine deficiency in lysinuric protein intolerance exacerbates intravascular coagulation. Metabolism 48:1136–1140

    Article  PubMed  CAS  Google Scholar 

  55. Kamada Y, Nagaretani H, Tamura S et al. (2001) Vascular endothelial dysfunction resulting from l-arginine deficiency in a patient with lysinuric protein intolerance. J Clin Invest 108:717–724

    PubMed  CAS  Google Scholar 

  56. Korman SH, Raas-Rothschild A, Elpeleg O, Gutman A (2002) Hypocarnitinemia in lysinuric protein intolerance. Mol Genet Metab 76:81–83

    Article  PubMed  CAS  Google Scholar 

  57. Palacin M, Bertran J, Chillaron J et al. (2004) Lysinuric protein intolerance: mechanisms of pathophysiology. Mol Genet Metab 81:27–37

    Article  Google Scholar 

  58. Tanner L, Näntö-Salonen K, Rashed MS et al. (2008) Carnitine deficiency and l-carnitine supplementation in lysinuric protein intolerance. Metabolism 57:549–554

    Article  PubMed  CAS  Google Scholar 

  59. Torrents D, Mykkänen J, Pineda M et al. (1999) Identification of SLC7A7, encoding y 002B;LAT-1, as the lysinuric protein intolerance gene. Nat Genet 21:293–296

    Article  PubMed  CAS  Google Scholar 

  60. Borsani G, Bassi MT, Sperandeo MP et al. (1999) SLC7A7, encoding a putative permease-related protein, is mutated in patients with lysinuric protein intolerance. Nat Genet 21:297–301

    Article  PubMed  CAS  Google Scholar 

  61. Sperandeo MP, Bassi MT, Riboni et al. (2000) Structure of the SLC7A7 gene and mutational analysis of patients affected by lysinuric protein intolerance. Am J Hum Genet 66:92–99

    Article  PubMed  CAS  Google Scholar 

  62. Sperandeo MP, Andria G, Sebastio G (2008) Lysinuric protein intolerance: update and extended mutation analysis of the SLC7A7 gene. Hum Mutat 29:14–21

    Article  PubMed  CAS  Google Scholar 

  63. Rajantie J, Simell O, Rapola J, Perheentupa J (1980) Lysinuric protein intolerance: a two-year trial of dietary supplementation therapy with citrulline and lysine. J Pediatr 97:927–932

    Article  PubMed  CAS  Google Scholar 

  64. Tanner LM, Näntö-Salonen K, Venetoklis J et al. (2007) Nutrient intake in lysinuric protein intolerance. J Inherit Metab Dis 30:716–21

    Article  PubMed  CAS  Google Scholar 

  65. Rajantie J, Simell O, Perheentupa J (1983) Oral administration of epsilon-N-acetyllysine and homocitrulline for lysinuric protein intolerance. J Pediatr 102:388–390

    Article  PubMed  CAS  Google Scholar 

  66. Lukkarinen M, Näntö-Salonen K, Pulkki K et al. (2003) Oral supplementation corrects plasma lysine concentrations in lysinuric protein intolerance. Metabolism 52:935–938

    Article  PubMed  CAS  Google Scholar 

  67. Tanner LM, Näntö-Salonen K, Niinikoski H, Huoponen K, Simell O (2007) Long-term oral lysine supplementation in lysinuric protein intolerance. Metabolism 56:185–189

    Article  PubMed  CAS  Google Scholar 

  68. Tanner L, Niinikoski H, Näntö-Salonen K, Simell O (2010) Combined hyperlipidemia and its treatment in patients with LPI. J Inherit Metab Dis 2010, EPub ahead of print

    Google Scholar 

  69. Brusilow SW, Danney M, Waber LJ et al. (1984) Treatment of episodic hyperammonemia in children with inborn errors of urea synthesis. N Engl J Med 310:1630–1634

    Article  PubMed  CAS  Google Scholar 

  70. Bader-Meunier B, Parez N, Muller S (2000) Treatment of hemophagocytic lymphohistiocytosis and alveolar proteinosis with cyclosporin A and steroids in a boy with lysinuric protein intolerance. J Pediatr 136:134

    PubMed  CAS  Google Scholar 

  71. Duoda DN, Farmakovski N, Dell S, Grasemann H, Palaniyar N (2009) SP-D counteracts GM-CSF-mediated increase of granuloma formation by alveolar macrophages in lysinuric protein intolerance. Orphanet J Rare Dis 4:29

    Article  Google Scholar 

  72. Boyd CAR, Shennan DB (2010) Breast milk and gene delivery: is lysinuric protein intolerance an exemplar? Mol Genet Metab 101:296

    Article  PubMed  CAS  Google Scholar 

  73. Baron DN, Dent CE, Harris H, Hart EW, Jepson JB (1956) Hereditary pellagra-like skin rash with temporary cerebellar ataxia, constant renal amino aciduria and other bizarre biochemical features. Lancet 2:421–428

    Article  Google Scholar 

  74. Scriver CR, Mahon B, Levy HL et al. (1987) The Hartnup phenotype: Mendelian transport disorder, multifactorial disease. Am J Hum Genet 40:401–412

    PubMed  CAS  Google Scholar 

  75. Kleta R, Romeo E, Ristic Z et al. (2004) Mutations in SLC6A19, encoding B0AT1, cause Hartnup disorder. Nat Genet 36:999–1002

    Article  PubMed  CAS  Google Scholar 

  76. Seow HF, Broer S, Broer A et al. (2004) Hartnup disorder is caused by mutation in the gene encoding the neutral amino acid transporter SLC6A19. Nat Genet 36:1003–1007

    Article  PubMed  CAS  Google Scholar 

  77. Broer S (2008) Apical transporters for neutral amino acids; physiology and pathophysiology Physiology 23:95–103

    CAS  Google Scholar 

  78. Scriver CR (1965) Hartnup disease: a genetic modification of intestinal and renal transport of certain neutral alpha amino acids. N Engl J Med 273:530–532

    Article  PubMed  CAS  Google Scholar 

  79. Scriver CR, Mahon B, Levy HL et al. (1987) The Hartnup phenotype: Mendelian transport disorder, multifactorial disease. Am J Hum Genet 40:401–412

    PubMed  CAS  Google Scholar 

  80. Azmanov DN, Kowalczuk S, Rodgers H et al. (2008) Further evidence for allelic heterogeneity in Hartnup disease. Hum Mutat 29:1217–1221

    Article  PubMed  CAS  Google Scholar 

  81. Broer S (2009) The role of the neutral amino acid transporter B0AT1 (SLC6A19) in Hartnup disorder and protein nutrition. IUBMB 61:591–599

    Article  CAS  Google Scholar 

  82. Mahon BE, Levy HL (1986) Maternal Hartnup disorder. Am J Med Genet 24:513–518

    Article  PubMed  CAS  Google Scholar 

  83. Bröer S (2008) Apical transporters for neutral amino acids: physiology and pathophysiology. Physiology 23:95–103

    Article  PubMed  Google Scholar 

  84. Camargo SMR, Bockenhauser D, Kleta R (2008) Aminoacidurias: clinical and molecular aspects. Kidney Int 73:918–925

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pediatrics, University of Turku, Klinamyllynkatu 4-8, 20520, Turku, Finland

    Kirsti Näntö-Salonen, Harri Niinikoski & Olli G. Simell

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  1. Kirsti Näntö-Salonen
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  2. Harri Niinikoski
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  3. Olli G. Simell
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Editors and Affiliations

  1. Department of Neurology Neurometabolic Unit, Hôpital Pitié Salpêtrière 47–83 Boulevard de l’Hôpital, Paris Cedex 13, 75651, Paris, France

    Jean-Marie Saudubray

  2. Laboratory of Physiological Chemistry de Duve Institute, University of Louvain Medical School, Avenue Hippocrate 75/39, 1200, Brussels, Belgium

    Georges van den Berghe

  3. Biochemical Genetics Unit Manchester Academic Health Science Centre, Central Manchester University Hospitals St Mary’s Hospital, Oxford Road, M13 9WL, Manchester, UK

    John H. Walter

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Näntö-Salonen, K., Niinikoski, H., Simell, O.G. (2012). Transport Defects of Amino Acids at the Cell Membrane: Cystinuria, Lysinuric Protein Intolerance and Hartnup Disorder. In: Saudubray, JM., van den Berghe, G., Walter, J.H. (eds) Inborn Metabolic Diseases. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-15720-2_26

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