Mammalian Genome

, Volume 8, Issue 2, pp 102–107 | Cite as

A candidate mouse model for Hartnup Disorder deficient in neutral amino acid transport

  • D. J. Symula
  • A. Shedlovsky
  • E. N. Guillery
  • W. F. Dove
Original Contribution


The mutant mouse strain HPH2 (hyperphenylalaninemia) was isolated after N-ethyl-N-nitrosourea (ENU) mutagenesis on the basis of delayed plasma clearance of an injected load of phenylalanine. Animals homozygous for the recessive hph2 mutation excrete elevated concentrations of many of the neutral amino acids in the urine, while plasma concentrations of these amino acids are normal. In contrast, mutant homozygotes excrete normal levels of glucose and phosphorus. These data suggest an amino acid transport defect in the mutant, confirmed in a small reduction in normalized values of 14C-labeled glutamine uptake by kidney cortex brush border membrane vesicles (BBMV). The hyperaminoaciduria pattern is very similar to that of Hartnup Disorder, a human amino acid transport defect. A subset of Hartnup Disorder cases also show niacin deficiency symptoms, which are thought to be multifactorially determined. Similarly, the HPH2 mouse exhibits a niacin-reversible syndrome that is modified by diet and by genetic background. Thus, HPH2 provides a candidate mouse model for the study of Hartnup Disorder, an amino acid transport deficiency and a multifactorial disease in the human.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Aronson PS, Sactor B (1975) The Na+ gradient-dependent transport of D-glucose in renal brush border membranes. J Biol Chem 250, 6032–6039PubMedGoogle Scholar
  2. Asatoor AM, Craske J, London DR, Milne MD (1963) Indole production in Hartnup Disorder. Lancet 1, 126PubMedCrossRefGoogle Scholar
  3. Baron DN, Dent CE, Haris H, Hart EW, Jepson JB (1956) Hereditary pellagra-like skin rash with temporary cerebellar ataxia, constant renal aminoaciduria, and other bizarre biochemical features. Lancet 2, 421–428CrossRefGoogle Scholar
  4. Bergeron M, Gougoux A (1989) The renal Fanconi syndrome. In The Metabolic Basis of Inherited Disease, CR Scriver, AL Beaudet, WS Sly, D Valle, eds. (New York: McGraw-Hill) pp. 2569–2580Google Scholar
  5. Chesney, R (1995) Iminoglycinuria, In The Metabolic and Molecular Bases of Inherited Disease, CR Scriver, AL Beaudet, WS Sly, D Valle, eds. (New York: McGraw-Hill) pp. 3643–3654Google Scholar
  6. Christensen, HN (1989) Distinguishing amino acid transport systems of a given cell or tissue. Methods Enzymol 173, 576–616PubMedCrossRefGoogle Scholar
  7. Christensen, HN (1990) Role of amino acid transport and counter transport in nutrition and metabolism. Physiol Rev 70, 43–77PubMedGoogle Scholar
  8. Curriden, S, Englesberg, E (1981) Inhibition of growth of proline-requiring Chinese hamster ovary cells (CHO-K1) resulting from antagonism by A system amino acids. J Cell Physiol 106, 245–252PubMedCrossRefGoogle Scholar
  9. Dillehay, AL, Bass, R, Englesberg, E (1980) Inhibition of growth cells in culture by L-phenylalanine as a model system for the analysis of phenylketonuria. I. Amino acid antagonism and the inhibition of protein synthesis. J Cell Physiol 102, 395–405PubMedCrossRefGoogle Scholar
  10. Evered, DF (1956) The excretion of amino acids by the human. Biochem J 62, 416–427PubMedGoogle Scholar
  11. Evers, J, Murer, H, Kinne, R (1976) Phenylalanine uptake in isolated renal brush border vesicles. Biochim Biophys Acta 426, 598–615PubMedCrossRefGoogle Scholar
  12. Forbush, B (1983) Assay of Na, K-ATPase in plasma membrane preparations: increasing the permeability of membrane vesicles using sodium dodecyl sulfate buffered with bovine serum albumin. Anal Biochem 128, 159–163PubMedCrossRefGoogle Scholar
  13. George, SG, Kenny, AJ (1973) Studies on the enzymology of purified preparations of brush border from rabbit kidney. Biochem J 134, 43–57PubMedGoogle Scholar
  14. Groth, U, Rosenberg, LE (1972) Transport of dibasic amino acids, cystine, and tryptophan by cultured human fibroblasts: absence of a defect in cystinuria and Hartnup disease. J Clin Invest 51, 2130–2142PubMedCrossRefGoogle Scholar
  15. Guillery, EN, Karniski, LP, Matthews, MS, Robillar, JE (1994) Maturation of proximal tubule Na+/H+ antiporter activity in sheep during transition from fetus to newborn. Am J Physiol 267, F537-F545PubMedGoogle Scholar
  16. Halvorsen, S, Hygstedt, O, Jagenburg, R, Sjaastad, O (1969) Cellular transport of L-histidine in Hartnup disease. J Clin Invest 48, 1552–1559PubMedCrossRefGoogle Scholar
  17. Heinz, E, Weinstein, AM (1984) The overshoot phenomenon in cotransport. Biochim Biophys Acta 776, 83–91PubMedCrossRefGoogle Scholar
  18. Kinsella, JL, Aronson, PS (1980) Properties of the Na+-H+ exchanger in renal microvillus membrane vesicles. Am J Physiol 238, F461-F469PubMedGoogle Scholar
  19. Lemieux, B, Auray-Blais, C, Giguere, R, Shapcott, D, Scriver, CR (1988) Newborn urine screening experience with over one million infants in Quebec Network of Genetic Medicine. J Inherited Metab Dis 11, 45–55PubMedCrossRefGoogle Scholar
  20. Les, EP (1966) Husbandry. In Biology of the Laboratory Mouse, EL Green, ed. (New York: McGraw-Hill) pp. 29–37Google Scholar
  21. Levy, HL (1995) Hartnup Disorder, In The Metabolic and Molecular Bases of Inherited Disease, CR Scriver, AL Beaudet, WS Sly, D Valle, eds. (New York: McGraw-Hill) pp. 3629–3642Google Scholar
  22. Lowry, OH, Rosenbaugh, NH, Farr, AL, Randall, RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193, 265–275PubMedGoogle Scholar
  23. McDonald, JD, Bode, VC (1988) Hyperphenylalaninemia in the hph-1 mouse mutant. Pediatr Res 23, 63–67PubMedCrossRefGoogle Scholar
  24. McDonald, JD, Bode, VC, Dove, WF, Shedlovsky, A (1990) Pah hph-5: a mouse mutant deficiency in phenylalanine hydroxylase. Proc Natl Acad Sci USA 87, 1965–1967PubMedCrossRefGoogle Scholar
  25. McKean, CM, Boggs, DE, Peterson, NA (1968) The influence of high phenylalanine and tyrosine on the concentrations of essential amino acids in brain. J Neurochem 15, 235–241PubMedCrossRefGoogle Scholar
  26. Mircheff, AK, Kippen, I, Hirayama, B, Wright, EM (1982) Delineation of sodium-stimulated amino acid transport pathways in rabbit kidney brush border vesicles. J Membr Biol 64, 113–122PubMedCrossRefGoogle Scholar
  27. Nielsen, EG, Vedso, S, Zimmmerman-Nielsen, C (1966) Hartnup disease in three siblings. Dan Med Bull 13, 155–161PubMedGoogle Scholar
  28. Olendorf, WH (1973) Saturation of blood brain barrier transport of amino acid in phenylketonuria. Arch Neurol 28, 45–48Google Scholar
  29. Oxender, DL, Christensen, HN (1963) Distinct mediating systems for the transport of neutral amino acids by the Ehrlich cell. J Biol Chem 238 3686–3699PubMedGoogle Scholar
  30. Peterson, GL (1977) A simplification of the protein assay method of Lowery et al. which is more generally applicable. Anal Biochem 83, 346–356PubMedCrossRefGoogle Scholar
  31. Pomeroy, J, Efron, ML, Dayman, J, Hoefnagal, D (1968) Hartnup Disease in a New England family. N Engl J Med 278, 1214–1216PubMedCrossRefGoogle Scholar
  32. Pontoglio, M, Barra, J, Hadchouel, M, Doyen, A, Kress, C, Bach, JP, Babinet, C (1996) Hepatocyte nuclear factor 1 inactivation results in hepatic dysfunction, phenylketonuria, and renal Fanconi syndrome. Cell 84, 575–585PubMedCrossRefGoogle Scholar
  33. Reizer, J, Reizer, A, Saier, MH (1994) A functional superfamily of sodium/ solute symporters. Biochim Biophys Acta 1197, 133–166PubMedGoogle Scholar
  34. Scriver, CR (1965) A genetic modification of intestinal and renal transport of certain neutral alpha-amino acids. N Engl J Med 273, 530–532PubMedGoogle Scholar
  35. Scriver, CR (1988) Nutrient-gene interactions: the gene is not the disease and vice-versa. Am J Clin Nutr 48, 1505–1509PubMedGoogle Scholar
  36. Scriver, CR, Mahon, B, Levy, HL, Clow, CL, Reade, TM, Kronick, J, Lemieux, B, Laberge, C (1987) The Hartnup phenotype: Mendelian transport disorder, multifactorial disease. Am J Hum Genet 40, 401–412PubMedGoogle Scholar
  37. Seakins, JWT (1977) Hartnup disease. In Metabolic and Deficiency diseases of the Nervous System, PJ Vinken, GW Bruyn, eds. (Amsterdam, North-Holland) pp. 149–170Google Scholar
  38. Segal, S, Thier, SO (1995) Cystinuria. In Metabolic and Molecular Bases of Inherited Disease, CR Scriver, AL Beaudet, WS Sly, D Valle, eds. (New York: McGraw-Hill), pp. 3581–3602Google Scholar
  39. Shaw, KNF, Redlich, D, Wright, SW, Jepson, JB (1960) Dependence of urinary indole excretion in Hartnup disease upon gut flora. Fed Proc 19, 194Google Scholar
  40. Shedlovsky, A, McDonald, JD, Symula, D, Dove, WF (1993) Mouse models of phenylketonuria. Genetics 134, 1205–1210PubMedGoogle Scholar
  41. Shih, VE, Bixby, EM, Alpers, DH, Bartsocas, CS, Thier, SO (1971) Studies of intestinal transport defect in Hartnup disease. Gastroenterology 61, part 1, 445–453PubMedGoogle Scholar
  42. Silbernagl, S (1992) Amino acids and oligopeptides, In The Kidney: Physiology and Pathophysiology, 2nd ed., DW Seldin, G Giebisch, eds. (New York: Raven Press, Ltd.) pp. 2889–2920Google Scholar
  43. Simell, O (1995) Lysinuric protein intolerance and other cationic aminoacidurias, In The Metabolic and Molecular Bases of Inherited Disease, CR Scriver, AL Beaudet, WS Sly, D Valle, eds. (New York: McGraw-Hill) pp. 3603–3628Google Scholar
  44. Slocum, RH, Cummings, JG (1991) Amino acid analysis of physiological samples. In Diagnostic Human Biochemical Genetics, FA Hommes, ed. (New York: Wiley-Liss) pp. 87–126Google Scholar
  45. Symula, DJ, Shedlovsky, A, Dove, WF (1996). Genetic mapping of hph2, a mutation affecting amino acid transport in mouse. Mamm Genome, 8, 98–101CrossRefGoogle Scholar
  46. Tada, K, Morikawa, T, Arakawa, T (1966) Tryptophan load and uptake of tryptophan by leukocytes in Hartnup disease. Tohoku J Exp Med 90, 337–346PubMedCrossRefGoogle Scholar
  47. Tarlow, MJ, Seakins, WT, Lloyd, JK, Cheng, B, Thomas, AJ (1972) Absorption of amino acids and peptides in a child with a variant of Hartnup Disease and coexistent coeliac disease. Arch Dis Child 47, 798–803PubMedCrossRefGoogle Scholar
  48. Wilcken, B, Yu, JS, Brown, DA (1977) Natural history of Hartnup disease. Arch Dis Child 52, 38–40PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1997

Authors and Affiliations

  • D. J. Symula
    • 1
    • 2
  • A. Shedlovsky
    • 1
  • E. N. Guillery
    • 3
  • W. F. Dove
    • 1
    • 2
  1. 1.McArdle Laboratory for Cancer ResearchUniversity of WisconsinMadisonUSA
  2. 2.Laboratory of GeneticsUniversity of WisconsinMadisonUSA
  3. 3.Department of PediatricsUniversity of WisconsinMadisonUSA

Personalised recommendations