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. 1993 Aug;134(4):1205–1210. doi: 10.1093/genetics/134.4.1205

Mouse Models of Human Phenylketonuria

A Shedlovsky 1, J D McDonald 1, D Symula 1, W F Dove 1
PMCID: PMC1205587  PMID: 8375656

Abstract

Phenylketonuria (PKU) results from a deficiency in phenylalanine hydroxylase, the enzyme catalyzing the conversion of phenylalanine (PHE) to tyrosine. Although this inborn error of metabolism was among the first in humans to be understood biochemically and genetically, little is known of the mechanism(s) involved in the pathology of PKU. We have combined mouse germline mutagenesis with screens for hyperphenylalaninemia to isolate three mutants deficient in phenylalanine hydroxylase (PAH) activity and cross-reactive protein. Two of these have reduced PAH mRNA and display characteristics of untreated human PKU patients. A low PHE diet partially reverses these abnormalities. Our success in using high frequency random germline point mutagenesis to obtain appropriate disease models illustrates how such mutagenesis can complement the emergent power of targeted mutagenesis in the mouse. The mutants now can be used as models in studying both maternal PKU and somatic gene therapy.

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Selected References

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  1. BICKEL H., GERRARD J., HICKMANS E. M. The influence of phenylalanine intake on the chemistry and behaviour of a phenyl-ketonuric child. Acta Paediatr. 1954 Jan;43(1):64–77. doi: 10.1111/j.1651-2227.1954.tb04000.x. [DOI] [PubMed] [Google Scholar]
  2. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  3. Figlewicz D. A., Druse M. J. Experimental hyperphenylalaninemia: effect on central nervous system myelin subfractions. Exp Neurol. 1980 Feb;67(2):315–329. doi: 10.1016/0014-4886(80)90232-0. [DOI] [PubMed] [Google Scholar]
  4. Friedman P. A., Lloyd T., Kaufman S. Production of antibodies to rat liver phenylalanine hydroxylase. Cross-reactivity with other pterin-dependent hydroxylases. Mol Pharmacol. 1972 Sep;8(5):501–510. [PubMed] [Google Scholar]
  5. GUTHRIE R., SUSI A. A SIMPLE PHENYLALANINE METHOD FOR DETECTING PHENYLKETONURIA IN LARGE POPULATIONS OF NEWBORN INFANTS. Pediatrics. 1963 Sep;32:338–343. [PubMed] [Google Scholar]
  6. Güttler F., DiLella A. G., Ledley F. D., Lidsky A. S., Kvok S. C., Marvit J., Woo S. L. Molecular biology of phenylketonuria. Eur J Pediatr. 1987;146 (Suppl 1):A5–11. doi: 10.1007/BF00442048. [DOI] [PubMed] [Google Scholar]
  7. Huether G., Neuhoff V. Use of alpha-methylphenylalanine for studies of brain development in experimental phenylketonuria. J Inherit Metab Dis. 1981;4(2):67–68. doi: 10.1007/BF02263594. [DOI] [PubMed] [Google Scholar]
  8. Kaufman S., Holtzman N. A., Milstien S., Butler L. J., Krumholz A. Phenylketonuria due to a deficiency of dihydropteridine reductase. N Engl J Med. 1975 Oct 16;293(16):785–790. doi: 10.1056/NEJM197510162931601. [DOI] [PubMed] [Google Scholar]
  9. Kwok S. C., Ledley F. D., DiLella A. G., Robson K. J., Woo S. L. Nucleotide sequence of a full-length complementary DNA clone and amino acid sequence of human phenylalanine hydroxylase. Biochemistry. 1985 Jan 29;24(3):556–561. doi: 10.1021/bi00324a002. [DOI] [PubMed] [Google Scholar]
  10. Lenke R. R., Levy H. L. Maternal phenylketonuria--results of dietary therapy. Am J Obstet Gynecol. 1982 Mar 1;142(5):548–553. doi: 10.1016/0002-9378(82)90759-1. [DOI] [PubMed] [Google Scholar]
  11. Levy H. L. Maternal phenylketonuria. Prog Clin Biol Res. 1988;281:227–242. [PubMed] [Google Scholar]
  12. Levy H. L., Waisbren S. E. Effects of untreated maternal phenylketonuria and hyperphenylalaninemia on the fetus. N Engl J Med. 1983 Nov 24;309(21):1269–1274. doi: 10.1056/NEJM198311243092101. [DOI] [PubMed] [Google Scholar]
  13. Lyon M. F., Phillips R. J., Bailey H. J. Mutagenic effects of repeated small radiation doses to mouse spermatogonia. I. Specific-locus mutation rates. Mutat Res. 1972 Jun;15(2):185–190. doi: 10.1016/0027-5107(72)90031-0. [DOI] [PubMed] [Google Scholar]
  14. Matalon R., Michals K. Phenylketonuria: screening, treatment and maternal PKU. Clin Biochem. 1991 Aug;24(4):337–342. doi: 10.1016/0009-9120(91)80008-q. [DOI] [PubMed] [Google Scholar]
  15. McDonald J. D., Bode V. C., Dove W. F., Shedlovsky A. Pahhph-5: a mouse mutant deficient in phenylalanine hydroxylase. Proc Natl Acad Sci U S A. 1990 Mar;87(5):1965–1967. doi: 10.1073/pnas.87.5.1965. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. RUSSELL W. L. X-ray-induced mutations in mice. Cold Spring Harb Symp Quant Biol. 1951;16:327–336. doi: 10.1101/sqb.1951.016.01.024. [DOI] [PubMed] [Google Scholar]
  17. Russell W. L., Kelly E. M., Hunsicker P. R., Bangham J. W., Maddux S. C., Phipps E. L. Specific-locus test shows ethylnitrosourea to be the most potent mutagen in the mouse. Proc Natl Acad Sci U S A. 1979 Nov;76(11):5818–5819. doi: 10.1073/pnas.76.11.5818. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Shedlovsky A., Guenet J. L., Johnson L. L., Dove W. F. Induction of recessive lethal mutations in the T/t-H-2 region of the mouse genome by a point mutagen. Genet Res. 1986 Apr;47(2):135–142. doi: 10.1017/s0016672300022977. [DOI] [PubMed] [Google Scholar]
  19. Sutrave P., Kelly A. M., Hughes S. H. ski can cause selective growth of skeletal muscle in transgenic mice. Genes Dev. 1990 Sep;4(9):1462–1472. doi: 10.1101/gad.4.9.1462. [DOI] [PubMed] [Google Scholar]
  20. Thompson N. E., Steinberg T. H., Aronson D. B., Burgess R. R. Inhibition of in vivo and in vitro transcription by monoclonal antibodies prepared against wheat germ RNA polymerase II that react with the heptapeptide repeat of eukaryotic RNA polymerase II. J Biol Chem. 1989 Jul 5;264(19):11511–11520. [PubMed] [Google Scholar]
  21. Tybulewicz V. L., Tremblay M. L., LaMarca M. E., Willemsen R., Stubblefield B. K., Winfield S., Zablocka B., Sidransky E., Martin B. M., Huang S. P. Animal model of Gaucher's disease from targeted disruption of the mouse glucocerebrosidase gene. Nature. 1992 Jun 4;357(6377):407–410. doi: 10.1038/357407a0. [DOI] [PubMed] [Google Scholar]
  22. WOOLF L. I., GRIFFITHS R., MONCRIEFF A. Treatment of phenylketonuria with a diet low in phenylalanine. Br Med J. 1955 Jan 8;1(4905):57–64. doi: 10.1136/bmj.1.4905.57. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Wilson J. M., Collins F. S. Cystic fibrosis. More from the modellers. Nature. 1992 Sep 17;359(6392):195–196. doi: 10.1038/359195a0. [DOI] [PubMed] [Google Scholar]
  24. Woo S. L., Lidsky A. S., Güttler F., Chandra T., Robson K. J. Cloned human phenylalanine hydroxylase gene allows prenatal diagnosis and carrier detection of classical phenylketonuria. Nature. 1983 Nov 10;306(5939):151–155. doi: 10.1038/306151a0. [DOI] [PubMed] [Google Scholar]

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