- THIS ARTICLE
- Full Text (PDF)
- Alert me when this article is cited
- Alert me if a correction is posted
- SERVICES
- Email this article to a friend
- Similar articles in this journal
- Similar articles in PubMed
- Alert me to new issues of the journal
- Download to citation manager
- Reprints & Permissions
- CITING ARTICLES
- Citing Articles via HighWire
- Citing Articles via Google Scholar
- GOOGLE SCHOLAR
- Articles by Shedlovsky, A.
- Articles by Dove, W. F.
- Search for Related Content
- PUBMED
- PubMed Citation
- Articles by Shedlovsky, A.
- Articles by Dove, W. F.
Genetics, Vol 134, 1205-1210, Copyright © 1993
INVESTIGATIONS |
Mouse Models of Human Phenylketonuria
A. Shedlovsky, J. D. McDonald, D. Symula and W. F. Dove
McArdle Laboratory for Cancer Research and Laboratory of Genetics, University of Wisconsin, Madison, Wisconsin 53706
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.
This article has been cited by other articles:
 |
|
 |
|
  C. N. Sarkissian, A. Gamez, L. Wang, M. Charbonneau, P. Fitzpatrick, J. F. Lemontt, B. Zhao, M. Vellard, S. M. Bell, C. Henschell, et al. Preclinical evaluation of multiple species of PEGylated recombinant phenylalanine ammonia lyase for the treatment of phenylketonuria PNAS, December 30, 2008; 105(52): 20894 - 20899. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Chen and S. L. C. Woo Complete and persistent phenotypic correction of phenylketonuria in mice by site-specific genome integration of murine phenylalanine hydroxylase cDNA PNAS, October 25, 2005; 102(43): 15581 - 15586. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. H. Bayle, F. Randazzo, G. Johnen, S. Kaufman, A. Nagy, J. Rossant, and G. R. Crabtree Hyperphenylalaninemia and Impaired Glucose Tolerance in Mice Lacking the Bifunctional DCoH Gene J. Biol. Chem., August 2, 2002; 277(32): 28884 - 28891. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. B. Smith and J. Kang Cerebral protein synthesis in a genetic mouse model of phenylketonuria PNAS, September 26, 2000; 97(20): 11014 - 11019. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Justice, JaniceK. Noveroske, JohnS. Weber, B. Zheng, and A. Bradley Mouse ENU Mutagenesis Hum. Mol. Genet., September 1, 1999; 8(10): 1955 - 1963. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Zagreda, J. Goodman, D. P. Druin, D. McDonald, and A. Diamond Cognitive Deficits in a Genetic Mouse Model of the Most Common Biochemical Cause of Human Mental Retardation J. Neurosci., July 15, 1999; 19(14): 6175 - 6182. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. L. Levy Phenylketonuria: Old disease, new approach to treatment PNAS, March 2, 1999; 96(5): 1811 - 1813. [Full Text] [PDF]
|
|
|
|
|
|
C. N. Sarkissian, Z. Shao, F. Blain, R. Peevers, H. Su, R. Heft, T. M. S. Chang, and C. R. Scriver A different approach to treatment of phenylketonuria: Phenylalanine degradation with recombinant phenylalanine ammonia lyase PNAS, March 2, 1999; 96(5): 2339 - 2344. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. C. Jean, C. O. Harding, S. M. Oakes, Q. Yu, P. K. Held, and M. Joyce-Brady {gamma}-Glutamyl transferase (GGT) deficiency in the GGTenu1 mouse results from a single point mutation that leads to a stop codon in the first coding exon of GGT mRNA Mutagenesis, January 1, 1999; 14(1): 31 - 36. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 An Oak Ridge Legacy: The Specific Locus Test and Its Role in Mouse Mutagenesis Genetics, January 1, 1998; 148(1): 7 - 12.
|
|
|
|
|
|
C. O. Harding, P. Williams, E. Wagner, D. S. Chang, K. Wild, R. E. Colwell, and J. A. Wolff Mice with Genetic gamma -Glutamyl Transpeptidase Deficiency Exhibit Glutathionuria, Severe Growth Failure, Reduced Life Spans, and Infertility J. Biol. Chem., May 9, 1997; 272(19): 12560 - 12567. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M A Bedell, N A Jenkins, and N G Copeland Mouse models of human disease. Part I: techniques and resources for genetic analysis in mice. Genes & Dev., January 1, 1997; 11(1): 1 - 10. [PDF]
|
|
|
|
|
|
M A Bedell, D A Largaespada, N A Jenkins, and N G Copeland Mouse models of human disease. Part II: recent progress and future directions. Genes & Dev., January 1, 1997; 11(1): 11 - 43. [PDF]
|
|
|
|
 |
|
 J. Takahashi, L. Pinto, and M. Vitaterna Forward and reverse genetic approaches to behavior in the mouse Science, June 17, 1994; 264(5166): 1724 - 1733. [Abstract] [PDF]
|
|
|
|
|
|
E. M. Rinchik, D. A. Carpenter, and D. K. Johnson Functional annotation of mammalian genomic DNA sequence by chemical mutagenesis: A fine-structure genetic mutation map of a 1- to 2-cM segment of mouse chromosome 7 corresponding to human chromosome 11p14-p15 PNAS, January 22, 2002; 99(2): 844 - 849. [Abstract] [Full Text] [PDF]
|
|