Potent mouse germline mutagenesis by ethylnitrosourea (ENU) is being combined with efficient breeding and screening protocols to generate an extended series of viable mouse mutants deficient in phenylalanine clearance. These hyperphenylalanemic (HPH) mutants will be characterized genetically and biochemically to assign each distinct lesion to a genetic locus and a step in phenylalanine catabolism. With lesions of particular interest, locus-specific mutant isolation methods will then be employed to obtain an extended series of mutant alleles, including lesions that may be lethal to development when homozygous. The development consequences of HPH will be investigated in two different situations-the exposure of genetically-affected neonates to high level of phenylalanine; and the exposure of mutant females to phenylalanine during pregnancy. The embryological investigations involved in these studies will be carried out collaboratively with Dr. Susan Lewis (Research Triangle Park, North Carolina). We are making these mouse mutant models available to laboratories that specialize in the biochemical analysis of mammalian PKU. A number of biological and biomedical investigations become possible, given the salient mutant lines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK040393-03
Application #
3240623
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1989-05-01
Project End
1994-04-30
Budget Start
1991-05-01
Budget End
1992-04-30
Support Year
3
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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Symula, D J; Shedlovsky, A; Guillery, E N et al. (1997) A candidate mouse model for Hartnup disorder deficient in neutral amino acid transport. Mamm Genome 8:102-7
Fang, B; Eisensmith, R C; Li, X H et al. (1994) Gene therapy for phenylketonuria: phenotypic correction in a genetically deficient mouse model by adenovirus-mediated hepatic gene transfer. Gene Ther 1:247-54
Kornguth, S; Anderson, M; Markley, J L et al. (1994) Near-microscopic magnetic resonance imaging of the brains of phenylalanine hydroxylase-deficient mice, normal littermates, and of normal BALB/c mice at 9.4 Tesla. Neuroimage 1:220-9
Shedlovsky, A; McDonald, J D; Symula, D et al. (1993) Mouse models of human phenylketonuria. Genetics 134:1205-10
McDonald, J D; Bode, V C; Dove, W F et al. (1990) Pahhph-5: a mouse mutant deficient in phenylalanine hydroxylase. Proc Natl Acad Sci U S A 87:1965-7