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The PKU mouse project: its history, potential and implications
Author(s) -
McDonald JD
Publication year - 1994
Publication title -
acta pædiatrica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.772
H-Index - 115
eISSN - 1651-2227
pISSN - 0803-5253
DOI - 10.1111/j.1651-2227.1994.tb13470.x
Subject(s) - phenylalanine hydroxylase , hyperphenylalaninemia , tetrahydrobiopterin , medicine , endocrinology , mutation , mutant , germline mutation , phenylketonurias , genetics , allele , phenylalanine , biology , gene , nitric oxide synthase , amino acid , nitric oxide
To produce genetic‐based animal models for the human disease phenylketonuria (PKU), we treated mice with the powerful germline mutagen ethylnitrosourea and screened the progeny of these animals for the symptom hyperphenylalaninemia (HPH). Six independent mutant strains have been produced to date that exhibit heritable HPH. The first mutation isolated was found to cause a reduced level of GTP‐cyclohydrolase I activity and, as such, yields a model for tetrahydrobiopterin‐dependent HPH. The next two mutations have yet to be fully characterized but cause syndromes that appear distinct from any PKU or HPH syndromes yet reported for humans and they are allelic. Next we isolated a mutation that caused a marked reduction in hepatic phenylalanine hydroxylase activity levels. The enzyme deficiency was not sufficient to cause a PKU syndrome but instead produced a mild HPH syndrome. This strain played an instrumental role, however, in the identification of two additional mutant strains that appear to model human PKU very accurately in the laboratory mouse. These latter strains have levels of HPH very similar to human PKU patients, exhibit a phenylalanine‐dependent hypopigmentation, and have reproductive difficulties that resemble human maternal PKU.