In a genetic mouse model of human phenylketonuria we have examined the offspring of hyperphenylalaninemic mothers for the presence of cardiovascular defects, an important feature of the pathology of the human maternal phenylketonuria syndrome. Beginning at 14.5 d after conception (75% through gestation), a variety of cardiovascular defects became apparent among the progeny of the hyperphenylalaninemic females. These defects ranged from mild to serious and correlated with the maternal but not the fetal Pah genotype. Nearly all of the defects were vascular, however, whereas the most reported in humans so far have been cardiac. The predisposing biochemical condition in this mouse disease model seems to be the same as in the human disease; elevated maternal blood phenylalanine levels concentrated across the placental barrier to produce a teratogenic developmental environment. This model for congenital cardiovascular defects should enhance two related areas of research. 1) It should allow a more thorough investigation of the relationship between maternal diet and maternal phenylketonuria birth defects, and 2) it should provide an experimental tool to gain insight into the normal process of cardiovascular development.

No abstract

No abstract

A valuable approach to investigating a biological process is to study the effect of mutations in the involved genes. By studying a diverse set of such mutations, one can gain important insights into the roles that the given gene product plays in the biological process. Although this approach has long been recognized, the scarcity of mammalian mutations has largely limited such investigations to simple organisms. It has recently been shown that highly efficient mutagenesis of the mouse germline with a random point mutagen can produce mutations that are valuable in several important ways. First, it can produce numerous different types of mutations. Second, it can be used to mutate genes that have yet to be cloned or characterized. Genes that have been marked by mutation can ultimately yield molecular access after mapping to high resolution and cloning from map position. Such new investigative capabilities will ultimately allow one to gain intimate knowledge of the molecular basis of complex biological processes like behavior and development. Third, mutations can be induced that yield animal models of human heritable diseases. Such disease models allow for intensive research into the etiology of the given disease and also permit the facile evaluation of new therapeutic regimens.