Tandem mass spectrometry in discovery of disorders of the metabolome
J. Clin. Invest. Arnold W. Strauss, et al. 113:354 doi:10.1172/JCI20924 [Go to this article.]

Figure 1
Clinical observation and clinically relevant screening of mutated mouse and zebrafish populations in gene discovery. The common approach that has allowed identification of novel genes essential in clinically relevant disorders or congenital malformations is illustrated. The first step is chemical mutagenesis, likely to produce point mutations, which is achieved by injection of a mutagen into a substantial number of animals. The second step is breeding of the offspring to search for either recessive or dominant phenotypes. The key third step is screening for clinically relevant phenotypes, illustrated here as either tandem mass spectrometry (MS/MS) for disorders of amino acid or fatty acid metabolism (1); measurement of blood pressure (in mice by tail cuff assessment) to find mutations causing hypertension; lipid analysis, either of plasma samples from mice or other whole animals or embryos in fish to assess lipoprotein or membrane lipid abnormalities; and clinical observation for congenital anomalies by noting abnormalities of organ development. The latter has been accomplished using the transparent zebrafish embryo to detect heart and vascular anomalies and aberrant gut or eye development and can also be assessed in mice by magnetic resonance imaging, echocardiography, or other clinically used imaging modalities. The subsequent steps of mapping of the mutated gene using polymorphisms and delineation of mutations by DNA sequencing of mapped regions or candidate genes provide proof that the mutated gene causes the observed phenotype.