Subject(s)
Antimalarials/adverse effects , Genetic Diseases, X-Linked/chemically induced , Glucosephosphate Dehydrogenase Deficiency/chemically induced , Glucosephosphate Dehydrogenase , Malaria, Vivax/drug therapy , Primaquine/adverse effects , Antimalarials/therapeutic use , Brazil , Fatal Outcome , Genetic Diseases, X-Linked/metabolism , Glucosephosphate Dehydrogenase Deficiency/metabolism , Humans , Male , Middle Aged , Primaquine/therapeutic useABSTRACT
We describe the clinical, genetic, biochemical, and molecular characterization of a mouse that arose in the first generation (G(1)) of a random mutagenesis screen with the chemical mutagen ethyl-nitrosourea. The mouse was observed to have skeletal abnormalities inherited with an X-linked dominant pattern of inheritance. The causative mutation, named Skeletal abnormality 1 (Ska1), was shown to be a single base pair mutation in a splice donor site immediately following exon 8 of the Phex (phosphate-regulating gene with homologies to endopeptidases located on the X-chromosome) gene. This point mutation caused skipping of exon 8 from Phex mRNA, hypophosphatemia, and features of rickets. This experimentally induced phenotype mirrors the human condition X-linked hypophosphatemia; directly confirms the role of Phex in phosphate homeostasis, normal skeletal development, and rickets; and illustrates the power of mutagenesis in exploring animal models of human disease.