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(American Journal of Pathology. 2002;161:1925-1933.)
© 2002 American Society for Investigative Pathology

Animal Model

An Ethyl-Nitrosourea-Induced Point Mutation in Phex Causes Exon Skipping, X-Linked Hypophosphatemia, and Rickets

Marina R. Carpinelli^*, Ian P. Wicks^*, Natalie A. Sims, Kristy O’Donnell^*, Katherine Hanzinikolas^*, Rachel Burt^*, Simon J. Foote^*, Melanie Bahlo^*, Warren S. Alexander^* and Douglas J. Hilton^*

From the Walter and Eliza Hall Institute of Medical Research,^* Post Office Royal Melbourne Hospital, Victoria; and The Cooperative Research Centre for Cellular Growth Factors, The Cooperative Research Centre for Discovery of Genes for Common Human Diseases, and the St. Vincent’s Institute of Medical Research, Fitzroy, Victoria, Australia

We describe the clinical, genetic, biochemical, and molecular characterization of a mouse that arose in the first generation (G₁) 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.

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