PARTIAL DELETION OF BOTH THE SPERMINE SYNTHASE GENE AND THE PEX GENE IN THE X-LINKED HYPOPHOSPHATEMIC, GYRO (GY) MOUSE

Gy, along with Hyp, is a dominant mutation of the normal gene Per caus ing X-linked hypophosphatemia in the mouse. Hemizygous Gy male mice, h owever, have greater defects in survival, bodily growth, skeletal mine ralization, and neurological function than those found in heterozygous Gy females or in Hyp mice. Since the gene for spermine synthase is im mediately upstream of the homologous human gene PEX, we compared the e ffects of the Gy and Hyp mutations on both the spermine synthase gene and the Per gene. Barely detectable levels of spermine (<5 % of normal ) with elevated levels of its precursor, spermidine, were found in org ans of Gy male mice compared to normal male littermates. Neither Gy fe males nor Hyp male mice were significantly affected. Four missing intr ons of the spermine synthase gene were identified in Gy male mice, sug gesting extensive gene disruption. A pseudogene for spermine synthase was also identified in the mouse genome. Pex mRNA was found in several but not all tissues studied in adult normal mice. Pex mRNA was altere d in both Gy and Hyp mice. All male Hyp mice were lacking the 3' end o f the Per message, whereas all male Gy mice were deficient at the 5' e nd. In summary, the Gy mutation is associated with a recessively expre ssed mutation of the spermine synthase gene, leading to spermine defic iency, and a dominantly expressed mutation of the Per gene, leading to hypophosphatemia. Alterations in two contiguous genes in Gy may expla in the additional phenotypic abnormalities present in the Gy male mous e. (C) 1998 Academic Press.