Evidence for Phex haploinsufficiency in murine X-linked hypophosphatemia

Mutations in the PHEX gene (phosphate-regulating gene with homology to endo peptidases on the X-chromosome) are responsible for X-linked hypophosphatem ia (HYP). We previously reported the full-length coding sequence of murine Phex cDNA and provided evidence of Phex expression in bone and tooth. Here, we report the cloning of the entire 3.5-kb 3'UTR of the Phex gene, yieldin g a total of 6248 bp for the Phex transcript. Southern blot and RT-PCR anal yses revealed that the 3' end of the coding sequence and the 3'UTR of the P hex gene, spanning exons 16 to 22, are deleted in Hyp, the mouse model for HYP. Northern blot analysis of bone revealed lack of expression of stable P hex mRNA from the mutant allele and expression of Phex transcripts from the wild-type allele in Hyp heterozygous females. Expression of the Phex prote in in heterozygotes was confirmed by Western analysis with antibodies raise d against a COOH-terminal peptide of the mouse Phex protein. Taken together , these results indicate that the dominant pattern of Hyp inheritance in mi ce is due to Phex haploinsufficiency.