Mutation watch: PEX PLUS? Gene(s) for X-linked hypophosphatemia and deafness.

Abstract

Three decades of work on X-linked hypophosphatemia in human and mouse reached fruition with the recent discovery of PEX, the ‘‘Phosphate regulating gene with homologies to Endopeptidases on the X chromosome’’ (HYP Consortium 1995; Strom et al. 1997). The mouse story began in 1966, when six males with shortened trunk and hindlimbs were discovered during a linkage experiment at The Jackson Laboratory (Eicher et al. 1976). Biochemical detective work identified hypophosphatemia as a critical defect, and administration of phosphate to the drinking water corrected many of the skeletal abnormalities and the dwarfing. Abnormal renal phosphate reabsorption accounts for the low level of phosphate in blood and the elevated level in urine. The mutation was inherited as an X-linked dominant and designated hypophosphatemia (Hyp). In 1986, a second dominant X-linked hypophosphatemia mutation, gyro (Gy), was described (Lyon et al. 1986). In addition to hypophosphatemia and skeletal defects that closely resemble Hyp, gyro mice exhibit circling behavior due to degeneration of hair cells in the vestibular apparatus and cochlea. The neuroepithelial abnormalities of the inner ear also result in a hearing deficiency (Steel 1995). Because the phenotypes of Hyp and Gy are dominant, it was not possible to draw conclusions about possible allelism from the phenotype of the compound heterozygote. Evidence for very close linkage was obtained from a cross between Gy +/+ Hyp females and normal males (Lyon et al. 1986). Among the 239 male offspring of this cross, one had normal blood phosphate levels and generated normal male offspring, indicating that he carried a recombinant + + chromosome. This recombination was interpreted as evidence that Hyp and Gy were mutations in distinct but closely linked and functionally related genes. However, recent molecular analysis found that Hyp and Gy are caused by independent mutations in the Pex gene that are separated by approximately 100 kb (Strom et al. 1997). The original recombination between Gy and Hyp was thus a rare example of intragenic recombination and reminds us that a single recombination does not provide a reliable estimate of genetic distance.