X-linked hypophosphatemic rickets (XLH) in humans is caused by mutations in the PHEX gene. Previously, three mutations in the mouse Phex gene have been reported: Phex Hyp , Gy, and Phex Ska1 . Here we report analysis of two new spontaneous mutations in the mouse Phex gene, Phex and Phex Hyp-Duk . Phex and Phex Hyp-Duk involve intragenic deletions of at least 7.3 kb containing exon 15, and 30 kb containing exons 13 and 14, respectively. Both mutations cause similar phenotypes in males, including shortened hind legs and tail, a shortened square trunk, hypophosphatemia, hypocalcemia, and rachitic bone disease. In addition, mice carrying the Phex Hyp-Duk mutation exhibit background-dependent variable expression of deafness, circling behavior, and cranial dysmorphology, demonstrating the influence of modifying genes on Phexrelated phenotypes. Cochlear cross-sections from Phex Hyp-2J /Y and Phex Hyp-Duk /Y males reveal a thickening of the temporal bone surrounding the cochlea with the presence of a precipitate in the scala tympani. Evidence of the degeneration of the organ of Corti and spiral ganglion also are present in the hearing-impaired Phex Hyp-Duk /Y mice, but not in the normal-hearing Phex Hyp-2J /Y mice. Analysis of the phenotypes noted in Phex Hyp-Duk /Y an Phex Hyp-2J /Y males, together with those noted in Phex Ska1 /Y and Phex Hyp /Y males, now allow XLH-related phenotypes to be separated from non-XLH-related phenotypes, such as those noted in Gy/Y males. Also, identification of the genetic modifiers of hearing and craniofacial dysmorphology in Phex Hyp-Duk / Y mice could provide insight into the phenotypic variation of XLH in humans.X-linked dominant hypophosphatemia (XLH) is the most frequently occurring familial form of hypophosphatemic rickets in humans with an incidence of 1 per 20,000 individuals (Burnett et al. 1964;Tenenhouse 1999
NIH-PA Author ManuscriptThe Hyp mutation is a spontaneous deletion that begins in exon 15 and extends through exons 16-22 (Strom et al. 1997) into downstream intergenic sequences (Sabbagh et al. 2002). The Ska1 mutation is a chemically induced point mutation in a splice donor site immediately following exon 8 (Carpinelli et al. 2002). The Gy mutation is a radiationinduced deletion that removes 160-190 kb, including exons 1-3 and the Sms (spermine synthase) gene (Lorenz et al. 1998;Strom et al. 1997). Given that the gyro deletion includes more than one gene, the previous allelic symbol Phex Gy is inadequate; this mutation is here renamed gyro deletion region, symbol Gy (Mouse Genome Database, http://www.informatics.jax.org). Because neither the Hyp nor Gy mutations is restricted to the Phex coding sequence, it has been problematic to assign a specific phenotype solely to the Phex gene.Here we report the identification of two new spontaneous intragenic deletions in the mouse Phex gene, hypophosphatemia-2 Jackson, symbolized Phex Hyp-2J (Hyp-2J) and hypophosphatemia-Duke, symbolized, Phex Hyp-Duk (Hyp-Duk). Mice carrying either mutation, together with those car...
