title: New intragenic deletions in the Phex gene clarify X-linked hypophosphatemia-related abnormalities in mice.
abstract: X-linked hypophosphatemic rickets (XLH) in humans is caused by mutation 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 mutation in the mouse Phex gene, Phex(Hyp-2J) and Phex(Hyp-Duk). Phex(Hyp-2J) 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 Phex-related phenotypes. Cochlear cross-sections from Phex(Hyp-2J)/Y and Phex(Hyp-Duk)/Y males reveal a thickening of the temporal bones 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 and 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.
authors.affiliation: Institute of Human Genetics, GSF National Research Center, München-Neuherberg, Germany. eme@jax.org
authors.forename: Bettina
authors.initials: B
authors.lastname: Lorenz-Depiereux
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Guido
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Johnson
authors.forename: Qing Yin
authors.initials: QY
authors.lastname: Zheng
authors.forename: Leona H
authors.initials: LH
authors.lastname: Gagnon
authors.forename: Joiel D
authors.initials: JD
authors.lastname: Bauschatz
authors.forename: Muriel T
authors.initials: MT
authors.lastname: Davisson
authors.forename: Linda L
authors.initials: LL
authors.lastname: Washburn
authors.forename: Leah Rae
authors.initials: LR
authors.lastname: Donahue
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.forename: Eva M
authors.initials: EM
authors.lastname: Eicher
mesh_terms: D015502:Absorptiometry, Photon; D000818:Animals; D001483:Base Sequence / Q000235:genetics*; D015139:Blotting, Southern; D001823:Body Composition; D001837:Body Weights and Measures; D015519:Bone Density; D003051:Cochlea / Q000002:abnormalities; D017931:DNA Primers; D004195:Disease Models, Animal; D016057:Evoked Potentials, Auditory, Brain Stem; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D006652:Histological Techniques; D017674:Hypophosphatemia / Q000235:genetics*; D008297:Male; D051379:Mice / Q000002:abnormalities / Q000235:genetics*; D008810:Mice, Inbred C57BL; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion / Q000235:genetics*; D012886:Skull / Q000002:abnormalities
chemical_list: D017931:DNA Primers; D011506:Proteins; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; C506232:Phex protein, mouse