title: An ethyl-nitrosourea-induced point mutation in phex causes exon skipping, x-linked hypophosphatemia, and rickets.
abstract: We describe the clinical, genetic, biochemical, and molecular characterization of a mouse that arose in the first generation (G(1)) of a random mutagenesis screen with the chemical mutagen ethyl-nitrosourea. The mouse was observed to have skeletal abnormalities inherited with an X-linked dominant pattern of inheritance. The causative mutation, named Skeletal abnormality 1 (Ska1), was shown to be a single base pair mutation in a splice donor site immediately following exon 8 of the Phex (phosphate-regulating gene with homologies to endopeptidases located on the X-chromosome) gene. This point mutation caused skipping of exon 8 from Phex mRNA, hypophosphatemia, and features of rickets. This experimentally induced phenotype mirrors the human condition X-linked hypophosphatemia; directly confirms the role of Phex in phosphate homeostasis, normal skeletal development, and rickets; and illustrates the power of mutagenesis in exploring animal models of human disease.
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Post Office Royal Melbourne Hospital, Victoria, Australia.
authors.forename: Marina R
authors.initials: MR
authors.lastname: Carpinelli
authors.forename: Ian P
authors.initials: IP
authors.lastname: Wicks
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Sims
authors.forename: Kristy
authors.initials: K
authors.lastname: O'Donnell
authors.forename: Katherine
authors.initials: K
authors.lastname: Hanzinikolas
authors.forename: Rachel
authors.initials: R
authors.lastname: Burt
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Foote
authors.forename: Melanie
authors.initials: M
authors.lastname: Bahlo
authors.forename: Warren S
authors.initials: WS
authors.lastname: Alexander
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Hilton
mesh_terms: D000483:Alleles; D000818:Animals; D001483:Base Sequence; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000473:pathology; D005038:Ethylnitrosourea; D005091:Exons; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000139:chemically induced / Q000175:diagnosis / Q000235:genetics*; D017674:Hypophosphatemia / Q000139:chemically induced / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009153:Mutagens; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; D017354:Point Mutation; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism; D011859:Radiography; D012279:Rickets / Q000139:chemically induced / Q000175:diagnosis / Q000235:genetics*
chemical_list: D009153:Mutagens; D011506:Proteins; D012333:RNA, Messenger; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; C506231:PHEX protein, human; C506232:Phex protein, mouse; D005038:Ethylnitrosourea