RESUMO
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.
Assuntos
Sequência de Bases/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Hipofosfatemia/genética , Camundongos/genética , Fenótipo , Proteínas/genética , Deleção de Sequência/genética , Absorciometria de Fóton , Animais , Southern Blotting , Composição Corporal , Pesos e Medidas Corporais , Densidade Óssea , Cóclea/anormalidades , Primers do DNA , Modelos Animais de Doenças , Potenciais Evocados Auditivos do Tronco Encefálico , Técnicas Histológicas , Masculino , Camundongos/anormalidades , Camundongos Endogâmicos C57BL , Endopeptidase Neutra Reguladora de Fosfato PHEX , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA , Crânio/anormalidadesRESUMO
Dr. Sandy C. Marks, Jr., has been a longtime collaborator of the Mouse Mutant Resource at The Jackson Laboratory and, most recently, was involved in the development of a Craniofacial Resource at TJL. The goals of this resource are to discover and supply to the scientific community mouse models of human craniofacial disease. A brief description of this collaboration is presented in Sandy's honor.