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New intragenic deletions in the Phex gene clarify X-linked hypophosphatemia-related abnormalities in mice

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Abstract

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 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 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.

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Acknowledgements

We thank Wesley G. Beamer and Tali Shalom-Barak for their careful review of this manuscript, as well as H. Hellebrand, Heping Yu, and Sandra Gray for their technical assistance and contribution to this study. We are indebted to Susan Poulton for originally discovering the Hyp-Duk mutation at The Urology Research Department at Duke University. We also thank Roderick Bronson for pathohistological evaluation and Coleen Marden for colony maintenance. This work was supported by grants from the Deutsche Forschungsgemeinschaft (STR304/2-1), by the National Institutes of Health grants RR01183, CF-DE13078-03, contract DC62108 and by the Cancer Core grant CA34196 from the National Cancer Institute.

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Authors and Affiliations

  1. Institute of Human Genetics, GSF National Research Center, Ingolstädter Landstr. 1,85764 München-Neuherberg, Germany

    Bettina Lorenz-Depiereux & Tim M. Strom

  2. The Jackson Laboratory, 600 Main Street, Bar Harbor, Maina 04609, USA

    Victoria E. Guido, Kenneth R. Johnson, Qing Yin Zheng, Leona H. Gagnon, Joiel D. Bauschatz, Muriel T. Davisson, Linda L. Washburn, Leah Rae Donahue & Eva M. Eicher

Authors
  1. Bettina Lorenz-Depiereux
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  2. Victoria E. Guido
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  3. Kenneth R. Johnson
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  4. Qing Yin Zheng
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  5. Leona H. Gagnon
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  6. Joiel D. Bauschatz
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  7. Muriel T. Davisson
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  8. Linda L. Washburn
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  9. Leah Rae Donahue
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  10. Tim M. Strom
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  11. Eva M. Eicher
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Correspondence to Eva M. Eicher.

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Lorenz-Depiereux, B., Guido, V.E., Johnson, K.R. et al. New intragenic deletions in the Phex gene clarify X-linked hypophosphatemia-related abnormalities in mice . Mamm Genome 15, 151–161 (2004). https://doi.org/10.1007/s00335-003-2310-z

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  • DOI: https://doi.org/10.1007/s00335-003-2310-z

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