Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

A gene (PEX) with homologies to endopeptidases is mutated in patients with X–linked hypophosphatemic rickets

Abstract

X–linked hypophosphatemic rickets (HYP) is a dominant disorder characterised by impaired phosphate uptake in the kidney, which is likely to be caused by abnormal regulation of sodium phosphate cotransport in the proximal tubules. By positional cloning, we have isolated a candidate gene from the HYP region in Xp22.1. This gene exhibits homology to a family of endopeptidase genes, members of which are involved in the degradation or activation of a variety of peptide hormones. This gene (which we have called PEX) is composed of multiple exons which span at least five cosmids. Intragenic non–overlapping deletions from four different families and three mutations (two splice sites and one frameshift) have been detected in HYP patients, which suggest that the PEX gene is involved in the HYP disorder.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

Stylianos E. Antonarakis, Brian G. Skotko, … Roger H. Reeves

References

  1. McKusick, V.A., Francomano, C.A. & Antonarakis, S.E. Mendelian Inheritance in Man. Catalogs of Autosomal Dominant, Autosomal Recessive, and X-linked Phenotypes, 10th Edition (The Johns Hopkins University Press, Baltimore, 1992).

    Google Scholar 

  2. Burnett, C.H., Dent, C.E., Harper, C. & Warland, B.J. Vitamin-D resistant rickets. Am. J. Med. 36, 222–232 (1964).

    Article  CAS  Google Scholar 

  3. Econs, M.J. & Drezner, M.K. Bone disease resulting from inherited disorders of renal tubule transport and vitamin D metabolism. In Disorders of Bone and Mineral Metabolism, (ed. M.J. Favus and F.L. Coe), 935–950 (Raven Press Ltd, New York, 1992).

    Google Scholar 

  4. Rowe, P.S.N. Molecular-biology of hypophosphatemic ricketsand oncogenic osteomalacia. Hum. Genet. 94, 457–467 (1994).

    Article  CAS  Google Scholar 

  5. Read, A.P. et al. Mapping of human X-linked hypophosphatemic rickets by multilocus linkage analysis. Hum. Genet. 73, 267–270 (1986).

    Article  CAS  Google Scholar 

  6. Machler, M. et al. X-linked dominant hypophosphatemia is closely linked to DNA markers DXS41 and DXS43 at Xp22. Hum. Genet. 73, 271–275 (1986).

    Article  CAS  Google Scholar 

  7. Thakker, R.V. et al. Bridging markers defining the map position of X-linked hypophosphatemic rickets. J. med. Genet. 24, 756–760 (1987).

    Article  CAS  Google Scholar 

  8. Meyer, R.A., Meyer, M.H. & Gray, R.W. Parabiosis suggests a humoral factor is involved in X-linked hypophosphatemia in mice. J. Bone miner. Res. 4, 493–500 (1989).

    Article  Google Scholar 

  9. Nesbitt, T., Coffman, T.M., Griffiths, R. & Drezner, M.K. Crosstransplantation of kidneys in normal and Hyp mice - evidence that the Hyp mouse phenotype is unrelated to an intrinsic renal defect. J. Clin. Invest. 89, 1453–1459 (1992).

    Article  CAS  Google Scholar 

  10. Morgan, J.M., Hawley, W.L., Chenoweth, A.I., Retan, W.J. & Diethelm, A.G. Renal transplantation in hypophosphatemia with vitamin D-resistant rickets. Arch. Intern. Med. 134, 549–552 (1974).

    Article  CAS  Google Scholar 

  11. Nesbitt, T. et al. Phosphate transport in immortalised cell cultures from the renal proximal tubule of normal and Hyp-mice: Evidence that the Hyp gene locus product is an extrarenal factor. J. Bone miner. Res. (in the press).

  12. Kos, C.H. et al. Localization of a renal sodium-phosphate cotransporter gene to human-chromosome 5q35. Genomics 19, 176–177 (1994).

    Article  CAS  Google Scholar 

  13. Chong, S.S., Kristjansson, K., Zoghbi, H.Y. & Hughes, M.R. Molecular cloning of the cDNA encoding a human renal sodium phosphate transport protein and its assignment to chromosome 6p21.3-p23. Genomics 18, 355–359 (1993).

    Article  CAS  Google Scholar 

  14. Tenenhouse, H.S. et al. Renal Na+-phosphate cotransport in murine X-linked hypophosphatemic rickets - molecular characterization. J. Clin. Invest. 93, 671–676 (1994).

    Article  CAS  Google Scholar 

  15. Eicher, E.M., Southard, J.L., Scriver, C.R. & Glorieux, F.H., Mouse model for human familial hypophosphatemic (vitamin D resistant) rickets. Proc. natn. Acad. Sci. U.S.A. 73, 4667–4671 (1976).

    Article  CAS  Google Scholar 

  16. Lyon, M.F. et al. The Gy mutation: Another cause of X-linked hypophosphatemia in mouse. Proc natn. Acad. Sci. U.S.A. 83, 4899–4903 (1986).

    Article  CAS  Google Scholar 

  17. Econs, M.J. et al. Flanking markers define the X-linked hypophosphatemic rickets gene locus. J. Bone miner. Res. 8, 1149–1152 (1993).

    Article  CAS  Google Scholar 

  18. Rowe, P.S.N. et al. New markers for linkage analysis of X-linked hypophosphatemic rickets. Hum. Genet. 91, 571–575 (1993).

    Article  CAS  Google Scholar 

  19. Rowe, P.S.N. et al. Refining the genetic-map for the region flanking the X-linked hypophosphatemic rickets locus (Xp22.1-22.2). Hum. Genet. 93, 291–294 (1994).

    Article  CAS  Google Scholar 

  20. Francis, F. et al. A YAC contig spanning the hypophosphatemic rickets disease gene (HYP) candidate region. Genomics 21, 229–237 (1994).

    Article  CAS  Google Scholar 

  21. Econs, M.J. et al. Fine-structure mapping of the human X-linked hypophosphatemic rickets gene locus. J. Clin. endocrin. Metab 79, 1351–1354 (1994).

    CAS  Google Scholar 

  22. Rowe, P.S.N. et al. The gene for X-linked hypophosphatemic rickets maps to a 300–400kb region in Xp22.1, and is located on a single YAC containing a putative vitamin D response element (VDRE). Hum. Genet. (in the press).

  23. D'Adamio, L., Shipp, M.A., Masteller, E.L. & Reinherz, E.L. Organization of the gene encoding common acute lymphoblastic leukemia antigen (neutral endopeptidase 24.11): Multiple miniexons and separate 5′ untranslated regions. Proc. natn. Acad. Sci. U.S.A. 86, 7103–7107 (1989).

    Article  CAS  Google Scholar 

  24. Xu, D. et al. ECE-1: A membrane-bound metalloprotease that catalyzes the proteolytic activation of Big Endothelin-1. Cell 78, 473–485 (1994).

    Article  CAS  Google Scholar 

  25. Lee, S., Zambas, E.D., Marsh, W.L. & Redman, C.M. Molecular cloning and primary structure of Kell blood group protein. Proc. natn. Acad. Sci. U.S.A. 88, 6353–6357 (1991).

    Article  CAS  Google Scholar 

  26. Uberbacher, E.C. & Mural, R.J. Locating protein-coding regions in human DMA-sequences by a multiple sensor neural network approach. Proc. natn. Acad. Sci. U.S.A. 88, 11261–11265 (1991).

    Article  CAS  Google Scholar 

  27. Altschul, S.F., Gish, W., Miller, W., Myers, E.W. & Lipman, D.J. Basic Local Alignment Search Tool. J. mol. Biol. 215, 403–410 (1990).

    Article  CAS  Google Scholar 

  28. Kyte, J. & Doolittle, R.F. A simple method for displaying the hydropathic character of a protein. J. mol. Biol. 157, 105–132 (1982).

    Article  CAS  Google Scholar 

  29. Shipp, M.A. et al. Downregulation of enkephalin-mediated inflammatory responses by CD10/neutral endopeptidase 24.11. Nature 347, 394–396 (1990).

    Article  CAS  Google Scholar 

  30. Shipp, M.A. et al. CD10/neutral endopeptidase 24.11 hydrolyzes bombesin-like peptides and regulates the growth of small cell carcinomas of the lung. Proc. natn. Acad. Sci. U.S.A. 88, 10662–10666 (1991).

    Article  CAS  Google Scholar 

  31. Yorimitsu, K. et al. Cloning and sequencing of a human endothelial converting enzyme in renal adenocarcinoma (ACHN) cells producing endothelin-2. Biochem. biophys. Res. Commun. 208, 721–727 (1995).

    Article  CAS  Google Scholar 

  32. Naggert, J.K. et al. Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity. Nature Genet. 10, 135–142 (1995).

    Article  CAS  Google Scholar 

  33. Qiu, Z.Q., Tenenhouse, H.S. & Scriver, C.R. Parental origin of mutant allele does not explain absence of gene dose in X-linked Hyp mice. Genet. Res. 62, 39–43 (1993).

    Article  CAS  Google Scholar 

  34. Fisher, E. & Scambler, P. Human haploinsufficiency — one for sorrow, two for joy. Nature Genet. 7, 5–7 (1994).

    Article  CAS  Google Scholar 

  35. Khamlichi, S. et al. Purification and partial characterisation of theerythrocyte Kx protein deficient in McLeod patients. Eur. J. Biochem. 228, 931–934 (1995).

    Article  CAS  Google Scholar 

  36. Ho, M. et al. Isolation of the gene for McLeod Syndrome that encodes a novel membrane transport protein. Cell 77, 869–880 (1994).

    Article  CAS  Google Scholar 

  37. Baxendale, S., Bates, G.P., MacDonald, M.E., Gusella, J.F. & Lehrach, H. The direct screening of cosmid libraries with YAC clones. Nucl. Acid Res. 19, 6651 (1991).

    Article  CAS  Google Scholar 

  38. Nizetic, D. et al. Construction, arraying, and high-density screening of large insert libraries of human chromosome-X and chromosome-21 —l their potential use as reference libraries. Proc. natn. Acad. Sci. U.S.A. 88, 3233–3237 (1991).

    Article  CAS  Google Scholar 

  39. Francis, F., Zehetner, G., Höglund, M. & Lehrach, H. Construction and preliminary analysis of the ICRF human P1 library. Genet Anal. Tech. Appl. 11, 148–157 (1994).

    Article  CAS  Google Scholar 

  40. Shepherd, N.S. et al. Preparation and screening of an arrayed human genomic library generated with the P1 cloning system. Proc. natn. Acad. Sci. U.S.A 91, 2629–2633 (1994).

    Article  CAS  Google Scholar 

  41. loannou, P. A. et al. A new bacteriophage P1-derived vector for the propagation of large human DMA fragments. Nature Genet. 6, 84–89 (1994).

    Article  Google Scholar 

  42. Sambrook, J., Fritsch, E.F. & Maniatis, T. Molecular Cloning: A Laboratory Manual. Second edition. (Cold Spring Harbor Press, New York, 1989).

    Google Scholar 

  43. Church, G.M. & Gilbert, W. Genomic sequencing. Proc. natn. Acad. Sci. U.S.A. 81, 1991–1995 (1984).

    Article  CAS  Google Scholar 

  44. Feinberg, A.P. & Vogelstein, B. A technique for radiolabeling DMA restriction endonuclease fragments to high specific activity. Anal. Biochem. 132, 6–13 (1983).

    Article  CAS  Google Scholar 

  45. Korn, B. et al. A strategy for the selection of transcribed sequences in the Xq28 region. Hum. molec. Gen. 1, 235–242 (1992).

    Article  CAS  Google Scholar 

  46. Dear, S. & Staden, R. A sequence assembly and editing program for efficient management of large projects. Nucl. Acids Res. 19, 3907–3911 (1991).

    Article  CAS  Google Scholar 

  47. Staden, R. Computer handling of DMA sequencing projects. In Nucleic Acids and Sequence Analysis: a practical approach (eds M.J. Bishop and C.J. Rawlings), 173–217 (IRL Press, Oxford, 1987).

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Francis, F., Hennig, S., Korn, B. et al. A gene (PEX) with homologies to endopeptidases is mutated in patients with X–linked hypophosphatemic rickets. Nat Genet 11, 130–136 (1995). https://doi.org/10.1038/ng1095-130

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1095-130

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing