A translocation causing increased α-Klotho level results in hypophosphatemic rickets and hyperparathyroidism

*Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510;
^†Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan;
^‡Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Saitama 332-0012, Japan; and
^§Departments of Pathology and
^¶Pediatrics (Endocrinology), Yale University School of Medicine, New Haven, CT 06520

Contributed by Richard P. Lifton, December 30, 2007 (received for review December 15, 2007)

Abstract

Phosphate homeostasis is central to diverse physiologic processes including energy homeostasis, formation of lipid bilayers, and bone formation. Reduced phosphate levels due to excessive renal loss cause hypophosphatemic rickets, a disease characterized by prominent bone defects; conversely, hyperphosphatemia, a major complication of renal failure, is accompanied by parathyroid hyperplasia, hyperparathyroidism, and osteodystrophy. Here, we define a syndrome featuring both hypophosphatemic rickets and hyperparathyroidism due to parathyroid hyperplasia as well as other skeletal abnormalities. We show that this disease is due to a de novo translocation with a breakpoint adjacent to α-Klotho, which encodes a β-glucuronidase, and is implicated in aging and regulation of FGF signaling. Plasma α-Klotho levels and β-glucuronidase activity are markedly increased in the affected patient; unexpectedly, the circulating FGF23 level is also markedly elevated. These findings suggest that the elevated α-Klotho level mimics aspects of the normal response to hyperphosphatemia and implicate α-Klotho in the selective regulation of phosphate levels and in the regulation of parathyroid mass and function; they also have implications for the pathogenesis and treatment of renal osteodystrophy in patients with kidney failure.

Footnotes

^‖To whom correspondence may be addressed. E-mail: richard.lifton{at}yale.edu or thomas.carpenter{at}yale.edu
Author contributions: C.A.B., F.A., C.N.-W., T.O.C., and R.P.L. designed research; C.A.B., F.A., C.N.-W., J.I., P.L., A.I., Y.-i.N., M.R.-M., and T.O.C. performed research; C.A.B., F.A., C.N.-W., P.L., M.R.-M., T.O.C., and R.P.L. analyzed data; and C.A.B., T.O.C., and R.P.L. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0712361105/DC1.
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