Details

Autor(en) / Beteiligte

• Brownstein, Catherine A
• Adler, Felix
• Nelson-Williams, Carol
• Iijima, Junko
• Li, Peining
• Imura, Akihiro
• Nabeshima, Yo-ichi
• Reyes-Mugica, Miguel
• Carpenter, Thomas O
• Lifton, Richard P

Titel

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

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2008-03, Vol.105 (9), p.3455-3460

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2008

Link zum Volltext

Quelle

Elektronische Zeitschriftenbibliothek (Open access)

Beschreibungen/Notizen

• 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.