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

作者：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

来源：Proceedings of the National Academy of Sciences, 2008, 105(9): 3455-3460.

DOI：10.1073/pnas.0712361105

• bone
• endocrinology
• genetics
• phosphorus

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 alpha-Klotho, which encodes a beta-glucuronidase, and is implicated in aging and regulation of FGF signaling. Plasma alpha-Klotho levels and beta-glucuronidase activity are markedly increased in the affected patient; unexpectedly, the circulating FGF23 level is also markedly elevated. These findings suggest that the elevated alpha-Klotho level mimics aspects of the normal response to hyperphosphatemia and implicate alpha-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.

• 出版日期2008-3-4