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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2008-03, Vol.105 (9), p.3455-3460
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Biological Sciences; Chromosome translocation; Chromosomes; Female; Gene expression regulation; Genetic mutation; Glucuronidase - blood; Glucuronidase - genetics; Homeostasis; Humans; Hyperparathyroidism; Hyperparathyroidism - genetics; Hyperplasia; Hypophosphatemia; Hypophosphatemia - etiology; Hypophosphatemia - genetics; Infant; Parathyroid Diseases; Phosphates; Rickets; Rickets - genetics; Syndrome; Translocation, Genetic
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0712361105

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.