A translocation causing increased alpha-klotho level results in hypophosphatemic rickets and hyperparathyroidism.
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.
Brownstein
Catherine A
CA
Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510.
Adler
Felix
F
Nelson-Williams
Carol
C
Iijima
Junko
J
Li
Peining
P
Imura
Akihiro
A
Nabeshima
Yo-Ichi
Y
Reyes-Mugica
Miguel
M
Carpenter
Thomas O
TO
Lifton
Richard P
RP
D005260:Female; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase / Q000097:blood* / Q000235:genetics; D006801:Humans; D006961:Hyperparathyroidism / Q000235:genetics*; D017674:Hypophosphatemia / Q000209:etiology / Q000235:genetics*; D007223:Infant; D000090265:Klotho Proteins; D010279:Parathyroid Diseases; D012279:Rickets / Q000235:genetics*; D013577:Syndrome; D014178:Translocation, Genetic
C000717427:FGF23 protein, human; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins