title: A translocation causing increased alpha-klotho level results in hypophosphatemic rickets and hyperparathyroidism.
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 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.
authors.affiliation: Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Brownstein
authors.forename: Felix
authors.initials: F
authors.lastname: Adler
authors.forename: Carol
authors.initials: C
authors.lastname: Nelson-Williams
authors.forename: Junko
authors.initials: J
authors.lastname: Iijima
authors.forename: Peining
authors.initials: P
authors.lastname: Li
authors.forename: Akihiro
authors.initials: A
authors.lastname: Imura
authors.forename: Yo-Ichi
authors.initials: Y
authors.lastname: Nabeshima
authors.forename: Miguel
authors.initials: M
authors.lastname: Reyes-Mugica
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Carpenter
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
mesh_terms: 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
chemical_list: C000717427:FGF23 protein, human; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins