A translocation causing increased α-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 ␣-Klotho, which encodes a ␤-glucuronidase, and is implicated in aging and regulation of FGF signaling. Plasma ␣-Klotho levels and ␤-glucuronidase activity are markedly increased in the affected patient; unexpectedly, the circulating FGF23 level is also markedly elevated. These findings suggest that the elevated ␣-Klotho level mimics aspects of the normal response to hyperphosphatemia and implicate ␣-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.bone ͉ endocrinology ͉ genetics ͉ phosphorus T he maintenance of normal phosphate homeostasis is critical for diverse biochemical processes in vivo. Its importance is illustrated by disorders featuring hypophosphatemia due to excessive renal phosphate loss. Affected patients develop rickets, a disorder in which abnormal mineralization of bone and growth plate cartilage results in diminished bone strength, deformity, short stature, and bone pain. Rapidly growing bones of the lower extremities generally show the most striking abnormalities (1). Conversely, high phosphate levels may also have adverse physiologic effects. These are most pronounced in patients with chronic kidney disease (CKD) who develop hyperphosphatemia due to impaired renal clearance. These patients develop hyperparathyroidism and renal osteodystrophy.The kidney plays a predominant role in the regulation of serum phosphorus levels. The vast majority of phosphate reabsorption occurs in the proximal tubule and is mediated by the sodium-phosphate cotransporter type IIa (NaPi-IIa), with additional contributions from the related protein NaPi-IIc (2, 3). Parathyroid hormone (PTH) has been considered the major regulator of NaPi-IIa and NaPi-IIc density in the proximal tubular cell apical membrane (3, 4), promoting the rapid removal of NaPi-IIa from the membrane and its subsequent degradation (5). In addition, high phosphate levels are known to promote proliferation of parathyroid cells and enhance PTH secretion and mRNA stability; these effects have been speculated to be mediated by means of reduced serum Ca 2ϩ levels, but the mechanism is uncertain (6-9).More recently, FGF23 and its receptor have been recognized to play fundamental roles in phosphate homeos...

Characterization of FN1–FGFR1 and novel FN1–FGF1 fusion genes in a large series of phosphaturic mesenchymal tumors

“…This patient has a de novo germline translocation involving the region upstream of the KL (Klotho) gene, which probably accounted for her congenital elevation of plasma α-Klotho level and hypophosphatemic rickets. 35 At age 30, two tumors were found in her bilateral mastoid bones, confirmed histopathologically to be phosphaturic mesenchymal tumors, and shown by CISH to express elevated levels of FGF23. Both tumors were fusion-negative and the one tested by immunohistochemistry showed diffuse and weak expression of FGFR1 and FGF1.…”

Klotho Deficiency Causes Vascular Calcification in Chronic Kidney Disease

“…Previous studies showed that overexpressing Klotho by viral-based gene transfer 34 or genetic manipulation 33 attenuated progressive renal injury, but the Klotho status and systemic complications of CKD were not studied. Because Klotho is present in multiple body fluids, 25,27,36,57 the restoration of Klotho clearly exerts multiple systemic effects in addition to renoprotection.…”

Promoter methylation and age-related downregulation of Klotho in rhesus monkey

“…Rare human cases of profound KL protein alterations result in life-threatening disorders including hypophosphatemic rickets (Brownstein et al 2008) and tumoral calcinosis (Ichikawa et al 2007) with decreased and increased KL protein, respectively. As well, KL polymorphisms, resulting in more subtle alterations in KL protein level or function, affect lifespan and the risk of disease development (Kuro-o 2009).…”