Npt2 encodes a renal-specific, brush-border membrane Na ؉ -phosphate (P i ) cotransporter that is expressed in the proximal tubule where the bulk of filtered P i is reabsorbed. Mice deficient in the Npt2 gene were generated by targeted mutagenesis to define the role of Npt2 in the overall maintenance of P i homeostasis, determine its impact on skeletal development, and clarify its relationship to autosomal disorders of renal P i reabsorption in humans. Homozygous mutants (Npt2 ؊/؊ ) exhibit increased urinary P i excretion, hypophosphatemia, an appropriate elevation in the serum concentration of 1,25-dihydroxyvitamin D with attendant hypercalcemia, hypercalciuria and decreased serum parathyroid hormone levels, and increased serum alkaline phosphatase activity. These biochemical features are typical of patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a Mendelian disorder of renal P i reabsorption. However, unlike HHRH patients, Npt2؊/؊ mice do not have rickets or osteomalacia. At weaning, Npt2 ؊/؊ mice have poorly developed trabecular bone and retarded secondary ossification, but, with increasing age, there is a dramatic reversal and eventual overcompensation of the skeletal phenotype. Our findings demonstrate that Npt2 is a major regulator of P i homeostasis and necessary for normal skeletal development.Inorganic phosphate (P i ) is essential for a variety of cellular processes including skeletal mineralization. Because a disturbance in P i availability can affect the functional integrity of many organ systems, specialized tissues have evolved to maintain the extracellular P i concentration. In mammals, the regulation of P i homeostasis is largely determined by the kidney, with 60-70% of the filtered P i load reclaimed in the proximal segment of the nephron (1). Transepithelial transport of P i from the renal lumen to the blood compartment involves uptake across the brushborder membrane (BBM), translocation across the cell, and efflux across the basolateral membrane (2). Evidence suggests that P i transport across the BBM is the rate-limiting step in the overall P i reabsorptive process and the major site for its regulation (2, 3). Kinetics studies demonstrated that the transport is mediated by high capacity, low affinity, and low capacity, high affinity Na ϩ -P i cotransport systems (4).Recently, cDNAs encoding two distinct low capacity, high affinity, renal BBM Na ϩ -P i cotransporters (NPT1 and NPT2) that share only 20% identity have been identified in several mammalian species by expression and homology cloning (5-13). NPT2 is expressed exclusively in the proximal convoluted tubule and is regulated by P i intake (14) and parathyroid hormone (PTH) (15), factors known to regulate renal BBM Na ϩ -P i cotransport. In contrast, NPT1 is expressed throughout the proximal tubule and is not subject to regulation by dietary P i (10).X-chromosome-linked and autosomal disorders of renal P i reabsorption have been described in humans (16). Both are characterized by growth retardation, ...
The question of localisation of spin wave states is considered in a dilute Heisenberg ferromagnet with nearest-neighbour exchange near the percolation threshold. Using a geometrical model of the percolating cluster introduced by de Gennes which assumes that it is connected by effectively one-dimensional chains, together with Dyson's solution for the properties of states on a disordered chain, we find that the mobility edge drops to zero energy as p --* p , like exp( -A/@ -P,)''~),
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