Disorders of renal phosphate wasting may lead to hypophos- phatemia, increase of 1,25(OH)2D3 and consequent excess of intestinal calcium absorption and hypercalciuria. A clear exam­ple is represented by Hereditary Hypophosphatemic Rickets with Hypercalciuria (HHRH), a phenotype similar, except for bone, to that of mice with deletion of the kidney-specific sodium-phosphate co-transporter gene, N p t 2. Mutational analysis of human Npt2a gene has been performed by Prie et al identifying two patients (2 out of 20) carrying NPT2a mutations, exhibiting urolithiasis or osteoporosis and persistent idiopathic hypophosphatemia, associated with a decrease in maximal renal phosphate reabsorption. Npt2a gene localizes at chromosome 5q35. One of the 2 subjects was a man with re­current renal stones, hypophosphatemia, and reduced renal phosphate reabsorption; the second patient was a 64-year-old woman with idiopathic bone demineralization, hypophos- phatemia, and reduced renal phosphate reabsorption. Her only daughter, who also had the mutation, had a spinal deformity and a history of arm fractures, with hypophosphatemia and low maximal renal phosphate reabsorption. NPT2a is a renal proxi­mal tubular, brush-border membrane Na+-phosphate co-trans­porter. Both NPT2a gene mutations (V147M and A48F) had a dominant negative effect on the phosphate-induced current in oocytes co-transfected with the wild and mutant RNAs. This may explain why these mutations may lead to an impairment in renal phosphate reabsorption, resulting in hypophosphatemia.  Discount drugs online

A low serum phosphate concentration, in turn, would be ex­pected to increase 1,25-(OH)2D3 production, leading to increased intestinal absorption of calcium and hypercalciuria. As mentioned above, this phenotype resembles that of heterozygous N p t 2 a deficient mice, with increased urinary phosphate and calcium excretion, elevated plasma concentra­tions of 1,25-(OH)2D3 (51), and nephrocalcinosis. These findings were consistent with a dominant negative effect of the mutant proteins on the function of the wild type carrier, leading to a substantial renal phosphate losses in heterozygous pa­tients. However, as correctly pointed out by Scheinman and Tenenhouse, this is at odds with the model with the target­ed inactivation of Npt2 gene, where the heterozygous animals have neither hypercalciuria nor nephrocalcinosis. The rea­son why renal phosphate leak leads to either calcium stones or bone demineralization is still unknown, although it might be due to gender, environmental factors, or other genetic differences. Although they did not search for mutations in introns or regula­tory regions of the NPT2a gene, other genes may also be in­volved in the renal phosphate leak in patients who did not dis­close NPT2a gene mutations. The reported mother to daughter mutation segregation suggests an autosomal dominant inheri­tance, but up to date no systematic analysis of kindreds with similar clinical phenotype has been performed.

“New” putative candidate genes

ECaC1 gene

Although no kindreds with familial hypercalciuria and/or renal stones linked to the Epithelial Ca2+ channel 1 (ECaC1) locus have been reported so far, Muller et al have looked for E C a C 1 gene mutations in 9 families in which hypercalciuria dominantly segregated. This channel has been recently iden­tified: it allows the apical calcium entry step facilitating tran- scellular calcium transport of the apical membranes of 1,25(OH)2D3-responsive epithelia in the kidney and small intes­tine. It is a high selective channel that might play a crucial role in Ca2+-related disorders. The gene is on chromo­some 7q35. The results from the Muller’s study were negative and they did not support a primary role for the hECaC1 in the pathogenesis of PH, but ECaC1 cannot be excluded as a can­didate gene in other families with PH as the pathogenesis of the disease is heterogeneous.