Clinical aspects of the phosphate transporters NaPi-IIa and NaPi-IIb: mutations and disease associations

Abstract

The Na-dependent phosphate transporter NaPi-IIa (SLC34A1) is mostly expressed in kidney, whereas NaPi-IIb (SLC34A2) has a wider tissue distribution with prominent expression in the lung and small intestine. NaPi-IIa is involved in renal reabsorption of inorganic phosphate (Pi) from urine, and patients with biallelic inactivating mutations in SLC34A1 develop hypophosphatemia, hypercalcemia, hypercalciuria and nephrocalcinosis, and nephrolithiasis in early childhood. Monoallelic mutations are frequent in the general population and may impact on the risk to develop kidney stones in adulthood. SNPs in close vicinity to the SLC34A1 locus associate with the risk to develop CKD. NaPi-IIb mediates high-affinity transport of Pi from the diet and appears to be mostly important during low Pi availability. Biallelic inactivating SLC34A2 mutations are found in patients with pulmonary alveolar microlithiasis, a lung disease characterized by the deposition of microcrystals. In contrast, no evidence for disturbed systemic Pi homeostasis has been reported in these patients to date. Nevertheless, NaPi-IIb-mediated intestinal Pi absorption may be a target for pharmaceutical interventions in patients with chronic kidney disease and Pi overload.

Parathyroid hormone initiates dynamic NHERF1 phosphorylation cycling and conformational changes that regulate NPT2A-dependent phosphate transport

“…Humans with NHERF1 inactivating mutations exhibit elevated phosphate excretion and a prominent bone phenotype with fractures (13,14). Likewise, knockout of Npt2a 5 (15) or SLC34A1 mutations disrupt phosphate metabolism with a constellation of mineral-ion and skeletal disorders (16,17).…”

An expert update on novel therapeutic targets for hyperphosphatemia in chronic kidney disease: preclinical and clinical innovations

“…Within the proximal tubule, phosphate transport from the ultrafiltrate across the proximal tubule epithelium is an energy dependent process that requires sodium [38]. The three renal sodium phosphate cotransporters, NaPi2a, NaPi2c, and PiT2, are all localised on the apical brush border membrane of renal proximal tubule cells and use the energy derived from the transport of sodium down its gradient to move inorganic phosphate from the luminal filtrate into the cell [39]. Mouse knockout experiments have shown that NaPi2a accounts for up to 70% of phosphate transport [40].…”

“…Collectively, preclinical studies have demonstrated that high phosphate diet appears to be linked to low expression of NaPi2b in the intestine, whereas dietary phosphate restriction leads to strong upregulation of NaPi2b [39,[80][81][82][83]. Moreover, many patients with advanced stages of CKD develop metabolic acidosis which in turn stimulates the expression and activity of NaPi2b [84].…”

Inherited Renal Tubulopathies—Challenges and Controversies

“…Mutations in SLC34A1 are also causal for AR infantile hypercalcemia [58][59][60], with many cases reported in the literature. Conversely, it was proposed by some [35,[61][62][63] and contested by others [64][65][66] that monoallelic mutations in the same gene determine AD hypophosphatemia and nephrocalcinosis, particularly in association with environmental factors. A dominant negative effect of heterozygous NaPiIIa mutations could not be demonstrated and phosphate transport has been mildly affected in some of the experiments [64,66].…”