Mutations in SLC34A3/NPT2c Are Associated with Kidney Stones and Nephrocalcinosis

Abstract

Compound heterozygous and homozygous (comp/hom) mutations in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium (Na + )-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a disorder characterized by renal phosphate wasting resulting in hypophosphatemia, correspondingly elevated 1,25(OH) 2 vitamin D levels, hypercalciuria, and rickets/osteomalacia. Similar, albeit less severe, biochemical changes are observed in heterozygous (het) carriers and indistinguishable from those changes encountered in idiopathic hypercalciuria (IH). Here, we report a review of clinical and laboratory records of 133 individuals from 27 kindreds, including 5 previously unreported HHRH kindreds and two cases with IH, in which known and novel SLC34A3 mutations (c.1357delTTC [p.F453del]; c.G1369A [p.G457S]; c.367delC) were identified. Individuals with mutations affecting both SLC34A3 alleles had a significantly increased risk of kidney stone formation or medullary nephrocalcinosis, namely 46% compared with 6% observed in healthy family members carrying only the wild-type SLC34A3 allele (P=0.005) or 5.64% in the general population (P,0.001). Renal calcifications were also more frequent in het carriers (16%; P=0.003 compared with the general population) and were more likely to occur in comp/hom and het individuals with decreased serum phosphate (odds ratio [OR], 0.75, 95% confidence interval [95% CI], 0.59 to 0.96; P=0.02), decreased tubular reabsorption of phosphate (OR, 0.41; 95% CI, 0.23 to 0.72; P=0.002), and increased serum 1,25(OH) 2 vitamin D (OR, 1.22; 95% CI, 1.05 to 1.41; P=0.008). Additional studies are needed to determine whether these biochemical parameters are independent of genotype and can guide therapy to prevent nephrocalcinosis, nephrolithiasis, and potentially, CKD.

Autosomal-Recessive Mutations in SLC34A1 Encoding Sodium-Phosphate Cotransporter 2A Cause Idiopathic Infantile Hypercalcemia

“…12,13 Meanwhile, patients with NaPi-IIc defects presenting with isolated hypercalciuria and nephrolithiasis have been described. 14,15 The identification of autosomal-recessive SLC34A1 mutations in infants with IIH now demonstrates a crucial role of NaPi-IIa for calcium metabolism as well as phosphate balance in humans, which are tightly linked because they share major control mechanisms comprising vitamin D, iPTH, and FGF23. FGF23 exerts two major effects in the proximal tubule.…”

The Case | Epistasis and urolithiasis

“…Gene sequencing revealed heterozygous mutation and variant of CYP24A1 and SLC34A3 genes (respectively encoding for 25-(OH) -vit D 3 -24-hydroxylase and NPT2c). 3 The CYP24A1 mutation identified in patient DNA (c.1226T>C; p.Leu409Ser) has been previously described. Heterozygous CYP24A1 mutation carriers, while usually asymptomatic, may present an increased risk of kidney stones.…”

“…Thus we could hypothesize that the patient had a primary renal phosphate wasting caused by defective NPT2c function, inducing "appropriate" but moderate increase in calcitriol production. 3 The second genetic defect affecting calcitriol degradation led subsequently to inappropriately high level of calcitriol, resulting in hypercalcemia, hypercalciuria and nephrolithiasis. 1 The finding of a "normal" PTH was quite surprising since CYP24A1 mutation and high calcitriol serum levels are associated with suppressed PTH.…”

The Role of Sodium-Dependent Phosphate Transporter in Phosphate Homeostasis

“…Functional studies suggest that homozygous or compound heterozygous mutation of NaPi-IIc significantly decreases NaPi transport activity in Xenopus oocytes and opossum kidney cells (11). A recent report suggested that mutations in NaPi-IIc are associated with kidney stones and nephrocalcinosis (12). NaPi-2c knockout (Npt2c KO) mice exhibit hypercalciuria and higher levels of serum 1,25-dihydroxyvitamin D3 concentrations, but not hypophosphatemia, rickets or nephrocalcinosis (6).…”