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.

Figure 1.

Frequency of renal calcifications is increased in carriers of SLC34A3/NPT2c mutations. Shown here is the prevalence of renal calcifications (i.e., nephrolithiasis and/or nephrocalcinosis) and bone disease (i.e., rickets/osteomalacia and/or osteopenia/osteoporosis) among individuals with two normal alleles as well as heterozygous and comp/hom carriers of SLC34A3/NPT2c mutations. Calc., calcification; dis., disease.

Figure 2.

Heterozygous carriers of SLC34A3/NPT2c mutations have intermediate biochemical findings. Summary of biochemical values of the presented and published kindreds analyzed with respect to genotype. Individual values with mean±95% confidence interval are shown for (A) normalized serum calcium, (B) normalized serum phosphorus, (C) normalized serum creatinine, and (D) serum 1,25(OH)₂ vitamin D. het, heterozygous; n/a, not applicable; wt, wild-type.

Figure 3.

Heterozygous carriers of SLC34A3/NPT2c mutations have intermediate biochemical findings. Summary of biochemical values of presented kindreds and published kindreds analyzed with respect to genotype. Individual values with mean±95% confidence interval are shown for (A) serum PTH levels, (B) normalized ALP, (C) uCa/uCrea, and (D) TRP. %UL, percent upper limit of normal; het, heterozygous; wt, wild-type.