Mutations in SLC34A3/NPT2c are associated with kidney stones and nephrocalcinosis

• Published in: Journal of the American Society of Nephrology Vol. 25; no. 10; pp. 2366 - 2375
• Main Authors: Dasgupta, Debayan, Wee, Mark J, Reyes, Monica, Li, Yuwen, Simm, Peter J, Sharma, Amita, Schlingmann, Karl-Peter, Janner, Marco, Biggin, Andrew, Lazier, Joanna, Gessner, Michaela, Chrysis, Dionisios, Tuchman, Shamir, Baluarte, H Jorge, Levine, Michael A, Tiosano, Dov, Insogna, Karl, Hanley, David A, Carpenter, Thomas O, Ichikawa, Shoji, Hoppe, Bernd, Konrad, Martin, Sävendahl, Lars, Munns, Craig F, Lee, Hang, Jüppner, Harald, Bergwitz, Clemens
• Format: Journal Article
• Language: English
• Published: United States American Society of Nephrology 01-10-2014
• Subjects: Adult; Child; Child, Preschool; Clinical Research; Female; Humans; Infant; Kidney Calculi - genetics; Male; Medicin och hälsovetenskap; Mutation, Missense; Nephrocalcinosis - genetics; Sodium-Phosphate Cotransporter Proteins, Type IIc - genetics
• ISSN: 1046-6673; 1533-3450; 1533-3450
• DOI: 10.1681/ASN.2013101085

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.