Loss of function of NaPiIIa causes nephrocalcinosis and possibly kidney insufficiency

Abstract

BACKGROUND Inherited metabolic disorders associated with nephrocalcinosis are rare conditions. The aim of this study was to identify the genetic cause of an Israeli-Arab boy from a consanguineous family with severe nephrocalcinosis and kidney insufficiency. METHODS Clinical and biochemical data of the proband and family members were obtained from both previous and recent medical charts. Genomic DNA was isolated from peripheral blood cells. The coding sequence and splice sites of candidate genes (CYP24A1, CYP27B1, FGF23, KLOTHO, SLC34A3 and SLC34A1) were sequenced directly. Functional studies were performed in Xenopus laevis oocytes and in transfected opossum kidney (OK) cells. RE-SULTS Our patient was identified as having nephrocalcinosis in utero, and at the age of 16.5 years, he had kidney insufficiency but no bone disease. Genetic analysis revealed a novel homozygous missense mutation, Arg215Gln, in SLC34A1, which encodes the renal sodium phosphate cotransporter NaPiIIa. Functional studies of the Arg215Gln mutant revealed reduced transport activity in Xenopus laevis oocytes and increased intracellular cytoplasmic accumulation in OK cells. CONCLUSIONS Our findings show that dysfunction of the human NaPiIIa causes severe renal calcification that may eventually lead to reduced kidney function, rather than complications of phosphate loss.

FGF23-Klotho signaling axis in the kidney

“…In contrast, humans with loss-of-function mutations in NaPi-2c are characterized by hypophosphatemia and renal phosphate wasting which obviously cannot be balanced by counter-regulatory changes in NaPi-2a [42]. Furthermore, in contrast to mice, lossof-function mutations in NaPi-2a do not invariably lead to hypophosphatemia and renal phosphate wasting in humans [43]. Therefore, species specific differences in the importance of phosphate transporters in the kidney need to be considered.…”

Response of Npt2a knockout mice to dietary calcium and phosphorus

“…As a result they develop intraluminal stones (nephrolithiasis) and mineral deposits in the renal parenchyma (nephrocalcinosis) [4–7]. Furthermore, NPT2a has also been associated with nephrolithiasis [8] and altered renal function [9–11] in genome-wide association studies. Although little is known about the prevalence in stone patients, one compound heterozygous NPT2a mutations and one compound heterozygous carrier of NPT2c mutations was identified in a small cohort comprised of 272 genetically unresolved individuals (106 children and 166 adults) from 268 families with nephrolithiasis (n = 256) or isolated nephrocalcinosis (n = 16) [12].…”

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

“…Many of these mutations are located within the predicted highly conserved transmembrane domains of the transporter possibly disturbing folding and/or stability of the protein in the membrane. Consistently, the functional analysis of several of these mutants demonstrated function possibly due to trafficking defects with intracellular retention of the mutant protein [88,81,19,17,23].…”

“…Monoallelic SLC34A1 mutations have been identified in adult patients with kidney stones and reduced bone density [78], whereas biallelic mutations were found in children with either hypophosphatemia and hyperphosphaturia [81], or with infantile idiopathic hypercalciuria [88] or with nephrocalcinosis and kidney stones [7,74,30,19,67,38]. Patients from one large family with a 21-nucleotide insertion in the transporter also showed symptoms of a more generalized proximal tubular dysfunction with unusually high calcitriol levels atypical for Fanconi-like syndromes [67,17].…”

“…Thirty mutated sites have been identified in SLC34A1, mostly causing missense mutations, small in-frame deletions, frame shifts or early stop-codons [74,7,19,30,67,78,81,79,17,38,57]. Many of these mutations are located within the predicted highly conserved transmembrane domains of the transporter possibly disturbing folding and/or stability of the protein in the membrane.…”