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

Abstract

Idiopathic infantile hypercalcemia (IIH) is characterized by severe hypercalcemia with failure to thrive, vomiting, dehydration, and nephrocalcinosis. Recently, mutations in the vitamin D catabolizing enzyme 25-hydroxyvitamin D 3 -24-hydroxylase (CYP24A1) were described that lead to increased sensitivity to vitamin D due to accumulation of the active metabolite 1,25-(OH) 2 D 3 . In a subgroup of patients who presented in early infancy with renal phosphate wasting and symptomatic hypercalcemia, mutations in CYP24A1 were excluded. Four patients from families with parental consanguinity were subjected to homozygosity mapping that identified a second IIH gene locus on chromosome 5q35 with a maximum logarithm of odds (LOD) score of 6.79. The sequence analysis of the most promising candidate gene, SLC34A1 encoding renal sodium-phosphate cotransporter 2A (NaPi-IIa), revealed autosomal-recessive mutations in the four index cases and in 12 patients with sporadic IIH. Functional studies of mutant NaPi-IIa in Xenopus oocytes and opossum kidney (OK) cells demonstrated disturbed trafficking to the plasma membrane and loss of phosphate transport activity. Analysis of calcium and phosphate metabolism in Slc34a1-knockout mice highlighted the effect of phosphate depletion and fibroblast growth factor-23 suppression on the development of the IIH phenotype. The human and mice data together demonstrate that primary renal phosphate wasting caused by defective NaPi-IIa function induces inappropriate production of 1,25-(OH) 2 D 3 with subsequent symptomatic hypercalcemia. Clinical and laboratory findings persist despite cessation of vitamin D prophylaxis but rapidly respond to phosphate supplementation. Therefore, early differentiation between SLC34A1 (NaPi-IIa) and CYP24A1 (24-hydroxylase) defects appears critical for targeted therapy in patients with IIH.

Clinical and Biochemical Features of Patients with CYP24A1 Mutations

“…In 2015, a new loss-of-function mutation in SLC34A1, which encodes the renal sodium-phosphate cotransporter 2A (NaPi-IIa), was recognised in this group [20]. These patients presented with a classical IIH phenotype, with symptoms of hypercalcaemia.…”

“…In patients with SLC34A1 mutations, renal phosphate wasting leads of inappropriately high levels of 1,25-dihydroxyvitamin-D 3 , which in turn causes hypercalcaemia. It is crucial to distinguish between patients carrying mutations in CYP24A1 versus SLC43A1, as different intervention is required to successfully treat their hypercalcaemia [20]. As SLC34A1 mutations have also been identified as a cause of nephrolithiasis, there is overlap between SLC34A1 and CYP24A1 mutation phenotypes in both paediatric and adult presentations [21].…”

Current approach in children with urinary calculi

“…SLC34A1 gen mutaşyonu da benzer klinik bulgulara neden olabilir (33) . Hipofosfatemi, HC ve raşitizm hastalığın esas bulgularıdır.…”

Exploration of gene variations in the transcytosis system as a policy proposal for the personalized therapy in type 2 diabetes mellitus

“…ClC5, FcRn, NaPi-IIa gene are related with metabolic renal disease. DAB2, GIPC has an uncertain meaning in human pathology, but their pathogenic effect must be explored [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25].Considering the interaction between these genes, it would be very useful to analyze the relationship between polymorphisms of single base changes (SNP) of these genes, or the blocks of haplotypes and haplogroups that can be constructed with sets of SNP in T2D patients. Specially, the relationship of such variants with the development of peripheral neuropathy and the appropriate metformin doses.…”

“…ClC5, FcRn, NaPi-IIa gene are related with metabolic renal disease. DAB2, GIPC has an uncertain meaning in human pathology, but their pathogenic effect must be explored [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25].…”