SLC34A3 Mutations in Patients with Hereditary Hypophosphatemic Rickets with Hypercalciuria Predict a Key Role for the Sodium-Phosphate Cotransporter NaPi-IIc in Maintaining Phosphate Homeostasis

Abstract

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare disorder of autosomal recessive inheritance that was first described in a large consanguineous Bedouin kindred. HHRH is characterized by the presence of hypophosphatemia secondary to renal phosphate wasting, radiographic and/or histological evidence of rickets, limb deformities, muscle weakness, and bone pain. HHRH is distinct from other forms of hypophosphatemic rickets in that affected individuals present with hypercalciuria due to increased serum 1,25-dihydroxyvitamin D levels and increased intestinal calcium absorption. We performed a genomewide linkage scan combined with homozygosity mapping, using genomic DNA from a large consanguineous Bedouin kindred that included 10 patients who received the diagnosis of HHRH. The disease mapped to a 1.6-Mbp region on chromosome 9q34, which contains SLC34A3, the gene encoding the renal sodium-phosphate cotransporter NaP(i)-IIc. Nucleotide sequence analysis revealed a homozygous single-nucleotide deletion (c.228delC) in this candidate gene in all individuals affected by HHRH. This mutation is predicted to truncate the NaP(i)-IIc protein in the first membrane-spanning domain and thus likely results in a complete loss of function of this protein in individuals homozygous for c.228delC. In addition, compound heterozygous missense and deletion mutations were found in three additional unrelated HHRH kindreds, which supports the conclusion that this disease is caused by SLC34A3 mutations affecting both alleles. Individuals of the investigated kindreds who were heterozygous for a SLC34A3 mutation frequently showed hypercalciuria, often in association with mild hypophosphatemia and/or elevations in 1,25-dihydroxyvitamin D levels. We conclude that NaP(i)-IIc has a key role in the regulation of phosphate homeostasis.

Mutational analysis of PHEX, FGF23, DMP1, SLC34A3 and CLCN5 in patients with hypophosphatemic rickets

“…8,9 Two types of HR differ biochemically from the four described types, as they are characterised by hypercalciuria: Hereditary HR with hypercalciuria (HHRH; MIM 241530), where the hypercalciuria is due to increased serum 1,25(OH) 2 D. The inheritance is autosomal recessive and the disease is caused by a mutation in the sodium-cotransporter gene (SLC34A3; MIM 609826), identified in 2006. 10,11 The second type is X-linked recessive HR (MIM 300554), characterised by proximal renal tubulopathy and Fanconi syndrome caused by a mutation in the gene coding for the chloride channel 5 (CLCN5; MIM 300008). 12,13 Current recommendations on medical treatment of the HR types without hypercalciuria are intermittent oral phosphate supplementation in combination with alfacalcidol, carefully adjusted to avoid the development of secondary hyperparathyroidism or nephrocalcinosis.…”

Phosphate transporters of the SLC20 and SLC34 families

“…Based on these findings it was assumed that NaPi-IIa has a major quantitative impact on renal reabsorption of P i . However, recent data suggest that NaPi-IIc may play more important role in humans (see 2.5.2) (Bergwitz et al, 2006;Miyamoto et al).…”

“…In contrast, there is a large number of reported mutations of NaPi-IIc in patients with hypophosphatemic rickets with hypercalciuria (HHRH), e.g. (Bergwitz et al, 2006). These findings have challenged the assumption of NaPi-IIa being the major P i -reabsorbing protein in the human kidney.…”

Searching for CYP24A1 mutations in cohorts of patients with calcium nephrolithiasis

“…Several rare monogenic disorders associated with hypercalciuria (urinary excretion >6.2 mmol/24 h in females and >7.5 mmol/24 h in males) that cause stones have been identified [7][8][9] . However, despite initial excitement, the genes involved in these disorders, such as CLCN5, have not proved to have a wider role in the more common 'idiopathic' renal stone disease 10 .…”