Hereditary Hypophosphatemic Rickets with Hypercalciuria Is Caused by Mutations in the Sodium-Phosphate Cotransporter Gene SLC34A3

Abstract

Hypophosphatemia due to isolated renal phosphate wasting results from a heterogeneous group of disorders. Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is an autosomal recessive form that is characterized by reduced renal phosphate reabsorption, hypophosphatemia, and rickets. It can be distinguished from other forms of hypophosphatemia by increased serum levels of 1,25-dihydroxyvitamin D resulting in hypercalciuria. Using SNP array genotyping, we mapped the disease locus in two consanguineous families to the end of the long arm of chromosome 9. The candidate region contained a sodium-phosphate cotransporter gene, SLC34A3, which has been shown to be expressed in proximal tubulus cells. Sequencing of this gene revealed disease-associated mutations in five families, including two frameshift and one splice-site mutation. Loss of function of the SLC34A3 protein presumably results in a primary renal tubular defect and is compatible with the HHRH phenotype. We also show that the phosphaturic factor FGF23 (fibroblast growth factor 23), which is increased in X-linked hypophosphatemic rickets and carries activating mutations in autosomal dominant hypophosphatemic rickets, is at normal or low-normal serum levels in the patients with HHRH, further supporting a primary renal defect. Identification of the gene mutated in a further form of hypophosphatemia adds to the understanding of phosphate homeostasis and may help to elucidate the interaction of the proteins involved in this pathway.

The emerging role of the fibroblast growth factor-23–klotho axis in renal regulation of phosphate homeostasis

“…Recently, a genome-wide scan combined with homozygosity mapping has found a single nucleotide deletion in the Na/Pi-2c cotransporter gene in all affected individuals with HHRH (Bergwitz et al 2006, Lorenz-Depiereux et al 2006a. Interestingly, genomic deletion of Na/Pi-2c from mice has produced minor phenotypes (Segawa et al 2006) when compared with Na/Pi-2a-ablated mice, again suggesting that there might be differences in the regulation of phosphate homeostasis in humans and mice, and that the Na/Pi-2c cotransporter may have more important regulatory functions in maintaining phosphate homeostasis in humans.…”

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.…”

Molecular and Biochemical Aspects of Hypophosphatemic Rickets; an Updated Review

“…Other types of mutations include silent and donor splice site mutations, and most of the mutations were associated with loss of function in SLC34A3 protein. 23 In the 21 kindred studies, 43% of described SLC34A3 mutations were homozygous while 38% and 19% consisted of compound heterozygous mutations and heterozygous mutations, respectively. 25 SLC34A1-3 encodes sodium-phosphate cotransporters type 2 (SLC34a1; Napi-2a/SLC34a2; Napi2b/SLC34a3; Napi-2c).…”

“…However, familial studies revealed that single mutations could also cause some clinical symptoms of HHRH. 23,28 Bone pain, muscle weakness, and pseudofractures are common symptoms of HHRH. In comparison with other types of rickets, patients affected by HHRH exhibit an increase in serum 1,25(OH)2D.…”

“…In comparison with other types of rickets, patients affected by HHRH exhibit an increase in serum 1,25(OH)2D. 23,24 Therefore, this biochemical feature can be used as a differential diagnosis of HHRH from other types of hypophosphatemia. Moreover, elevated levels of 1,25OH 2 D 3 are accompanied by hypercalciuria and suppression of PTH secretion.…”