Hereditary hypophosphatemic rickets with hypercalciuria is caused by mutations in the sodium-phosphate cotransporter gene SLC34A3

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.