Disease relevance of SLC34A3

• Hereditary Hypophosphatemic Rickets with Hypercalciuria Is Caused by Mutations in the Sodium-Phosphate Cotransporter Gene SLC34A3 [1].
• 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 [2].
• However, unlike HHRH patients, Npt2(-/-) mice do not have rickets or osteomalacia [3].
• 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 [2].
• We characterized the bone disease of transilial biopsy specimens from children with hereditary hypophosphatemic rickets with hypercalciuria (HHRH) and genetically related asymptomatic hypercalciuric subjects [4].

High impact information on SLC34A3

• Among 59 closely related members of one Bedouin tribe, we identified 9 who had the characteristic features of hereditary hypophosphatemic rickets with hypercalciuria (HHRH) [5].
• We conclude that the subjects with hypercalciuria and the patients with HHRH shared a hereditary renal phosphate leak that led to hypophosphatemia, elevated serum concentrations of 1,25-(OH)2D, increased intestinal calcium absorption, and hypercalciuria [5].
• Mean serum levels of 1,25-dihydroxyvitamin D (1,25-(OH)2D) were 303 pg per milliliter in HHRH and 145 pg per milliliter in idiopathic hypercalciuria (upper normal limit, 110) [5].
• The urinary calcium concentration was 0.43 +/- 0.14 mg per milligram of creatinine (mean +/- SD) in the patients with HHRH, 0.34 +/- 0.07 in the subjects with idiopathic hypercalciuria, and 0.14 +/- 0.05 in normal subjects from the same tribe [5].
• 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 [2].

Chemical compound and disease context of SLC34A3

• Nephrocalcinosis, presenting as hyperechogenicity of the medullary pyramids, was found in 2 of the 5 XLH patients and only in 2 HHRH patients who had been treated with excessive doses of vitamin D2 and calcium, prior to the true diagnosis being established [6].

Biological context of SLC34A3

• 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 [2].
• Loss of function of the SLC34A3 protein presumably results in a primary renal tubular defect and is compatible with the HHRH phenotype [1].
• Design and Setting: Mutation analysis of exons and adjacent introns in the SLC34A3 gene was conducted at an academic research laboratory and medical center [7].
• Haplotype analysis of the SLC34A3 locus in the family showed that the two deletions are on different haplotypes [7].
• The identification of three independent deletions in introns 9 and 10 suggests that the SLC34A3 gene may be susceptible to unequal crossing over because of sequence misalignment during meiosis [7].

Anatomical context of SLC34A3

• Two distinct renal Na-dependent Pi transporters, type IIa (NPT2a, SLC34A1) and type IIc (NPT2c, SLC34A3), are expressed in brush border membrane of proximal tubular cells where the bulk of filtered Pi is reabsorbed [8].

Other interactions of SLC34A3

• The candidate region contained a sodium-phosphate cotransporter gene, SLC34A3, which has been shown to be expressed in proximal tubulus cells [1].
• 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 [1].

References