Slc34a1, encoding renal sodium-phosphate cotransporter 2A (NaPi-IIa), plays a crucial role in maintaining phosphate homeostasis. It is involved in the process of renal phosphate reabsorption, and its function is vital for normal calcium and phosphate metabolism [1,2,3,5].

Mutations in Slc34a1 have been linked to several diseases. Autosomal-recessive mutations in Slc34a1 cause idiopathic infantile hypercalcemia (IIH) [1,2,4]. In affected patients, there is renal phosphate wasting, which leads to inappropriate production of 1,25-(OH)2D3 and subsequent symptomatic hypercalcemia. Analysis of Slc34a1-knockout mice highlighted that phosphate depletion and fibroblast growth factor-23 suppression contribute to the development of the IIH phenotype [1]. However, a mouse model carrying the 91del7 in-frame deletion, a human pathogenic mutation, showed no signs of impaired phosphate homeostasis under normal or low-phosphate dietary conditions [3]. Biallelic SLC34A1 variant carriers in humans showed polyuria, failure to thrive, vomiting, constipation, hypercalcemia and nephrocalcinosis in infancy, and an attenuation of clinical features was observed after infancy, independent of treatment [5].

In conclusion, Slc34a1 is essential for renal phosphate reabsorption and maintaining calcium and phosphate homeostasis. The study of Slc34a1-knockout mouse models has significantly contributed to understanding its role in the development of idiopathic infantile hypercalcemia, highlighting its importance in this disease area [1,3,5].

References:

1. Schlingmann, Karl P, Ruminska, Justyna, Kaufmann, Martin, Wagner, Carsten A, Konrad, Martin. 2015. Autosomal-Recessive Mutations in SLC34A1 Encoding Sodium-Phosphate Cotransporter 2A Cause Idiopathic Infantile Hypercalcemia. In Journal of the American Society of Nephrology : JASN, 27, 604-14. doi:10.1681/ASN.2014101025. https://pubmed.ncbi.nlm.nih.gov/26047794/

2. De Paolis, Elisa, Scaglione, Giovanni Luca, De Bonis, Maria, Minucci, Angelo, Capoluongo, Ettore. . CYP24A1 and SLC34A1 genetic defects associated with idiopathic infantile hypercalcemia: from genotype to phenotype. In Clinical chemistry and laboratory medicine, 57, 1650-1667. doi:10.1515/cclm-2018-1208. https://pubmed.ncbi.nlm.nih.gov/31188746/

3. Bieri, Cornelia, Daryadel, Arezoo, Bettoni, Carla, Hernando, Nati, Wagner, Carsten A. 2022. The human pathogenic 91del7 mutation in SLC34A1 has no effect in mineral homeostasis in mice. In Scientific reports, 12, 6102. doi:10.1038/s41598-022-10046-w. https://pubmed.ncbi.nlm.nih.gov/35414099/

4. Wang, Qiao, Chen, Jia-Jia, Wei, Li-Ya, Su, Chang, Gong, Chun-Xiu. 2024. Biallelic and monoallelic pathogenic variants in CYP24A1 and SLC34A1 genes cause idiopathic infantile hypercalcemia. In Orphanet journal of rare diseases, 19, 126. doi:10.1186/s13023-024-03135-8. https://pubmed.ncbi.nlm.nih.gov/38504242/

5. Brunkhorst, Max, Brunkhorst, Lena, Martens, Helge, Emma, Francesco, Haffner, Dieter. 2024. Presentation and outcome in carriers of pathogenic variants in SLC34A1 and SLC34A3 encoding sodium-phosphate transporter NPT 2a and 2c. In Kidney international, 107, 116-129. doi:10.1016/j.kint.2024.08.035. https://pubmed.ncbi.nlm.nih.gov/39461557/