CYP24A1 and SLC34A1 genetic defects associated with idiopathic infantile hypercalcemia: from genotype to phenotype

Abstract

Loss of function mutations in the CYP24A1 gene, involved in vitamin D catabolism and in calcium homeostasis, are known to be the genetic drivers of both idiopathic infantile hypercalcemia (IIH) and adult renal stone disease. Recently, also defects in the SLC34A1 gene, encoding for the renal sodium-phosphate transporter NaPi-IIa, were associated with the disease. IIH typically affects infants and pediatric patients with a syndrome characterized by severe hypercalcemia, hypercalciuria, suppressed parathyroid hormone level and nephrolithiasis. In SLC34A1 mutated carriers, hypophosphatemia is also a typical biochemical tract. IIH may also persist undiagnosed into adulthood, causing an increased risk of nephrocalcinosis and renal complication. To note, a clinical heterogeneity characterizes IIH manifestation, principally due to the controversial gene-dose effect and, to the strong influence of environmental factors. The present review is aimed to provide an overview of the current molecular findings on the IIH disorder, giving a comprehensive description of the association between genotype and biochemical and clinical phenotype of the affected patients. We also underline that patients may benefit from genetic testing into a targeted diagnostic and therapeutic workflow.

Duplex high resolution melting analysis (dHRMA) to detect two hot spot CYP24A1 pathogenic variants (PVs) associated to idiopathic infantile hypercalcemia (IIH)

“…In the first Italian report, performed in a small cohort of patients, Gigante et al [10]. describes 6 different CYP24A1 mutation, including one small deletion (p.Glu143del), 4 missense mutations (p.Leu148Pro; p.Arg396Trp; p.Pro503 Leu; p.Glu383Gln) and one non sense mutation (p.Tyr220*) [10,13]. Recently, Brancatella et al [12], screened for CYP24A1 mutations a large Italian family, reporting a nonsense CYP24A1 gene mutation, the (p.Arg223*), previously described by two other research groups [6,9].…”

Membrane Transport Proteins in Osteoclasts: The Ins and Outs

“…For instance, outside of bone, SLC34A1 is highly expressed in the kidneys. Inactivating mutations in SLC34A1 have been associated with idiopathic infantile hypercalcemia 2 (IIH2), a disease usually attributed to mutations in CYP24A1 (Schlingmann et al, 2011;De Paolis et al, 2019). Thus, a major role of SLC34A1 is to facilitate reabsorption of glomerularfiltered phosphate in the proximal tubule, with disruption of this transporter leading to hypophosphatemia.…”

Parenteral iron therapy and phosphorus homeostasis: A review

“… 40 Fanconi syndrome (many causes including Dent disease), hereditary hypophosphatemic rickets with hypercalciuria, and other primary disorders of the renal proximal tubule are associated with low or suppressed serum concentrations of FGF23 25 . It has been shown that mutations in sodium‐phosphate cotransporter genes involved in renal phosphate reabsorption, SLC34A1 and SLC34A3 , cause hypophosphatemia in idiopathic infantile hypercalcemia and hereditary hypophosphatemic rickets with hypercalciuria, respectively 43,44 …”