Hereditary hypophosphatemias: New genes in the bone–kidney axis (Review Article)

Abstract

SUMMARY:Hypophosphatemia due to isolated renal phosphate wasting is a genetically heterogeneous disease. Two new genes linked to two different forms of hereditary hypophosphatemias have recently been described. Autosomal recessive form of hypophosphatemic rickets was mapped to chromosome 4q21 and identified homozygous mutations in dentin matrix protein 1 (DMP1) gene, which encodes a non-collagenous bone matrix protein. Intact plasma levels of the phosphaturic protein FGF23 (fibroblast growth factor 23) were clearly elevated in some of the affected individuals, providing a possible explanation for the phosphaturia and inappropriately normal 1,25(OH)2D levels, and suggesting that DMP1 may regulate FGF23 expression. Hereditary hypophosphatemic rickets with hypercalciuria is another rare disorder of autosomal recessive inheritance. Affected individuals present with hypercalciuria due to increased serum 1,25-dihydroxyvitamin D levels and increased intestinal calcium absorption. The disease was mapped to a 1.6 Mbp region on chromosome 9q34, which contains SLC34A3, the gene encoding the renal sodium-phosphate cotransporter NaPi-IIc. This was the first demonstration that NaPi-IIc has a key role in the regulation of phosphate homeostasis. Thus, DMP1 and NaPi-IIc add two new members to the bone-kidney axis proposed since it was discovered that the first phosphatonin, FGF23, was of osteoblastic/osteocyte origin. This provides a mechanism for the skeleton to communicate with the kidney to coordinate the mineralization of extracelular matrix and the renal handling of phosphate.KEY WORDS: bone mineralization, dentin matrix protein 1, hereditary hypophosphatemias, renal phosphate wasting, sodium-phosphate cotransporter IIc.

Intrinsically disordered proteins and biomineralization

“…Defects in DMP1, for example, are associated with Dentinogenesis Imperfecta type III and autosomal recessive hypophosphatemic rickets [134,135]. Although the observed phenotype may be linked to low phosphate levels and inappropriate FGF23 expression in those with aberrant DMP1, these condition were the first directly linked to a defect in an IDP, and thus deserves mention.…”

Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation

“…Clinical manifestations of hypophosphatemia include respiratory failure, cardiac arrhythmia, hemolysis, rhabdomyolysis, seizures, and coma acutely and myalgia and osteomalacia chronically (3). Hypophosphatemia originates from diverse pathophysiologic mechanisms, most importantly from renal phosphate wasting, an inherited or acquired condition in which renal tubular reabsorption of phosphate is impaired (5,6).…”

Novel SLC34A3 mutation causing hereditary hypophosphataemic rickets with hypercalciuria in a Gambian family

“…These are NaPi-Type IIa and -Type IIc, both of which are regulated by FGF23 and PTH. Although NaPi-IIa is thought to account for up to 70% of renal P reabsorption [5], we show in this study that NaPi-IIc must also play an integral role in P homeostasis. Additionally, we describe a novel mutation in the SLC34AC gene.…”