Familial hypocalciuric hypercalcemia type I (FHH1) is caused by heterozygous loss-of-function mutations in the CaSR gene, and is characterized by the combination of hypercalcemia, hypocalciuria, normal to elevated PTH, and facultatively hypermagnesemia and mild bone mineralization defects. To date, only heterozygous Casr null mice have been available as model for FHH1. We present a novel mouse FHH1 model identified in a large ENU-screen that carries an c.2579 T > A (p.Ile859Asn) variant in the Casr gene (CasrBCH002 mice). To dissect direct effects of the genetic variant from PTH-dependent effects, we crossed CasrBCH002 mice with PTH deficient mice. Heterozygous CasrBCH002 mice were fertile, had normal growth and body weight, were hypercalcemic and hypermagnesemic with inappropriately normal PTH levels and urinary calcium excretion replicating some features of FHH1. Hypercalcemia and hypermagnesemia were independent from PTH and correlated with higher expression of claudin 16 and 19 in kidneys. Likewise, reduced expression of the renal TRPM6 channel in CasrBCH002 mice was not dependent on PTH. In bone, mutations in Casr rescued the bone phenotype observed in Pth null mice by increasing osteoclast numbers and improving the columnar pattern of chondrocytes in the growth zone.
The CaSR also participates in sensing extracellular phosphate to control PTH-dependent renal elimination of phosphate. However, acute phosphaturia is only partly dependent on PTH and FGF23. The CaSR has been reported to be expressed in the same nephron segment, so we used the mouse models described above and pharmacological modulators of CaSR activity to examine a possible role of the CaSR in phosphate balance beyond PTH. Our results indicate that the acute phosphaturia is independent from the CaSR, and only partly dependent on PTH or FGF23.
The new mouse model allows gaining further insights into the pathophysiology of FHH1 and the role of the CaSR in cntrolling mineral balance.