Familial hypocalciuric hypercalcemia type 1 (FHH1) is a rare inherited condition resulting from heterozygous loss-of-function mutations in the calcium-sensing receptor (CaSR) gene. FHH1 presents with a distinctive clinical profile including elevated serum calcium, reduced urinary calcium excretion, PTH levels that are normal or increased, and occasionally elevated magnesium levels alongside mild disturbances in bone mineralization.

Until now, preclinical research has relied mostly on heterozygous Casr knockout mice as an FHH1 model. This work introduces a newly discovered mouse model of FHH1, identified through an extensive ENU mutagenesis screen, harboring a c.2579 T > A (p.Ile859Asn) substitution in the Casr gene (designated CasrBCH002 mice). To distinguish direct consequences of the mutation from those mediated by PTH, CasrBCH002 mice were bred with PTH-deficient animals.

Heterozygous CasrBCH002 mice demonstrated normal fertility, growth, and body mass, while exhibiting hypercalcemia and hypermagnesemia despite inappropriately normal PTH concentrations and urinary calcium excretion patterns that mirror characteristic FHH1 features. Both hypercalcemia and hypermagnesemia occurred independently of PTH and were associated with elevated renal expression of claudin 16 and 19. Similarly, diminished expression of the renal TRPM6 channel in CasrBCH002 mice was not PTH-dependent. In skeletal tissue, Casr mutations counteracted the bone abnormalities seen in Pth-deficient mice by elevating osteoclast counts and restoring the organized columnar arrangement of chondrocytes within the growth plate.

Collectively, CasrBCH002 mice constitute a valuable new tool for investigating FHH1 pathophysiology. Our findings reveal that PTH mediates only a portion of the FHH1 phenotype, underscoring the significance of PTH-independent CaSR actions in maintaining calcium and mineral homeostasis.