The Journal of clinical endocrinology and metabolism · 2025
Heterogeneous Origins of Calcium Homeostasis Disorders Arising From 5 Heterozygous Calcium-Sensing Receptor Variants.
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Du Wei, Boisen Ida Marie, Rahman Sabrina N, Poulsen Nadia Nicholine, Mathiesen Jesper M, Blomberg Jensen Martin, Bräuner-Osborne Hans, Jensen Anders A
Аннотация
CONTEXT: The human calcium-sensing receptor (CaSR) plays a key role in calcium homeostasis, and most identified CASR variants are associated with hypercalcemic and hypocalcemic disorders.
OBJECTIVE: Here we characterized the pharmacological implications of 5 heterozygous CASR variants from individuals with familial hypocalciuric hypercalcemia 1 (FHH1: Y63C, I81T, Q459R, W818stop) or autosomal dominant hypocalcemia 1 (ADH1: R955stop).
METHODS: Total and cell surface expression levels of wild-type (WT) and variant CaSRs expressed in human embryonic kidney 293T (HEK293T) cells were determined using enzyme-linked immunosorbent assay, and the pharmacological properties of the receptors were delineated in 2 functional assays.
RESULTS: The Y63C and I81T variations in the extracellular domain (ECD) of CaSR yielded markedly reduced cell surface expression and Ca2+ responsiveness, while Q459R displayed WT-like expression and functional properties. Truncation of the 7-transmembrane domain (7TMD) in W818stop eliminated cell surface expression, whereas R955stop in the intracellular carboxy-terminal yielded modestly increased surface expression and Ca2+ potency compared with WT CaSR. Interestingly, the effectiveness of positive allosteric modulators (PAMs) at the variants varied. Ca2+-mediated signaling through Y63C and I81T was significantly augmented by 7TMD-binding PAMs (NPS R-568 and evocalcet) but not by ECD-binding PAMs (etelcalcetide and Nb4), whereas signaling through Q459R and R955stop were robustly potentiated by all four PAMs.
CONCLUSION: While the molecular phenotypes exhibited by the 5 CaSR variants concord with the clinical phenotypes in individuals harboring them, CASR variant-induced calcium homeostasis disorders clearly arise from diverse molecular origins, and the effectiveness of calcimimetics in these disorders could differ depending on the specific variants.
OBJECTIVE: Here we characterized the pharmacological implications of 5 heterozygous CASR variants from individuals with familial hypocalciuric hypercalcemia 1 (FHH1: Y63C, I81T, Q459R, W818stop) or autosomal dominant hypocalcemia 1 (ADH1: R955stop).
METHODS: Total and cell surface expression levels of wild-type (WT) and variant CaSRs expressed in human embryonic kidney 293T (HEK293T) cells were determined using enzyme-linked immunosorbent assay, and the pharmacological properties of the receptors were delineated in 2 functional assays.
RESULTS: The Y63C and I81T variations in the extracellular domain (ECD) of CaSR yielded markedly reduced cell surface expression and Ca2+ responsiveness, while Q459R displayed WT-like expression and functional properties. Truncation of the 7-transmembrane domain (7TMD) in W818stop eliminated cell surface expression, whereas R955stop in the intracellular carboxy-terminal yielded modestly increased surface expression and Ca2+ potency compared with WT CaSR. Interestingly, the effectiveness of positive allosteric modulators (PAMs) at the variants varied. Ca2+-mediated signaling through Y63C and I81T was significantly augmented by 7TMD-binding PAMs (NPS R-568 and evocalcet) but not by ECD-binding PAMs (etelcalcetide and Nb4), whereas signaling through Q459R and R955stop were robustly potentiated by all four PAMs.
CONCLUSION: While the molecular phenotypes exhibited by the 5 CaSR variants concord with the clinical phenotypes in individuals harboring them, CASR variant-induced calcium homeostasis disorders clearly arise from diverse molecular origins, and the effectiveness of calcimimetics in these disorders could differ depending on the specific variants.