Calcium-sensing receptor (CaSR) mutations in hypercalcaemic and hypocalcaemic patients cluster at the extracellular dimer interface

Loss-and gain-of-function mutations of the calcium-sensing receptor (CaSR) cause familial hypocalciuric hypercalcaemia (FHH) and autosomal dominant hypocalcaemia (ADH), respectively. The CaSR is a homodimeric receptor that has a 612 amino acid extracellular domain (ECD), which binds extracellular calcium (Ca 2+ e) and mediates dimer interactions upon ligand binding. The ECD consists of lobes 1 and 2, and a cysteine-rich domain (CRD). To elucidate the structure-function relationships of the ECD, we examined the location of CaSR ECD mutations reported to date in FHH and ADH probands using recently established CaSR crystal structures. These studies identified that 121 FHH and 65 ADH mutations affected ECD residues, with> 50% of FHH mutations and> 75% of ADH mutations being located at the dimer interface. Mutations predicted to disrupt key CaSR dimer-dimer interactions included: a lobe 1 …