Evolutionary history of calcium-sensing receptors unveils hyper/hypocalcemia-causing mutations

Despite advancements in understanding the structure and functions of the Calcium Sensing Receptor (CaSR), gaps persist in our knowledge of the specific functions of its residues. In this study, we used phylogeny-based techniques to identify functionally equivalent orthologs of CaSR, predict residue significance, and compute specificity-determining position (SDP) scores to understand its evolutionary basis. The analysis revealed exceptional conservation of the CaSR subfamily, emphasizing the critical role of residues with high SDP scores in receptor activation and pathogenicity. To further enhance the findings, gradient-boosting trees were applied to differentiate between gain- and loss-of-function mutations responsible for hypocalcemia and hypercalcemia. Lastly, we investigated the importance of these mutations in the context of receptor activation dynamics. In summary, through comprehensive exploration of the evolutionary history of the CaSR subfamily, coupled with innovative phylogenetic methodologies, we identified activating and inactivating residues, providing valuable insights into the regulation of calcium homeostasis and its connections to associated disorders.Author summary: CaSR plays a crucial role in maintaining calcium balance in the body. Our study investigates the evolutionary history of CaSR to better understand its function and the impact of mutations. By using phylogenetic techniques, we identified key residues that are critical for CaSR’s function. These residues are highly conserved, indicating their importance in receptor activation and calcium regulation.