Evolutionary History of Calcium-Sensing Receptors Unveils Hyper/Hypocalcemia-Causing Mutations

Calcium-sensing receptor evolution highlights hyper/hypocalcemia-causing mutations The Calcium Sensing Receptor (CaSR) is a key player in regulating calcium levels and has been linked to disorders like hypercalcemia and hypocalcemia. Despite advancements in understanding CaSR’s structure and functions, there are still gaps in our understanding of its specific residues and their differences from receptors within the same class. 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, with high SDP scores being critical 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.