Functional evaluation of a novel nonsense variant of the calcium-sensing receptor gene leading to hypocalcemia.

This article focuses on the functional characterization of a novel nonsense variant [c.2897_2898insCTGA, p.(Gln967*)] in the calcium-sensing receptor gene (CASR) identified in a pediatric patient with chronic hypocalcemia. Contrary to typical truncating CASR mutations that cause loss-of-function and hypercalcemia, this variant results in a truncated receptor with gain-of-function properties, exhibiting constitutive activity and impaired sensitivity to extracellular calcium changes. Functional assays in HEK293T cells demonstrated that the mutant receptor has increased baseline activation of mitogen-activated protein kinase (MAPK) signaling pathways and altered phosphorylation dynamics, consistent with the patient's hypocalcemic phenotype. These findings underscore the importance of functional validation of genetic variants to inform clinical management and therapeutic strategies in calcium homeostasis disorders such as autosomal dominant hypocalcemia type 1 (ADH1).