Abstract

Purpose: Activating mutations of the calcium-sensing receptor (CASR) are a rare genetic disorder, and result in autosomal dominant hypocalcemia with hypercalciuria (ADHH). ADHH exhibited varying degrees of hypocalcemia. In this study, we report the clinical and molecular characteristics of activating variants in CASR patients diagnosed in Korea. Methods: This study included three patients with activating variants of CASR confirmed by biochemical and molecular analysis of CASR. Clinical and biochemical findings were reviewed chart retrospectively. Mutation analysis of CASR was performed by Sanger sequencing. Results: Subject 1 showed severe symptoms from the neonatal period and had difficulty in controlling the medications that were administered. Subject 2 was identified as having a novel variant of CASR with hypocalcemia and a low parathyroid hormone that were found in the neonatal period. During a course without medication, hypocalcemia occurred suddenly around 2 years of age. Subject 3 was diagnosed with hypoparathyroidism with hypocalcemic seizures starting from the neonatal period. About 4 years without taking medication with any symptom. However, at 10 years old revisited by repetitive hypocalcemic seizure events. Subject 1 and 3, were heterozygous for c.2474A>T (p.Y825F), c.2395G>A (p.E799K) located in the transmembrane domain (TMD) of CASR. Subject 2 was heterozygous for c.403A>C (S430L) located in the extracellular domain (ECD) of CASR. Conclusion: We reported 3 patients who have activating CASR variant with different onset and severity of symptoms. In the future, further study is needed to determine how the protein level according to the location of the mutation of CASR affects the degree of symptoms.