Mutations of calcium-sensing receptor gene: two novel mutations and overview of impact on calcium homeostasis

Abstract

ObjectiveGenetic disorders of calcium metabolism arise in a familial or sporadic setting. The calcium-sensing receptor (CASR) plays a key role in maintaining calcium homeostasis and study of theCASRgene can be clinically useful in determining etiology and appropriate therapeutic approaches. We report two cases of novelCASRgene mutations that illustrate the varying clinical presentations and discuss these in terms of the current understanding of CASR function.Patients and methodsA 16-year-old patient had mild hypercalcemia associated with low-normal urinary calcium excretion and normal-to-high parathyroid hormone (PTH) levels. Because of negative family history, familial hypocalciuric hypercalcemia was originally excluded. The second patient was a 54-year-old man with symptomatic hypocalcemia, hyperphosphatemia, low PTH, and mild hypercalciuria. Familial investigation revealed the same phenotype in the patient's sister. The coding region of theCASRgene was sequenced in both probands and their available first-degree relatives.ResultsThe first patient had a novel heterozygous inactivatingCASRmutation in exon 4, which predicted a p.A423K change; genetic analysis was negative in the parents. The second patient had a novel heterozygous activatingCASRmutation in exon 6, which predicted a p.E556K change; the affected sister of the proband was also positive.ConclusionsWe reported two novel heterozygous mutations of theCASRgene, an inactivating mutation in exon 4 and the first activating mutation reported to date in exon 6. These cases illustrate the importance of genetic testing ofCASRgene to aid correct diagnosis and to assist in clinical management.