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

Abstract

Objective: Genetic disorders of calcium metabolism arise in a familial or sporadic setting. The calciumsensing receptor (CASR) plays a key role in maintaining calcium homeostasis and study of the CASR gene can be clinically useful in determining etiology and appropriate therapeutic approaches. We report two cases of novel CASR gene mutations that illustrate the varying clinical presentations and discuss these in terms of the current understanding of CASR function. Patients and methods: A 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 the CASR gene was sequenced in both probands and their available first-degree relatives. Results: The first patient had a novel heterozygous inactivating CASR mutation in exon 4, which predicted a p.A423K change; genetic analysis was negative in the parents. The second patient had a novel heterozygous activating CASR mutation in exon 6, which predicted a p.E556K change; the affected sister of the proband was also positive. Conclusions: We reported two novel heterozygous mutations of the CASR gene, 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 of CASR gene to aid correct diagnosis and to assist in clinical management.

Two novel mutations of the calcium-sensing receptor gene affecting the same amino acid position lead to opposite phenotypes and reveal the importance of p.N802 on receptor activity

“…Indeed, inappropriate high PTH level and normal calciuria to hypercalciuria are observed in the proband and in her sister. Similar observations have already been made in FHH families (3,27,28). High PTH level could be explained by vitamin D deficiency, as vitamin D supplementation has been shown to reduce serum PTH levels to the normal range in FHH patients (29).…”

“…It is responsive to very small changes in the circulating calcium concentration and, once activated, it inhibits parathyroid hormone (PTH) secretion and renal tubule calcium reabsorption. The importance of this receptor as a 'calciostat' has been emphasized by the identification of naturally occurring mutations in the CASR gene: inactivating and activating mutations cause hypercalcemic or hypocalcemic disorders respectively (2,3,4,5). Individuals heterozygous for loss-of-function mutations of CASR develop familial hypocalciuric hypercalcemia (FHH) and homozygotes present with neonatal severe hyperparathyroidism (NSHPT).…”

Calcium-sensing receptor 20 years later

“…Several de novo activating mutations have been reported in patients with sporadic hypoparathyroidism (5,35,76). Further genetic testing of the parents in these cases failed to demonstrate the mutations (5,35,76).…”

“…Several de novo activating mutations have been reported in patients with sporadic hypoparathyroidism (5,35,76). Further genetic testing of the parents in these cases failed to demonstrate the mutations (5,35,76). Nevertheless, not all cases of sporadic idiopathic hypoparathyroidism were associated with activating mutations in the CaSR, suggesting that other mechanisms are involved (119).…”