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

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.

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Insights into calcium-sensing receptor trafficking and biased signalling by studies of calcium homeostasis

Journal of Molecular Endocrinology ◽

10.1530/jme-18-0049 ◽

2018 ◽

Vol 61 (1) ◽

pp. R1-R12 ◽

Cited By ~ 6

Author(s):

Caroline M Gorvin

Keyword(s):

G Protein ◽

Calcium Homeostasis ◽

Calcium Release ◽

Transmembrane Domain ◽

Hormone Secretion ◽

Adaptor Protein ◽

Structural Motif ◽

Calcium Excretion ◽

Calcium Sensing Receptor ◽

Calcium Sensing

The calcium-sensing receptor (CASR) is a class C G-protein-coupled receptor (GPCR) that detects extracellular calcium concentrations, and modulates parathyroid hormone secretion and urinary calcium excretion to maintain calcium homeostasis. The CASR utilises multiple heterotrimeric G-proteins to mediate signalling effects including activation of intracellular calcium release; mitogen-activated protein kinase (MAPK) pathways; membrane ruffling; and inhibition of cAMP production. By studying germline mutations in the CASR and proteins within its signalling pathway that cause hyper- and hypocalcaemic disorders, novel mechanisms governing GPCR signalling and trafficking have been elucidated. This review focusses on two recently described pathways that provide novel insights into CASR signalling and trafficking mechanisms. The first, identified by studying a CASR gain-of-function mutation that causes autosomal dominant hypocalcaemia (ADH), demonstrated a structural motif located between the third transmembrane domain and the second extracellular loop of the CASR that mediates biased signalling by activating a novel β-arrestin-mediated G-protein-independent pathway. The second, in which the mechanism by which adaptor protein-2 σ-subunit (AP2σ) mutations cause familial hypocalciuric hypercalcaemia (FHH) was investigated, demonstrated that AP2σ mutations impair CASR internalisation and reduce multiple CASR-mediated signalling pathways. Furthermore, these studies showed that the CASR can signal from the cell surface using multiple G-protein pathways, whilst sustained signalling is mediated only by the Gq/11 pathway. Thus, studies of FHH- and ADH-associated mutations have revealed novel steps by which CASR mediates signalling and compartmental bias, and these pathways could provide new targets for therapies for patients with calcaemic disorders.

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Successful use of cinacalcet to treat parathyroid-related hypercalcemia in two pediatric patients

Endocrinology Diabetes and Metabolism Case Reports ◽

10.1530/edm-18-0009 ◽

2018 ◽

Vol 2018 ◽

Cited By ~ 1

Author(s):

E Mogas ◽

A Campos-Martorell ◽

M Clemente ◽

L Castaño ◽

A Moreno-Galdó ◽

...

Keyword(s):

Pediatric Patients ◽

Receptor Gene ◽

Gene Mutations ◽

Rare Condition ◽

List Type ◽

Calcium Sensing Receptor ◽

Calcium Sensing ◽

Severe Hypercalcemia ◽

The Right ◽

Learning Points

Summary Two pediatric patients with different causes of hyperparathyroidism are reported. First patient is a 13-year-old male with severe hypercalcemia due to left upper parathyroid gland adenoma. After successful surgery, calcium and phosphate levels normalized, but parathormone levels remained elevated. Further studies revealed a second adenoma in the right gland. The second patient is a 13-year-old female with uncommon hypercalcemia symptoms. Presence of pathogenic calcium-sensing receptor gene (CASR) mutation was found, resulting in diagnosis of symptomatic familial hypocalciuric hypercalcemia. Cinacalcet, a calcium-sensing agent that increases the sensitivity of the CASR, was used in both patients with successful results. Learning points: Hyperparathyroidism is a rare condition in pediatric patients. If not treated, it can cause serious morbidity. Genetic tests searching for CASR or MEN1 gene mutations in pediatric patients with primary hyperparathyroidism should be performed. Cinacalcet has been effective for treating different causes of hyperparathyroidism in our two pediatric patients. Treatment has been well tolerated and no side effects have been detected.

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Cinacalcet Treatment of Primary Hyperparathyroidism

International Journal of Endocrinology ◽

10.1155/2011/415719 ◽

2011 ◽

Vol 2011 ◽

pp. 1-5 ◽

Cited By ~ 11

Author(s):

H. M. Rothe ◽

O. Liangos ◽

P. Biggar ◽

A. Petermann ◽

M. Ketteler

Keyword(s):

Primary Hyperparathyroidism ◽

Stone Formation ◽

Receptor Gene ◽

Calcium Excretion ◽

Mineral Density ◽

Calcium Sensing Receptor ◽

Calcium Sensing ◽

First Choice ◽

Patient Subgroups ◽

Urine Calcium Excretion

Although parathyroidectomy remains the only curative approach to most primary hyperparathyroidism cases, medical treatment with cinacalcet HCl has been proven to be a reasonable alternative for several patient subgroups. Cinacalcet almost always controls hypercalcemia and hypophosphatemia sufficiently. PTH levels are lowered, and cognitive parameters improve. While an increase in bone mineral density DEXA scan scores was not demonstrated in cinacalcet trials, the same applies to more than half of patients after parathyroidectomy. Medical therapy should be first choice in patients with hyperplasia in all glands rather than an isolated adenoma (10–15%), patients with persisting HPT following unsuccessful surgery or inoperable cases due to comorbidities, and patients detected in lab screens for hypercalcemia before developing symptoms who should be treated early but are usually reluctant to undergo surgery. Nephrolithiasis was not found to occur more frequently in cinacalcet trial groups, but urine calcium excretion as one major risk factor of this complication of primary HPT may increase on cinacalcet. Patients carrying the rs1042636 polymorphism of the calcium-sensing receptor gene respond more sensitively to cinacalcet and have a higher risk of calcium stone formation. Cinacalcet is usually administered twice daily but three or four doses per day should be discussed to mimic the beneficial pulsatile PTH-pattern.

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