Laboratory for Molecular Diagnostics
Center for Nephrology and Metabolic Disorders

Calcium sensing receptor

The gene codes the calcium sensing receptor excerting its funtion in renal tubules and the parathyroid gland. Hypocalciuric hypercalcemia ensues in heterozygous individuals, and two affected alleles cause neonatal hyperparathyroidism.

Epidemiology

Only few families with such disorders are described. Patients with less severe symptoms might be more often in patients with hypertension, osteoporosis or enuresis.

Gene Structure

The gene of the calcium sensing receptor (CASR) is about 103 kb in size. It is localized on chromosome 3 (3q13.3-q21). There are two splice variants. Both consists of 7 exons but they have different first exon and promoter. Both promoters contain a vitamin D reseponse element (VDRE) the binding site of the vitamin D receptor. Translation starts in second exon. This way both splice variants don't differ in there amino acid content.

Phenotype

The loss of function mutations in this gene result in familial hypercalcemic hypocalciuria (FHH) or in severe neonatal hyperparathyroidism (NSHPT). In FHH, PTH secretion shows a reduced sensitivity to extracellular calcium concentration whereas in NSHPT there is absolutly no response. Compared to plasma calcium we find an inadequitly hight PTH level an a reduced renal clearance of calcium and magnesium. Hypocalciuria persists after parathyroidectomy. Only loop diuretics can increase calcium excretion. On the other hand gain of function mutations are described leading to autosomal dominant hypocalcemia characterized by significantly low PTH levels.

Pathology

This extracellular sensing calcium receptor is a G-protein-coupled glycoprotein that contains seven membrane spanning helical structures, an extracellular domain and an intracellular carboxyterminal tail. The receptor has amino acid sequence similarity with cerebral metabotropic glutamate receptor (GRM2) and both receptors might have there origin in bacterial nutrient binding proteins. The calcium sensing receptor can be found in parathyroid gland, thyroid C cells and along all the tubules of the nephron. It does not contain one of the well known height-affinity calcium binding motifs. It seems that large negatively charged parts of the extracellular domain of the receptor can bind several divalent ions and hereby modulate the receptor response over the whole range of physiological calcium concentrations.

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Test Strategy

The indication for this therapy exists in cases with severe disorders of calcium homeostasis where symptoms are conform with one of the types of mutations in this gene. Consequences for medical services should exit.

Interpretation

The detected of a relevant mutation in the gene can confirm the diagnosis and help in family consulting.

Genetests:

Clinic Method Carrier testing
Turnaround 5 days
Specimen type genomic DNA
Clinic Method Multiplex Ligation-Dependent Probe Amplification
Turnaround 20 days
Specimen type genomic DNA
Clinic Method Genomic sequencing of the entire coding region
Turnaround 20 days
Specimen type genomic DNA
Clinic Method Massive parallel sequencing
Turnaround 25 days
Specimen type genomic DNA

Related Diseases:

Osteoporosis/renal Osteodystrophy
CASR
LRP5
RXRA
VDR
Hypoparathyroidism
AP2S1
CASR
GCM2
GNA11
Hypoparathyroidism, sensorineural deafness, and renal dysplasia syndrome
GATA3
Hypoparathyroidism-retardation-dysmorphism syndrome
TBCE
Kenny-Caffey syndrome
TBCE
PTH
Familial hypocalciuric hypercalcemia type 1
CASR
Hypercalciuric hypocalcemia 1
CASR
Susceptibility to nephrolithiasis
ALPL
CASR
SLC26A1
TRPV5
ZNF365

References:

1.

Canaff L et al. (2002) Human calcium-sensing receptor gene. Vitamin D response elements in promoters P1 and P2 confer transcriptional responsiveness to 1,25-dihydroxyvitamin D.

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2.

Hebert SC et al. (1997) Role of the Ca(2+)-sensing receptor in divalent mineral ion homeostasis.

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3.

Scillitani A et al. (2004) Blood ionized calcium is associated with clustered polymorphisms in the carboxyl-terminal tail of the calcium-sensing receptor.

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4.

Cole DE et al. (2001) Association between total serum calcium and the A986S polymorphism of the calcium-sensing receptor gene.

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5.

Cole DE et al. (1999) A986S polymorphism of the calcium-sensing receptor and circulating calcium concentrations.

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Update: Sept. 26, 2018