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CASR
calcium sensing receptor
The CASR gene provides instructions for the calcium-sensing receptor protein, a crucial component in regulating the body's calcium balance. The CASR gene encodes the calcium-sensing receptor (CaSR), a protein primarily located in the parathyroid glands and kidneys.
CASR is located on the long (q) arm of chromosome 3, at band 3q13.33-q21.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The CASR gene provides the genetic blueprint for synthesising the calcium-sensing receptor (CaSR) protein, which is integral to calcium homeostasis in the human body. This receptor detects changes in extracellular calcium concentrations and initiates appropriate physiological responses. Its function is particularly important in the parathyroid glands and kidneys, which are key organs involved in calcium regulation.
Dysregulation of the CASR protein due to genetic variants can lead to conditions characterised by abnormal calcium levels, such as familial hypocalciuric hypercalcaemia and neonatal severe hyperparathyroidism.
What the gene does
The CASR protein acts as a critical regulator of calcium levels within the body by sensing calcium ions. In the parathyroid glands, CaSR detects elevated blood calcium, leading to a reduction in parathyroid hormone (PTH) secretion. This action helps to lower blood calcium by preventing its release from bones and reducing calcium reabsorption in the kidneys. Conversely, when calcium levels are low, CaSR activity decreases, allowing PTH release to increase blood calcium.
In the kidneys, CaSR also influences calcium reabsorption. When activated by high calcium levels, it inhibits calcium reabsorption, allowing excess calcium to be excreted in the urine. This coordinated action across different tissues underscores the importance of CASR in maintaining precise calcium balance, which is essential for bone health, nerve function, and muscle contraction.
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Chromosome location
The CASR gene is situated on chromosome 3, specifically mapped to the region 3q13.33-q21.1. This location indicates its position on the long arm (q) of chromosome 3, within bands 13.33 to 21.1. The precise chromosomal address helps in understanding its genomic context and potential interactions with other genes in the vicinity.
Protein structure
The CASR protein is composed of 1078 amino acids, featuring several distinct functional domains. The protein includes two ligand-binding regions, Ligand-binding 1 (amino acids 22-188) and Ligand-binding 2 (amino acids 189-324), which are crucial for calcium sensing. A Cysteine-rich region (amino acids 542-612) is also present. The intracellular domain contains Intracellular loop 1 (amino acids 637-648), Intracellular loop 2 (amino acids 699-722), and Intracellular loop 3 (amino acids 790-805), which are important for signal transduction. The C-terminus (amino acids 855-1078) further includes an interaction site with RNF19A (amino acids 880-900), an Arginine-rich retention motif (amino acids 890-898), and three disordered regions (amino acids 892-963, 986-1006, and 1030-1055).
Key variants
Variants within the CASR gene can impact the structure and function of the calcium-sensing receptor protein. These genetic changes can lead to either reduced or increased activity of the receptor, consequently affecting calcium regulation. The specific clinical outcome often depends on the nature and location of the variant, and whether it results in a gain or loss of function.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1163C>A | p.Ser388Ter | Pathogenic | ★★☆☆ | Familial hypocalciuric hypercalcemia |
c.1378_1379insAGCAAAGG | - | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal dominant hypocalcemia 1 |
c.2011G>T | p.Glu671Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal dominant hypocalcemia 1 |
c.2024G>A | p.Trp675Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Familial hypocalciuric hypercalcemia |
c.2182G>T | p.Val728Phe | Pathogenic/Likely pathogenic | ★★☆☆ | Familial hypocalciuric hypercalcemia |
c.2361CTT[2] | p.Phe790del | Pathogenic | ★★☆☆ | Autosomal dominant hypocalcemia 1 |
c.2440TTC[1] | p.Phe815del | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal dominant hypocalcemia 1 |
c.2504C>A | p.Ala835Asp | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal dominant hypocalcemia 1 |
c.2T>C | p.Met1Thr | Pathogenic/Likely pathogenic | ★★☆☆ | Familial hypocalciuric hypercalcemia |
c.490C>T | p.Gln164Ter | Pathogenic | ★★☆☆ | Autosomal dominant hypocalcemia 1 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in the CASR gene are associated with several conditions that involve disruptions in calcium metabolism. These include Familial hypocalciuric hypercalcaemia (AD), characterised by elevated blood calcium and reduced urinary calcium excretion, and Neonatal severe hyperparathyroidism (AR), a more severe condition presenting shortly after birth with profoundly high calcium levels due to uncontrolled parathyroid hormone production. Other conditions, such as autosomal dominant hypocalcaemia, are also linked to CASR variants.
- Familial hypocalciuric hypercalcaemia
- Neonatal severe hyperparathyroidism Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic CASR variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The CASR gene is included in several Green RAG (Red Amber Green) rated panels within the UK's National Health Service (NHS) Genomic Medicine Service, indicating that there is strong evidence for its association with specific conditions and that genetic testing is considered clinically useful. These panels include Calcium-sensing receptor phenotypes (R319), Familial hyperparathyroidism or Hypocalciuric hypercalcaemia (R151), Familial hypoparathyroidism (R153), Foetal anomalies (R21), Nephrocalcinosis or nephrolithiasis (R256), Osteogenesis imperfecta (R102), Renal tubulopathies (R198), and Skeletal dysplasia (R104).
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the CASR gene?
The CASR gene provides instructions for creating the calcium-sensing receptor (CaSR) protein, which monitors and regulates calcium levels in the blood. It does this by influencing parathyroid hormone production and kidney reabsorption of calcium.
Which conditions are associated with variants in the CASR gene?
Variants in the CASR gene can lead to conditions such as Familial hypocalciuric hypercalcaemia (AD) and Neonatal severe hyperparathyroidism (AR), both of which involve abnormal calcium levels due to impaired receptor function.
Where is the CASR gene located in the human genome?
The CASR gene is located on chromosome 3, specifically within the region designated as 3q13.33-q21.1. This position indicates its place on the long arm of chromosome 3.
References
- Kinoshita Y, Hori M, Taguchi M. Functional activities of mutant calcium-sensing receptors determine clinical presentations in patients with autosomal dominant hypocalcemia. The Journal of clinical endocrinology and metabolism. 2014. PMID: 24297799
- Thim SB, Birkebaek NH, Nissen PH. Activating calcium-sensing receptor gene variants in children: a case study of infant hypocalcaemia and literature review. Acta paediatrica (Oslo, Norway : 1992). 2014. PMID: 25039540
- Ranieri M, Tamma G, Di Mise A. Excessive signal transduction of gain-of-function variants of the calcium-sensing receptor (CaSR) are associated with increased ER to cytosol calcium gradient. PloS one. 2013. PMID: 24244430
- Raue F, Pichl J, Dörr HG. Activating mutations in the calcium-sensing receptor: genetic and clinical spectrum in 25 patients with autosomal dominant hypocalcaemia - a German survey. Clinical endocrinology. 2011. PMID: 21645025
- Hannan FM, Nesbit MA, Christie PT. A homozygous inactivating calcium-sensing receptor mutation, Pro339Thr, is associated with isolated primary hyperparathyroidism: correlation between location of mutations and severity of hypercalcaemia. Clinical endocrinology. 2010. PMID: 20846291
- Hendy GN, Guarnieri V, Canaff L. Calcium-sensing receptor and associated diseases. Progress in molecular biology and translational science. 2009. PMID: 20374733
- Warner J, Epstein M, Sweet A. Genetic testing in familial isolated hyperparathyroidism: unexpected results and their implications. Journal of medical genetics. 2004. PMID: 14985373