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CASQ2
calsequestrin 2
The CASQ2 gene provides instructions for making calsequestrin 2, a protein vital for regulating calcium storage and release in cardiac muscle cells, influencing heart rhythm. The CASQ2 gene is responsible for producing calsequestrin 2, a protein primarily found in the heart.
CASQ2 is located on the short (p) arm of chromosome 1, at band 1p13.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The CASQ2 gene encodes for calsequestrin 2, a protein predominantly expressed in cardiac (heart) muscle cells. Calsequestrin 2 governs how calcium ions are held and mobilised within cardiac myocytes, a process that enables rhythmic heart function. Understanding the CASQ2 gene and its protein is important for comprehending certain inherited heart conditions that affect electrical stability.
Pathogenic variants in CASQ2 can disrupt this delicate calcium balance, potentially leading to abnormal heart rhythms. The gene is classified as an ACMG Secondary Finding, indicating that variants can have significant health implications.
What the gene does
The CASQ2 gene produces calsequestrin 2, a protein located within the sarcoplasmic reticulum of heart muscle cells. The sarcoplasmic reticulum acts as a critical storage compartment for calcium ions (positively charged calcium atoms) inside the cell. Calsequestrin 2's primary function is to bind and store a large proportion of these calcium ions, effectively concentrating them within the sarcoplasmic reticulum [PMID:21200171].
Beyond its calcium storage role, calsequestrin 2 also helps regulate the ryanodine receptor 2 (RYR2) channel. This channel is responsible for controlling the flow of calcium ions out of the sarcoplasmic reticulum into the surrounding cytoplasm of the cell. Normal cardiac rhythm depends on cardiac myocytes cycling between contracted and relaxed states, a process initiated by carefully timed calcium flux across cellular compartments.
When specific signals are received, calcium ions bound to calsequestrin 2 are released via the RYR2 channel into the cytoplasm, prompting cardiac muscle contraction. Subsequently, these calcium ions are transported back into the sarcoplasmic reticulum, allowing the heart muscle to relax. This finely tuned mechanism, heavily reliant on calsequestrin 2, ensures a regular and coordinated heart rhythm [PMID:16520444].
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Chromosome location
The CASQ2 gene is situated on the short arm of chromosome 1, specifically at position 1p13.1. Chromosomes are highly organised structures found within the nucleus of cells, carrying our genetic information. The '1' denotes chromosome 1, 'p' refers to the short arm of the chromosome, and '13.1' indicates the precise band location on that arm. This gene spans approximately 17,200 base pairs of DNA.
Protein structure
The calsequestrin 2 protein is composed of 399 amino acids. A notable feature of its structure is a disordered region. This segment, located at amino acids 365-399, lacks a fixed three-dimensional structure and can adopt various conformations. Such disordered regions are often involved in protein-protein interactions and regulatory functions within the cell.
Key variants
Variants in the CASQ2 gene refer to alterations in its DNA sequence. These changes can range from single nucleotide substitutions to larger deletions or insertions. Such genetic variations may impact the production or function of the calsequestrin 2 protein. Depending on their nature and location, CASQ2 variants can affect how effectively the protein manages calcium levels in heart muscle cells, potentially leading to disruptions in heart rhythm. Some variants might alter specific amino acids, while others could prevent the protein from being produced at all.
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.1017dup | p.Asp340Ter | Pathogenic | ★★☆☆ | Catecholaminergic polymorphic ventricular tachycardia 1 |
c.1028G>A | p.Trp343Ter | Pathogenic | ★★☆☆ | Cardiovascular phenotype |
c.115G>T | p.Glu39Ter | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.164A>G | p.Tyr55Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Catecholaminergic polymorphic ventricular tachycardia 2 |
c.199C>T | p.Gln67Ter | Pathogenic | ★★☆☆ | Cardiovascular phenotype |
c.213del | p.Gln71fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.261dup | p.Ala88fs | Pathogenic/Likely pathogenic | ★★☆☆ | Cardiovascular phenotype |
c.2T>C | p.Met1Thr | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.320-2A>G | - | Pathogenic | ★★☆☆ | Catecholaminergic polymorphic ventricular tachycardia 2 |
c.339_354del | p.Ser113fs | Pathogenic | ★★☆☆ | Catecholaminergic polymorphic ventricular tachycardia 2 |
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 CASQ2 gene are primarily associated with inherited cardiac conditions that disturb the heart's electrical activity. The proper functioning of the calsequestrin 2 protein is crucial for maintaining a stable heart rhythm, and disruptions due to genetic variants can compromise this stability [PMID:16520444].
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is the main condition linked to CASQ2 variants. Over 30 different pathogenic variants in the CASQ2 gene have been identified in individuals with CPVT. These variants can lead to CPVT by altering single protein building blocks (amino acids) in the calsequestrin 2 protein or by preventing the cell from producing the protein entirely [PMID:23018260]. This disruption in calsequestrin 2 function results in uncontrolled calcium release within cardiac cells, leading to potentially life-threatening arrhythmias, especially during stress or exercise.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic CASQ2 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 CASQ2 gene is recognised within the UK's genomic medicine framework, specifically for its association with Catecholaminergic polymorphic ventricular tachycardia (CPVT). It is listed as 'green' on PanelApp, indicating that there is strong evidence supporting its role in this condition, and it is routinely assessed in clinical genetic testing panels in the UK.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Maintaining a heart-healthy lifestyle is generally recommended for overall cardiovascular well-being. This typically includes a balanced diet rich in fruits, vegetables, and whole grains, alongside regular physical activity. Avoiding smoking and limiting alcohol intake are also common recommendations. While research suggests these lifestyle choices can support general heart health, there is no conclusive evidence that specific lifestyle changes can prevent the onset or progression of conditions directly linked to CASQ2 variants.
Supplement considerations
There is no scientific evidence to suggest that specific supplements can prevent, treat, or cure conditions associated with CASQ2 variants. Individuals considering any supplement for heart health should discuss this with a healthcare professional to ensure it is appropriate and safe, especially given potential interactions with medications or underlying health conditions.
Frequently asked questions
What is the CASQ2 gene?
The CASQ2 gene provides the genetic instructions for creating calsequestrin 2, a protein primarily found in cardiac muscle cells. This protein is essential for regulating the storage and release of calcium ions, which are vital for proper heart function.
Where is the CASQ2 gene located?
The CASQ2 gene is located on chromosome 1, specifically on the short arm at position 1p13.1. This precise location helps geneticists identify and study the gene.
What does calsequestrin 2 do?
Calsequestrin 2 is critical for calcium management within heart muscle cells. It stores calcium ions in the sarcoplasmic reticulum and helps regulate their release, which is necessary for the heart's rhythmic contraction and relaxation cycle.
What conditions are associated with CASQ2 variants?
Variants in the CASQ2 gene are primarily associated with Catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited heart condition that affects the electrical stability and rhythm of the heart.
Is the CASQ2 gene considered in UK clinical genetic testing?
Yes, the CASQ2 gene is included in UK clinical genetic testing panels, particularly for Catecholaminergic polymorphic ventricular tachycardia (CPVT). Its 'green' status on PanelApp indicates strong evidence for its involvement in this condition.
References
- Wang Q, Michalak M. Calsequestrin. Structure, function, and evolution. Cell calcium. 2020. PMID: 32574906
- Katz G, Arad M, Eldar M. Catecholaminergic polymorphic ventricular tachycardia from bedside to bench and beyond. Current problems in cardiology. 2009. PMID: 19068246
- Györke S. Molecular basis of catecholaminergic polymorphic ventricular tachycardia. Heart rhythm. 2009. PMID: 19121813
- Cerrone M, Napolitano C, Priori SG. Catecholaminergic polymorphic ventricular tachycardia: A paradigm to understand mechanisms of arrhythmias associated to impaired Ca(2+) regulation. Heart rhythm. 2009. PMID: 19879546
- Liu N, Priori SG. Disruption of calcium homeostasis and arrhythmogenesis induced by mutations in the cardiac ryanodine receptor and calsequestrin. Cardiovascular research. 2008. PMID: 18006488
- Valle G, Galla D, Nori A. Catecholaminergic polymorphic ventricular tachycardia-related mutations R33Q and L167H alter calcium sensitivity of human cardiac calsequestrin. The Biochemical journal. 2008. PMID: 18399795
- Mohamed U, Napolitano C, Priori SG. Molecular and electrophysiological bases of catecholaminergic polymorphic ventricular tachycardia. Journal of cardiovascular electrophysiology. 2007. PMID: 17578347
- Terentyev D, Nori A, Santoro M. Abnormal interactions of calsequestrin with the ryanodine receptor calcium release channel complex linked to exercise-induced sudden cardiac death. Circulation research. 2006. PMID: 16601229
- di Barletta MR, Viatchenko-Karpinski S, Nori A. Clinical phenotype and functional characterization of CASQ2 mutations associated with catecholaminergic polymorphic ventricular tachycardia. Circulation. 2006. PMID: 16908766
- Viatchenko-Karpinski S, Terentyev D, Györke I. Abnormal calcium signaling and sudden cardiac death associated with mutation of calsequestrin. Circulation research. 2004. PMID: 14715535
- Postma AV, Denjoy I, Hoorntje TM. Absence of calsequestrin 2 causes severe forms of catecholaminergic polymorphic ventricular tachycardia. Circulation research. 2002. PMID: 12386154