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DSC2
desmocollin 2
The DSC2 gene provides instructions for making desmocollin-2, a protein crucial for cell-to-cell adhesion, particularly in the heart muscle and skin. Desmocollin-2 is a key component of desmosomes, specialised structures that help bind neighbouring cells together, providing strength and stability to tissues.
DSC2 is located on the long (q) arm of chromosome 18, at band 18q12.1. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 18 in the library →Overview
The DSC2 gene, also known as desmocollin 2, encodes a protein called desmocollin-2. This protein is broadly distributed across various body tissues, but its function is especially important in the heart muscle and the skin. Desmocollin-2 is an integral part of desmosomes, which are cellular junctions that secure adjacent cells, contributing to tissue integrity and mechanical strength.
Changes in the DSC2 gene can lead to alterations in desmosome function, potentially resulting in conditions that affect the heart's structure and rhythm, as well as skin integrity. These conditions are typically inherited in an autosomal dominant pattern.
What the gene does
The desmocollin-2 protein, encoded by the DSC2 gene, plays a critical role in cellular adhesion by forming part of desmosomes. These complex structures are responsible for anchoring cells together, thereby imparting resilience and stability to tissues that experience mechanical stress, such as the cardiac muscle and the epidermis of the skin. Desmosomes function as robust adhesion points, preventing cells from separating under strain.
Beyond their structural role, desmosomes, and by extension desmocollin-2, are thought to participate in other crucial cellular processes. These include chemical signalling pathways that allow cells to communicate, cellular differentiation where cells mature to perform specific functions, and apoptosis, which is the programmed self-destruction of cells. Dysfunction of desmocollin-2 can compromise the structural integrity of tissues, leading to clinical manifestations primarily in the heart and skin.
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Chromosome location
The DSC2 gene is located on chromosome 18, specifically at position 18q12.1. This position indicates that the gene resides on the long arm (q) of chromosome 18, within region 12.1.
Protein structure
The desmocollin-2 protein is composed of 901 amino acids and features a distinct domain organisation essential for its function in cell adhesion. It contains multiple cadherin domains, which are characteristic of cell adhesion proteins. Specifically, the protein includes Cadherin 1, located between amino acids 136 and 243; Cadherin 2, found between amino acids 244 and 355; Cadherin 3, spanning amino acids 356 to 471; Cadherin 4, from amino acids 472 to 579; and Cadherin 5, situated between amino acids 580 and 694. These cadherin domains are crucial for the protein's ability to mediate cell-to-cell binding within desmosomes.
Key variants
Genetic variations within the DSC2 gene can lead to changes in the desmocollin-2 protein, potentially impacting its ability to contribute to desmosome formation and function. These changes can range from small alterations in the DNA sequence to larger structural rearrangements. Pathogenic variants in DSC2 are typically inherited in an autosomal dominant manner, meaning a single altered copy of the gene is sufficient to increase the likelihood of developing an associated condition. The clinical impact of these variants can vary, influencing the type and severity of the associated health condition.
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.1187dup | p.Leu396fs | Pathogenic | ★★☆☆ | Cardiovascular phenotype |
c.123del | p.Lys42fs | Pathogenic/Likely pathogenic | ★★☆☆ | Arrhythmogenic right ventricular dysplasia 11 |
c.1660C>T | p.Gln554Ter | Pathogenic | ★★☆☆ | ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 11, WITH OR WITHOUT MILD PALMOPLANTAR KERATODERMA |
c.1777G>T | p.Glu593Ter | Pathogenic | ★★☆☆ | Arrhythmogenic right ventricular dysplasia 11 |
c.1858C>T | p.Gln620Ter | Pathogenic | ★★☆☆ | Cardiovascular phenotype |
c.2084G>A | p.Trp695Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Arrhythmogenic right ventricular dysplasia 11 |
c.2112_2116del | p.Phe708fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.2186del | p.Pro729fs | Pathogenic | ★★☆☆ | Arrhythmogenic right ventricular dysplasia 11 |
c.30G>A | p.Trp10Ter | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.379G>T | p.Glu127Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Arrhythmogenic right ventricular dysplasia 11 |
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 DSC2 gene are associated with inherited conditions primarily affecting the heart and skin. These conditions include Arrhythmogenic right ventricular cardiomyopathy, a heart muscle disorder. Additionally, some DSC2 variants are linked to keratoderma with woolly hair, a condition characterised by specific skin and hair abnormalities alongside a risk of cardiac involvement.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic DSC2 variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
The DSC2 gene is included on several panels within the UK National Health Service (NHS) Genomic Medicine Service's PanelApp, indicating its relevance in clinical genetic testing in the UK. It is featured on panels for Arrhythmogenic right ventricular cardiomyopathy (R133), Dilated and arrhythmogenic cardiomyopathy (R132), Ichthyosis and erythrokeratoderma (R165), Paediatric or syndromic cardiomyopathy (R135), Palmoplantar keratoderma and erythrokeratodermas, and Palmoplantar keratodermas (R166). This inclusion highlights the gene's established role in these conditions within the UK healthcare system.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
For individuals with DSC2 variants, maintaining a heart-healthy lifestyle is generally recommended, as for the wider population. This typically includes a balanced diet rich in fruits, vegetables, and whole grains, and low in saturated fats and processed foods. Regular physical activity, tailored to individual health status and in consultation with a healthcare professional, can also support cardiovascular health. Managing stress and avoiding smoking are further general lifestyle considerations that contribute to overall well-being and heart health.
Supplement considerations
There is currently no conclusive evidence to suggest that specific dietary supplements can prevent or treat conditions associated with DSC2 gene variants. While some supplements are promoted for heart health, their efficacy in genetically predisposed individuals is not well-established. Individuals considering supplements should consult with a healthcare professional to ensure they are safe and appropriate, particularly given potential interactions with medications or existing health conditions.
Frequently asked questions
What is the main function of the DSC2 gene?
The DSC2 gene provides instructions for the desmocollin-2 protein, which is a key component of desmosomes. Desmosomes are crucial for holding cells together, particularly in the heart and skin, providing structural integrity to tissues.
How are conditions related to DSC2 inherited?
Conditions associated with variants in the DSC2 gene are typically inherited in an autosomal dominant manner. This means that an individual needs only one copy of the altered gene to have an increased likelihood of developing the condition.
What health conditions are associated with DSC2 gene variants?
Variants in the DSC2 gene are primarily associated with arrhythmogenic right ventricular cardiomyopathy, a heart muscle disorder, and some forms of keratoderma with woolly hair, which affects both skin and hair with potential cardiac involvement.
Is the DSC2 gene part of routine genetic testing in the UK?
Yes, the DSC2 gene is included on several panels within the NHS Genomic Medicine Service's PanelApp, indicating its role in UK clinical genetic testing for conditions like various cardiomyopathies and palmoplantar keratodermas.
Can lifestyle changes prevent DSC2-related conditions?
While lifestyle changes like a heart-healthy diet and regular exercise are generally recommended for overall well-being, there is no conclusive evidence that they can prevent the development of inherited conditions associated with DSC2 variants. Always consult a healthcare professional for personalised advice.
References
- Lorenzon A, Pilichou K, Rigato I. Homozygous Desmocollin-2 Mutations and Arrhythmogenic Cardiomyopathy. The American journal of cardiology. 2015. PMID: 26310507
- Gehmlich K, Syrris P, Peskett E. Mechanistic insights into arrhythmogenic right ventricular cardiomyopathy caused by desmocollin-2 mutations. Cardiovascular research. 2011. PMID: 21062920
- De Bortoli M, Beffagna G, Bauce B. The p.A897KfsX4 frameshift variation in desmocollin-2 is not a causative mutation in arrhythmogenic right ventricular cardiomyopathy. European journal of human genetics : EJHG. 2010. PMID: 20197793
- Simpson MA, Mansour S, Ahnood D. Homozygous mutation of desmocollin-2 in arrhythmogenic right ventricular cardiomyopathy with mild palmoplantar keratoderma and woolly hair. Cardiology. 2009. PMID: 18957847
- Syrris P, Ward D, Evans A. Arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in the desmosomal gene desmocollin-2. American journal of human genetics. 2006. PMID: 17033975
- Heuser A, Plovie ER, Ellinor PT. Mutant desmocollin-2 causes arrhythmogenic right ventricular cardiomyopathy. American journal of human genetics. 2006. PMID: 17186466