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DSP
desmoplakin
The DSP gene provides instructions for making desmoplakin, a key protein in desmosomes that helps cells adhere to each other, particularly in the heart and skin. Desmoplakin, encoded by the DSP gene, is a vital component of desmosomes, which are specialised cell junctions.
DSP is located on the short (p) arm of chromosome 6, at band 6p24.3. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 6 in the library →Overview
The DSP gene encodes the desmoplakin protein, a critical structural component of desmosomes. Desmosomes are complex protein structures found between cells, functioning as strong adhesion sites that provide mechanical strength and stability to tissues, particularly those under physical stress like the heart and skin. Desmoplakin acts as an anchor within these structures, connecting intermediate filaments inside the cell to the desmosomal cadherins that link adjacent cells.
Dysfunction of desmoplakin, caused by pathogenic variants in the DSP gene, can lead to a range of inherited conditions. These conditions often affect tissues where desmosomes are abundant, manifesting as cardiac abnormalities, skin disorders, or a combination of both. Understanding the role of the DSP gene and its protein product is fundamental to comprehending the pathogenesis of these disorders.
What the gene does
The desmoplakin protein, encoded by the DSP gene, plays a crucial role in maintaining cellular integrity and tissue strength by acting as an essential component of desmosomes. Desmosomes are cell-to-cell adhesion junctions that tether the intermediate filament cytoskeleton of adjacent cells, effectively creating a strong and resilient network throughout tissues. Desmoplakin is a large, multidomain protein that spans the cytoplasmic plaque of the desmosome, linking the transmembrane desmosomal cadherins (such as desmogleins and desmocollins) to the intracellular intermediate filament network.
Specifically, desmoplakin's N-terminal domain interacts with plakoglobin (gamma-catenin) and plakophilins, which in turn bind to the intracellular tails of the desmosomal cadherins. Its C-terminal domain contains binding sites for intermediate filament proteins, such as keratins in epithelial cells and desmin in cardiac muscle cells. This intricate connection ensures that mechanical forces applied to the tissue are effectively distributed across cells and their internal cytoskeletons, preventing cellular detachment and tissue damage.
Beyond its primary structural role, desmoplakin may also be involved in various cellular processes. Research suggests desmosomes, and by extension desmoplakin, can influence cell signalling pathways, cellular differentiation, and programmed cell death (apoptosis). In the heart, desmoplakin is vital for maintaining the structural integrity of cardiomyocytes, enabling them to withstand the constant mechanical forces of contraction. In the skin, it ensures the robust adhesion of keratinocytes, protecting against mechanical injury and maintaining barrier function. Therefore, proper desmoplakin function is indispensable for the normal physiology of these critical organs.
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Chromosome location
The DSP gene is located on the short arm of chromosome 6, specifically at position 6p24.3. This genomic address specifies its precise position within the human genome. Chromosome 6 is one of the 23 pairs of chromosomes in humans, containing a significant number of genes. The p-arm denotes the shorter arm of the chromosome, and 24.3 refers to the specific band and sub-band region. The exact number of exons for the DSP gene can vary depending on the specific transcript isoform, but it generally consists of multiple exons that are spliced together to form the mature messenger RNA, which then serves as a template for desmoplakin protein synthesis.
Protein structure
The desmoplakin protein, with a length of 2871 amino acids, exhibits a complex multi-domain structure crucial for its function as a linker in desmosomes. It comprises a central fibrous rod domain flanked by globular head and tail regions. The N-terminal region contains a large Globular 1 domain (amino acids 1-1056). Within this N-terminal part, several regions are identified for protein-protein interactions, including Interaction with MAPRE1 (amino acids 1-883), Interaction with JUP and PKP2 (amino acids 1-584), and Interaction with DSG1 (amino acids 10-1097).
This N-terminal region also features several Spectrin repeats: Spectrin 1 (amino acids 178-271), Spectrin 2 (amino acids 272-375), Spectrin 3a (amino acids 376-446), Spectrin 3b (amino acids 516-545), Spectrin 4 (amino acids 546-627), Spectrin 5 (amino acids 654-769), and Spectrin 6 (amino acids 770-883). Additionally, an SH3 domain (amino acids 458-515) is present in this part of the protein. Another interaction region, Interaction with PKP1, is found between amino acids 180-375.
The large Central fibrous rod domain (amino acids 1057-1945) is largely composed of a Coiled coil structure (amino acids 1018-1945). This rod domain is responsible for the elongated shape of desmoplakin and its ability to span the desmosomal plaque. The C-terminal domain, though not explicitly detailed in the provided data, typically contains binding sites for intermediate filaments, anchoring the desmosome to the intracellular cytoskeleton.
Key variants
Genetic variations in the DSP gene can range from single nucleotide changes to larger deletions or insertions. Variants are classified based on their predicted impact on the desmoplakin protein. Pathogenic variants are those that are known to cause disease by significantly altering protein function or production. Likely pathogenic variants are highly suspected to cause disease, but with less conclusive evidence. Variants of uncertain significance (VUS) have an unknown clinical impact, meaning there isn't enough information to classify them as pathogenic or benign. Benign and likely benign variants are considered not to cause disease. The specific location and type of variant within the DSP gene can influence the resulting clinical presentation and severity of associated conditions.
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.5671_*835+957del4738insAGAACAGTCTT | - | Pathogenic/Likely pathogenic | ★★☆☆ | Cardiovascular phenotype |
c.1042G>T | p.Glu348Ter | Pathogenic | ★★☆☆ | Arrhythmogenic cardiomyopathy with wooly hair and keratoderma |
c.1054_1059delinsCA | p.Asp352fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1060_1061del | p.Leu354fs | Pathogenic | ★★☆☆ | Arrhythmogenic right ventricular dysplasia 8 |
c.1080G>A | p.Trp360Ter | Pathogenic | ★★☆☆ | Arrhythmogenic cardiomyopathy with wooly hair and keratoderma |
c.1087C>T | p.Gln363Ter | Pathogenic | ★★☆☆ | Cardiovascular phenotype |
c.1119del | p.Glu374fs | Pathogenic | ★★☆☆ | Arrhythmogenic cardiomyopathy with wooly hair and keratoderma |
c.1146del | p.Phe382fs | Pathogenic | ★★☆☆ | Arrhythmogenic right ventricular cardiomyopathy |
c.1162del | p.Thr388fs | Pathogenic | ★★☆☆ | Arrhythmogenic right ventricular dysplasia 8 |
c.1188_1195del | p.Gln396fs | Pathogenic | ★★☆☆ | Arrhythmogenic cardiomyopathy with wooly hair and keratoderma |
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
Pathogenic variants in the DSP gene are associated with a spectrum of inherited conditions primarily affecting the heart and skin, reflecting the critical role of desmoplakin in these tissues. One significant condition is Arrhythmogenic right ventricular cardiomyopathy (ARVC), an inherited heart muscle disorder characterised by progressive fibrofatty replacement of the myocardium, particularly in the right ventricle, leading to arrhythmias and an increased risk of sudden cardiac death. DSP variants can also cause various skin conditions, such as keratoderma with woolly hair, which involves thick skin on palms and soles, and abnormal hair texture, sometimes accompanied by cardiac involvement.
Inheritance pattern
Conditions caused by pathogenic DSP variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
The DSP gene is recognised within the UK's NHS Genomic Medicine Service due to its clinical significance in various inherited conditions. It is listed on several NHS Genomic Test Directory panels, indicating that testing for DSP variants is considered appropriate for patients presenting with specific clinical features. For instance, DSP is included on panels for Arrhythmogenic right ventricular cardiomyopathy (R133), Dilated and arrhythmogenic cardiomyopathy (R132), Paediatric or syndromic cardiomyopathy (R135), and Epidermolysis bullosa (R164). Its inclusion in these panels signifies its established role in the aetiology of these disorders, supporting its use in diagnostic and predictive genetic testing within the NHS.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
For individuals with genetic predispositions related to DSP gene variants, particularly those affecting cardiac function, lifestyle modifications may play a supportive role. For instance, in conditions like arrhythmogenic right ventricular cardiomyopathy, managing physical activity levels is often recommended. Research suggests that intense endurance exercise may exacerbate disease progression in some individuals with ARVC, though specific recommendations should come from a healthcare provider. Avoiding activities that put excessive strain on the heart is generally prudent. Maintaining a healthy weight through a balanced diet and regular, moderate physical activity (as advised by a doctor) can support overall cardiovascular health. Additionally, avoiding smoking and excessive alcohol consumption are general recommendations for cardiac well-being that may be particularly relevant for those with underlying cardiac susceptibilities. However, it is crucial to understand that lifestyle changes do not prevent the genetic condition but may help manage symptoms or reduce the risk of complications.
Supplement considerations
Currently, there is no conclusive scientific evidence to suggest that specific dietary supplements can prevent, treat, or cure conditions directly caused by pathogenic variants in the DSP gene. The primary management for such conditions typically involves medical interventions and monitoring tailored to the specific symptoms and organ systems affected. While some supplements are marketed for general heart health or skin health, their efficacy in individuals with DSP-related conditions is not established. For example, while omega-3 fatty acids are sometimes promoted for cardiovascular health, there is no evidence they specifically mitigate the effects of desmoplakin dysfunction. Individuals considering any supplements should discuss this with their healthcare provider to ensure safety, avoid potential interactions with medications, and confirm that there is no risk of adverse effects, especially given the complex nature of inherited cardiac and skin disorders.
Frequently asked questions
What is the main function of the DSP gene?
The DSP gene provides instructions for making the desmoplakin protein, which is a crucial component of desmosomes. Desmosomes are cell structures that help hold neighbouring cells together, providing strength and stability to tissues, especially in the heart and skin.
What happens if the DSP gene doesn't work correctly?
If the DSP gene has pathogenic variants, the desmoplakin protein may not function correctly. This can lead to weakened cell adhesion in tissues, causing conditions that affect the heart, such as Arrhythmogenic right ventricular cardiomyopathy, and skin conditions like keratoderma with woolly hair.
Is DSP associated with heart conditions?
Yes, pathogenic variants in the DSP gene are well-known to be associated with several heart conditions, most notably Arrhythmogenic right ventricular cardiomyopathy (ARVC). This is because desmoplakin is essential for maintaining the structural integrity of heart muscle cells.
Can DSP variants affect the skin?
Indeed, DSP variants can affect the skin. Conditions like keratoderma with woolly hair, which involves thickened skin on the palms and soles and abnormal hair texture, are linked to pathogenic changes in the DSP gene, reflecting its role in skin cell adhesion.
What is the inheritance pattern for DSP-related conditions?
Conditions caused by pathogenic variants in the DSP gene typically follow an autosomal dominant inheritance pattern. This means that inheriting just one copy of the altered gene from either parent is sufficient to increase the likelihood of developing the condition.
How is the DSP gene relevant in the NHS?
The DSP gene is included on several NHS Genomic Test Directory panels for conditions like various cardiomyopathies and epidermolysis bullosa. This indicates its established clinical significance and its use in diagnostic genetic testing within the NHS for patients presenting with related symptoms.
References
- Pigors M, Schwieger-Briel A, Cosgarea R. Desmoplakin mutations with palmoplantar keratoderma, woolly hair and cardiomyopathy. Acta dermato-venereologica. 2015. PMID: 25227139
- Rasmussen TB, Hansen J, Nissen PH. Protein expression studies of desmoplakin mutations in cardiomyopathy patients reveal different molecular disease mechanisms. Clinical genetics. 2013. PMID: 23137101
- Chalabreysse L, Senni F, Bruyère P. A new hypo/oligodontia syndrome: Carvajal/Naxos syndrome secondary to desmoplakin-dominant mutations. Journal of dental research. 2011. PMID: 20940358
- Bolling MC, Veenstra MJ, Jonkman MF. Lethal acantholytic epidermolysis bullosa due to a novel homozygous deletion in DSP: expanding the phenotype and implications for desmoplakin function in skin and heart. The British journal of dermatology. 2010. PMID: 20302578
- Hobbs RP, Han SY, van der Zwaag PA. Insights from a desmoplakin mutation identified in lethal acantholytic epidermolysis bullosa. The Journal of investigative dermatology. 2010. PMID: 20613772
- Yang Z, Bowles NE, Scherer SE. Desmosomal dysfunction due to mutations in desmoplakin causes arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circulation research. 2006. PMID: 16917092
- Jonkman MF, Pasmooij AM, Pasmans SG. Loss of desmoplakin tail causes lethal acantholytic epidermolysis bullosa. American journal of human genetics. 2005. PMID: 16175511
- Norgett EE, Hatsell SJ, Carvajal-Huerta L. Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma. Human molecular genetics. 2000. PMID: 11063735