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PKP2
plakophilin 2
The PKP2 gene provides instructions for making plakophilin 2, a crucial protein for the structural integrity of heart muscle cells, particularly within desmosomes. Plakophilin 2, encoded by the PKP2 gene, is primarily found in the myocardium, the muscular wall of the heart.
PKP2 is located on the short (p) arm of chromosome 12, at band 12p11.21. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 12 in the library →Overview
The PKP2 gene provides the genetic blueprint for a protein known as plakophilin 2. This protein is predominantly located within the myocardium, which constitutes the muscular walls of the heart. Plakophilin 2 plays a vital role as a component of desmosomes, specialised structures that serve as junctions to connect adjacent cells. These desmosomal connections are essential for maintaining the mechanical strength of the myocardium and for facilitating intercellular signalling within the heart [PMID:17965415].
Disruptions in the PKP2 gene, through various genetic changes, can lead to the production of an altered or non-functional plakophilin 2 protein. Such alterations are frequently implicated in the development of certain inherited heart conditions. Understanding the function of PKP2 is therefore critical for comprehending the molecular basis of these cardiac disorders and for advancing diagnostic and therapeutic strategies.
What the gene does
The plakophilin 2 protein, encoded by the PKP2 gene, is a fundamental constituent of desmosomes, which are complex intercellular junctions primarily responsible for providing strong adhesion between cells. In the heart, particularly within the myocardium, these desmosomes are critical for ensuring the structural integrity and mechanical resilience of cardiac muscle tissue. Plakophilin 2 acts as a linker protein, connecting desmosomal cadherins (such as desmoglein and desmocollin) to the intermediate filament cytoskeleton, thereby anchoring these junctions securely within the cell [PMID:19001649].
Beyond its structural role, plakophilin 2 also participates in cell signalling pathways that are vital for cardiac function. It helps to regulate processes such as cell growth, differentiation, and apoptosis (programmed cell death) within the heart. The protein's involvement in these signalling cascades contributes to the proper development and maintenance of the myocardial architecture. Research suggests that plakophilin 2 can interact with various proteins involved in Wnt/beta-catenin signalling, a pathway crucial for cardiac development and remodelling [PMID:18987157].
Specifically, plakophilin 2 is known to modulate the activity of genes involved in cardiac cell adhesion and electrical coupling. Its presence at intercalated discs, specialised junctions between heart muscle cells, is essential for coordinating the synchronous contraction of the heart. Defective plakophilin 2 can compromise both the mechanical coupling and electrical synchronisation of cardiomyocytes, leading to impaired heart function. The precise mechanisms by which PKP2 mutations disrupt these functions are complex, often involving altered protein expression, mislocalisation, or impaired binding to its desmosomal partners, ultimately weakening cell-cell adhesion and altering signalling pathways in the heart.
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Chromosome location
The PKP2 gene is situated on the short arm of chromosome 12, specifically at position 11.21, denoted as 12p11.21. This genomic location specifies where the gene resides within the human genome. The PKP2 gene spans a considerable region on this chromosome, contributing to the genetic information that codes for the plakophilin 2 protein. This chromosomal address helps in identifying and locating the gene during genetic studies and diagnostic investigations.
Protein structure
The plakophilin 2 protein is composed of 881 amino acids and features several distinct functional regions and armadillo (ARM) repeats. The N-terminal region, spanning amino acids 1-360, is required for binding to single-stranded DNA, indicating a potential role in nucleic acid interactions. An overlapping region, amino acids 1-348, is specifically required for interaction with the influenza A virus RNA polymerase subunit PB1, suggesting involvement in host-pathogen interactions.
A disordered region is present from amino acids 282-314, which typically implies flexibility and participation in various protein-protein interactions. The protein also contains multiple ARM repeats, which are characteristic protein motifs involved in mediating protein-protein interactions and often form structural scaffolds. These include ARM 1 (amino acids 341-383), ARM 2 (amino acids 385-424), ARM 3 (amino acids 427-467), ARM 4 (amino acids 571-616), ARM 5 (amino acids 671-711), ARM 6 (amino acids 719-758), ARM 7 (amino acids 763-804), and ARM 8 (amino acids 807-849). These ARM repeats are critical for the assembly and function of desmosomes and for mediating plakophilin 2's interactions with other desmosomal components.
Key variants
Genetic variants within the PKP2 gene encompass a range of changes, including point mutations, small insertions, and deletions, which can alter the production or function of the plakophilin 2 protein. These variants can lead to a spectrum of clinical presentations, primarily affecting heart health. Understanding the specific nature of these genetic changes is crucial for accurate diagnosis and for guiding clinical management strategies. The impact of a variant can depend on its location within the gene and how it affects the critical functional domains of the plakophilin 2 protein.
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.1003G>T | p.Glu335Ter | Pathogenic | ★★☆☆ | Arrhythmogenic right ventricular dysplasia 9 |
c.1063C>T | p.Arg355Ter | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1125_1132del | p.Phe376fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1132C>T | p.Gln378Ter | Pathogenic | ★★☆☆ | not provided |
c.1138G>T | p.Glu380Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Familial isolated arrhythmogenic right ventricular dysplasia |
c.1147C>T | p.Gln383Ter | Pathogenic | ★★☆☆ | not provided |
c.1162C>T | p.Arg388Trp | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1170+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Arrhythmogenic right ventricular dysplasia 9 |
c.1170+1G>C | - | Pathogenic | ★★☆☆ | Arrhythmogenic right ventricular dysplasia 9 |
c.1170+2T>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Arrhythmogenic right ventricular cardiomyopathy |
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 PKP2 gene are strongly associated with inherited cardiac conditions, most notably Arrhythmogenic right ventricular cardiomyopathy (AD) (ARVC). This condition primarily affects the muscular wall of the right ventricle of the heart, leading to progressive replacement of heart muscle with fibrous and fatty tissue. Such changes can disrupt the heart's electrical signals, increasing the risk of abnormal heart rhythms (arrhythmias) and sudden cardiac death. The inheritance pattern for conditions linked to PKP2 variants is typically autosomal dominant, meaning only one altered copy of the gene is sufficient to increase the likelihood of developing the condition.
Inheritance pattern
Conditions caused by pathogenic PKP2 variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
The PKP2 gene is included in several active genomic testing panels within the UK National Health Service (NHS) Genomic Medicine Service. It is listed on the 'Arrhythmogenic right ventricular cardiomyopathy' panel (R133), the 'Dilated and arrhythmogenic cardiomyopathy' panel (R132), and the 'Paediatric or syndromic cardiomyopathy' panel (R135). Its inclusion on these panels signifies its established role in the diagnosis of these inherited heart conditions within a clinical setting in the UK.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
For individuals with PKP2 variants or an associated condition like arrhythmogenic right ventricular cardiomyopathy, certain lifestyle considerations may be beneficial, though these are generally aimed at overall cardiovascular health rather than specifically mitigating the genetic effect. Maintaining a healthy weight through a balanced diet rich in fruits, vegetables, and lean proteins is often recommended. Regular, moderate physical activity, as advised by a healthcare professional, can support cardiovascular fitness. However, individuals with ARVC are generally advised to limit or avoid intense endurance exercise, as some research suggests it may accelerate disease progression or trigger arrhythmias. It is important to discuss any exercise regimen with a cardiologist. Avoiding excessive alcohol consumption and refraining from smoking are also standard recommendations for promoting heart health in the general population and may be particularly relevant for those with underlying cardiac vulnerabilities. These lifestyle adjustments should always be discussed with a healthcare provider, who can offer personalised advice based on individual health status.
Supplement considerations
Currently, there is no conclusive scientific evidence to suggest that specific dietary supplements can prevent, treat, or reverse conditions associated with PKP2 gene variants, such as arrhythmogenic right ventricular cardiomyopathy (ARVC). While some supplements are marketed for general heart health, their efficacy in genetic cardiac conditions has not been established. For instance, omega-3 fatty acids, often promoted for cardiovascular benefits, lack specific evidence for managing ARVC. Similarly, antioxidants or vitamins, while important for overall health, have not been shown to directly impact the progression of PKP2-related conditions. It is crucial for individuals considering any supplement to discuss it thoroughly with their healthcare provider, especially given potential interactions with medications or underlying health conditions. A healthcare professional can provide guidance on safe and appropriate dietary and supplement choices.
Frequently asked questions
What is the primary function of the PKP2 gene?
The PKP2 gene provides instructions for plakophilin 2, a protein essential for forming desmosomes in heart muscle cells. Desmosomes are critical for cell-to-cell adhesion and structural integrity in the heart.
What condition is most commonly associated with PKP2 variants?
Variants in the PKP2 gene are most commonly associated with Arrhythmogenic right ventricular cardiomyopathy (ARVC), a genetic heart condition affecting the right ventricle.
How are PKP2-related conditions inherited?
Conditions linked to PKP2 variants are typically inherited in an autosomal dominant pattern. This means that inheriting just one altered copy of the PKP2 gene is sufficient to increase the likelihood of developing the condition.
Can lifestyle changes prevent PKP2-related heart conditions?
While lifestyle changes cannot prevent a genetically determined condition, maintaining a healthy lifestyle, avoiding intense endurance exercise (if advised by a doctor), and managing cardiovascular risk factors can support overall heart health. Always consult a healthcare provider for personalised advice.
Is PKP2 included in NHS genetic testing panels?
Yes, the PKP2 gene is included in several NHS Genomic Medicine Service panels, such as those for Arrhythmogenic right ventricular cardiomyopathy and Dilated and arrhythmogenic cardiomyopathy.
Are there supplements that can treat PKP2-related conditions?
There is currently no conclusive evidence that specific dietary supplements can treat or reverse conditions associated with PKP2 variants. Any supplement use should be discussed with a healthcare provider.
References
- Cerrone M, Montnach J, Lin X. Plakophilin-2 is required for transcription of genes that control calcium cycling and cardiac rhythm. Nature communications. 2017. PMID: 28740174
- Hall C, Li S, Li H. Arrhythmogenic right ventricular cardiomyopathy plakophilin-2 mutations disrupt desmosome assembly and stability. Cell communication & adhesion. 2009. PMID: 19533476
- Bass-Zubek AE, Hobbs RP, Amargo EV. Plakophilin 2: a critical scaffold for PKC alpha that regulates intercellular junction assembly. The Journal of cell biology. 2008. PMID: 18474624
- Joshi-Mukherjee R, Coombs W, Musa H. Characterization of the molecular phenotype of two arrhythmogenic right ventricular cardiomyopathy (ARVC)-related plakophilin-2 (PKP2) mutations. Heart rhythm. 2008. PMID: 19084810
- Syrris P, Ward D, Asimaki A. Clinical expression of plakophilin-2 mutations in familial arrhythmogenic right ventricular cardiomyopathy. Circulation. 2006. PMID: 16415378
- Dalal D, Molin LH, Piccini J. Clinical features of arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in plakophilin-2. Circulation. 2006. PMID: 16549640
- van Tintelen JP, Entius MM, Bhuiyan ZA. Plakophilin-2 mutations are the major determinant of familial arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circulation. 2006. PMID: 16567567
- Gerull B, Heuser A, Wichter T. Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. Nature genetics. 2004. PMID: 15489853