What is PLN?
Phospholamban is a small protein that plays a key role in regulating the heart’s pumping activity on a beat-to-beat basis as well as during exercise. Abnormalities in phospholamban function lead to heart diseases. R14 Del (PLN) is a rare genetic mutation in the phospholamban gene that results in deletion of amino acid 14 (arginine) in phospholamban. This mutation can have significant implications leading to conditions such as arrhythmias (irregular heart beat and life threatening heart rhythm problems), cardiomyopathy (heart becomes weaker and less efficient), and heart failure. Identified in 2006, it primarily affects certain populations but has global implications. This disease is called PLN for simplicity.
Key Facts about PLN
The scientific term for the PLN mutation is PLN p.Arg14del. This genetic abnormality causes a heart muscle disease (cardiomyopathy) in which the heart muscle may enlarge and pump less effectively. This primarily happens in the left ventricle of the heart, but it can also occur in the right ventricle.
There is a significant amount of connective tissue in the heart chamber. A typical characteristic is that life-threatening heart rhythm disorders occur frequently in people with the PLN mutation, making the disease potentially life-threatening. Carriers of the gene mutation are often compared to having a ticking time bomb. The disease can suddenly manifest and lead to death.
The number of PLN carriers in North America is close to 120 carriers. Known carriers in North America remain low although we know that there are many more. That’s why it’s important to find and enlighten carriers about this genetic heart disease. In the Netherlands our mother foundation is located. The PLN-mutation is a Dutch disease and spread around the world because of travel and immigration. There are around 1700 carriers known in the Netherlands. We believe that the number of true carriers lies somewhere around 12,000 people in the Netherlands.
Discovered in a Frisian ancestor 700 years ago Presumably, about 700 years ago, a Frisian ancestor lived in whom the genetic mutation first occurred. All carriers of the PLN mutation are descendants of this ancestor. Many PLN carriers live in the northern provinces of the Netherlands. Due to migrations and emigration, carriers are also found to a lesser extent in other parts of the Netherlands and abroad (1).
In 2006, a mutation (genetic change) in the PLN gene was linked to the development of a heart muscle disease in the Netherlands. This is how the PLN mutation was discovered.
The PLN mutation is an inherited disease and is passed down from generation to generation. The mutation is inherited in an autosomal dominant fashion. This means that if someone is a carrier of the PLN mutation, they have a 50% chance of passing on the predisposition to each of their children. The predisposition occurs equally in both men and women.
A lot of research is being done on PLN and on affordable treatment methods. As a foundation, we actively promote this research. At this point, we can say that a solution is in sight! This is good news, of course. Why? Because we now have access to 3 studies, the results of which were alarming:
- A study of a group of 51 patients with a heart muscle disease and the PLN mutation showed that 47% of these patients experienced a rhythm disorder that led to a shock from an implantable defibrillator (ICD) to restore normal heart rhythm (2). In this group of patients, 18% underwent a heart transplant, and 36% had a closely related family member who died suddenly from cardiac arrest before reaching the age of 50.
- During a study of a group of 403 people with the PLN mutation, it was found that the risk of death is much higher compared to the general population, especially in the age group of 20 to 25 years (3).
- In a subgroup of 295 people who underwent testing with a cardiologist, 19% experienced life-threatening rhythm disorders during a period of 42 months, and 11% experienced severe heart failure.
(1)This gene mutation has also been found in people in Germany, Greece, Spain, the United States, and Canada. In these countries, it concerns several dozen patients, many of whom have Dutch ancestors.
(2) Van der Zwaag PA, van Rijsingen IA, Asimaki A, et al. Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy. Eur J Heart Fail. 2012;14:1199–207.
(3) Van Rijsingen IA, van der Zwaag PA, Groeneweg JA, Nannenberg EA, Jongbloed JD, Zwinderman AH, Pinto YM, Dit Deprez RH, Post JG, Tan HL, de Boer RA, Hauer RN, Christiaans I, van den Berg MP, van Tintelen JP, Wilde AA. Outcome in phospholamban R14del carriers: results of a large multicentre cohort study. Circ Cardiovasc Genet. 2014 Aug;7(4):455-65. doi: 10.1161/CIRCGENETICS.113.000374. Epub 2014 Jun 8.
Contributors to this factsheet: Pieter Doevendans – UMC Utrecht | Stefan Koudstaal – UMC Utrecht | Folkert Asselbergs – UMC Utrecht | Hamid El Azzouzi – UMC Utrecht | Peter van Tintelen – UMC Utrecht | Arthur Wilde – Amsterdam UMC.
The Gene and Symptoms
Due to this genetic abnormality, the PLN protein may not function properly. By the age of 70, half of the carriers experience serious heart problems, such as heart failure or severe heart rhythm disorders. It is not yet clear why some carriers develop symptoms while others do not; even within families, symptoms may vary.
Diagnosis and Treatment
Currently, there is no curative treatment for the PLN mutation. The treatment approach is individualized to reduce symptoms for each patient. Sometimes, medications are used, while in other cases, an implantable cardioverter-defibrillator (ICD), a type of pacemaker, is used to intervene in heart rhythm disorders.
Mutated phospholamban proteins (PLN) are produced from the mutated PLN gene in DNA. Many potential therapies for PLN, currently under investigation, intervene at specific points in this production process. For example, research is being conducted on ways to “repair” the mutation in DNA using gene-editing techniques like CRISPR-Cas or Prime Editing.
There are also explorations into intercepting the faulty mRNA using short interfering RNA, short hairpin RNA, or antisense RNA. This could prevent the production of the faulty PLN protein.
Inheritance
The PLN mutation is inherited in an autosomal dominant fashion, meaning that an individual only needs one copy of the mutated gene to potentially exhibit symptoms of the disease. Each carrier has a 50% chance of passing it on to each of their children. The predisposition occurs equally in both men and women. However, the severity and age of onset can vary.
Family Members
When a specialist informs an individual that he/she is a carrier of the PLN mutation, it is essential to try and inform the other family members so that they can, if they wish, undergo testing. Family members who wish to investigate whether they are carriers of the PLN mutation and may have an increased risk of this condition can do so through blood sampling. Siblings, parents, and children of someone who carries the PLN mutation each have a 50% chance of carrying it as well. Children of deceased siblings who carried this genetic predisposition can also carry it and are eligible for testing.
More genetic testing can be found at:
PLN Resources
Overcome PLN
The PLN Foundation is a patient-led organization committed to supporting PLN patients worldwide by building a global research network focused on improving diagnosis, raising awareness, and ultimately finding a cure. The North American foundation operates independently of the “Dutch PLN Foundation”, aiming to reach, inform, and support North-American carriers. We maintain close ties with the Dutch PLN Foundation and actively collaborate with them.