Wat is PLN?
PLN, also known as phospholamban, is a gene that plays a role in the functioning of the heart. A mutation on the PLN gene causes certain proteins not to be produced correctly, which can affect the function of the heart muscle. When this effect occurs, symptoms such as heart rhythm disorders, chest pain, and shortness of breath may occur.
Key Facts about PLN
The full term for the PLN mutation is PLN R14del 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.
1500 people know they are carriers Currently, we know about 1500 people who are carriers of the PLN mutation. We estimate that in the northern part of the Netherlands, 1 in 1500 people has the mutation. This means that there are thousands of people with this mutation in the Netherlands. We believe that the number of carriers lies somewhere between 10,000 to 15,000 people.
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 2010, 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 autosomal dominantly. 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 an affordable treatment method. 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.
The Genetic Heart Muscle Disease PLN Foundation is a public benefit organization (ANBI). We were established to put an end to this life-threatening heart muscle disease. You can also contribute to eliminating PLN from the world. Donations are always welcome, and we are happy to help you set up an initiative to raise funds. We guarantee that 100% of the donations raised will go to research projects that the foundation supports. We operate with volunteers and have sponsors that cover other costs. So, every euro we receive truly contributes to a world without PLN.
(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
In 2010, a mutation (genetic change) in the PLN gene was linked to the development of a heart muscle disease in the Netherlands. The Dutch mutation involves the absence of the amino acid arginine (Arg) at position 14. Therefore, the scientific name is PLN p.Arg14del. Other scientific names are c.40_42delAGA and R14del.
The origin of PLN
The mutation is believed to have occurred between 1200 and 1400 in someone from the southeast of Friesland. All carriers of the mutation in the Netherlands are descendants of this Frisian ancestor. The disease is primarily found in the northern provinces of the Netherlands, such as Friesland, Groningen, and North Holland.
Awareness of PLN
Currently, there are just over 1500 PLN carriers known in the Netherlands. This makes PLN a rare disease. It is estimated that there are about 10,000 - 14,000 carriers of PLN in the Netherlands. Over the past centuries, the Dutch have traveled around the world Therefore, the mutation has also been discovered in countries such as America, Canada, Spain and Norway.
Symptons of PLN
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 rhythm disorders. an implantable cardioverter-defibrillator (ICD), a type of pacemaker, is used to intervene in 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
PLN is an inherited disease and is thus passed down from generation to generation. The mutation is inherited autosomal dominantly. This means that each carrier of the PLN mutation has a 50% chance of passing on the predisposition to their children.
The predisposition occurs equally in both men and women. The mutation has likely spread because it often only manifests after the fertile age. Most carriers have already had children before experiencing disease symptoms.
Family Members
When a specialist informs you that you are a carrier of the PLN mutation, it can cause distress. PLN has an unpredictable course, making the future uncertain. This can also be concerning for family members, as an inherited predisposition to heart problems has been identified in your family. Therefore, you will receive a family letter after the diagnosis. It is essential to try to inform family members with this letter so that they can, if they wish, undergo testing.
Family members who wish to investigate whether they 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.
If the parents of someone with the predisposition have passed away, further family members from both parents (siblings or, if they have passed away, their children) are eligible for testing.