The first DC-related gene is found – https://europepmc.org/article/MED/9590285
The core symptoms of dyskeratosis congenita (DC) – white patches inside the mouth, abnormal skin pigmentation, misshapen nails and bone marrow problems – have been known about for around a hundred years. Clinicians recognised that the disease tends to run in families, suggesting a genetic link, but it wasn’t until 1998 that the first disease-related gene was discovered…
Nina Heiss and colleagues studied the DNA of cells taken from patients with DC and found mutations in a gene called DKC1. They knew that the gene resides on the X chromosome and that it carries instructions for making a protein called dyskerin, but beyond that, very little was known about either the gene or the protein.
Researchers knew that equivalent versions of both the gene and the protein were present in different species, where the protein was thought to play an important, if unspecified role inside the cell’s control centre or ‘nucleus.’ They were on the right track. It’s now known that dyskerin does indeed play a role inside the nucleus, where it helps to maintain the integrity of important structures called telomeres. Telomeres are the protective endings of chromosomes, and when they become damaged or frayed, cells can no longer function properly.
A link emerges between DC and telomerase – https://europepmc.org/article/MED/11574891
Telomeres are the protective ends of chromosomes. Every time a cell divides, its telomeres get a little bit shorter. If this continues unchecked, and the telomeres get too short, the cell either starts to function abnormally or it dies. In the 1980s, researchers discovered an enzyme, called telomerase, that helps to prevent this from happening, but no one knew what would happen if someone was born with a genetic mutation that prevented them from making telomerase.
In 2001, Tom Vulliamy and colleagues studied three families, in which dyskeratosis congenita (DC) was passed down the generations. They found that affected individuals all carried the same mutation, in a gene that is now known as TERC. The TERC gene provides the instructions needed to make part of the telomerase enzyme, so here, for the first time was a definitive link between DC and telomerase. DC is what happens if a person is born without the functioning telomerase enzyme.
TERC was the second gene to be implicated in DC. A few years earlier, researchers had identified a gene called DKC1, which is mutated in some people with DC, and which also plays a role in helping to keep telomeres healthy. Today, around 20 telomere-related genes have been implicated, and DC is firmly established as a telomere biology disorder (TBD).
Aplastic anaemia linked to telomere defects – https://europepmc.org/article/MED/12090986
Aplastic anaemia occurs when the bone marrow can’t make enough blood cells. It can be caused by a number of different factors, including, sometimes, genetics.
In this 2002 paper, Tom Vulliamy and colleagues studied blood samples from 50 individuals with aplastic anaemia and found that five of them had mutations in a gene, now known as TERC.
The TERC gene helps to keep telomeres healthy. Telomeres are the protective caps found at the end of chromosomes. As cells divide, the telomeres can erode, but the TERC gene helps to prevent this.
The team found that patients who had a mutation in the TERC gene had shorter telomeres than a healthy control group of people. So, the study suggests that sometimes, aplastic anaemia is caused by a fault in the TERC gene, which leads to shortened telomeres.
When telomeres get too short, cells stop being able to function normally or die. In this case, the mutation is in bone marrow stem cells, which then become unable to produce adequate amounts of blood cells.
Researchers already knew that the same gene can be mutated in people with some blood cancers, and also in a condition called dyskeratosis congenita (DC) which often involves aplastic anaemia. So, the picture that was emerging, around 20 years ago, was of a group of genetic disorders, all with defects in their telomeres, which lead to bone marrow problems. Today, these are known as telomere biology disorders, and they include DC, some blood cancers and aplastic anaemia.
A second telomerase gene is implicated in aplastic anaemia – https://europepmc.org/article/MED/15814878
The telomerase enzyme helps to keep telomeres healthy and long. A few years before this study, researchers discovered that some patients with aplastic anaemia have mutations in a telomerase-related gene called TERC. In this study, a second telomerase-related gene is implicated.
Aplastic anaemia occurs when stem cells in the bone marrow are unable to produce enough blood cells. In 2005, Hiroki Yamaguchi and colleagues studied cells from around 200 aplastic anaemia patients and found that seven unrelated individuals had mutations in a gene called TERT.
Telomerase is made up of two key components which work together to add repeating sequences of DNA to the ends of chromosomes. TERC provides the template for building these sequences, whilst TERT is the enzyme that adds them to the end of the chromosomes. Both components are needed for telomerase to do its job.
The effects of the patients’ TERT mutations could be seen at the level of the cell. White blood cells taken from them were found to have low levels of telomerase activity, and shortened telomeres.
The study shows that some, but not all, cases of aplastic anaemia are caused by a defect in telomere-related genes. Since then, mutations in both TERT and TERC have been found in patients with other conditions, including liver disease, leukaemia and pulmonary fibrosis (scarring of the lungs). So, we now realise telomere biology disorders can affect far more than just the bone marrow. They are diverse range of disorders with the potential to cause diverse symptoms in different body parts.
Telomere disorders can be treated with danazol – https://europepmc.org/article/MED/27192671
Telomere biology disorders (TBDs), such as aplastic anaemia, dyskeratosis congenita and pulmonary fibrosis are caused by mutations in the genes that usually help to keep telomeres long and healthy. As a result, people with these disorders develop progressively shorter telomeres, which then leads to problems, such as bone marrow failure.
This 2016 study, led by Danielle Townsley, describes the results of a clinical trial that was set up to see if a drug called danazol can slow the attrition of telomeres in people with TBDs.
Around two dozen people took part in the study. They took danazol, twice a day, every day for two years, and during this time, their telomeres didn’t just shrink less; they actually got bigger. Most of those involved had longer telomeres at the end of the study than at the start of it.
Their blood test results also improved. Haemoglobin levels increased, as did their numbers of neutrophils, immature red blood cells and platelets. Before starting danazol treatment, 13 of the patients needed regular transfusions. After the treatment, all but one, no longer did. Indeed, the results were so positive, that the trial was halted early, to enable danazol to be rolled out more widely.
Danazol is a synthetic male sex hormone. Similar drugs, such as oxymetholone, have been used to treat TBD before, but whilst they help to elongate telomeres and improve blood counts, they can also cause ‘masculine’ side effects, such as facial hair growth and deepening of the voice. Danazol is less likely to do this, which makes it an attractive alternative for the treatment of TBDs. It is currently not authorised for use in treating TBDs.
New drug restores telomere length in an animal model of DC – https://europepmc.org/article/MED/32320679
A newly discovered group of drugs may help to ease the symptoms of dyskeratosis congenita (DC) and other telomere biology disorders (TBDs).
People with telomere biology disorders have genetic mutations that cause them to have less of an enzyme called telomerase. Telomerase is important because it helps to keep telomeres long and healthy. Low levels of the enzyme cause cells to age prematurely and die, leading to the symptoms of TBDs, which include bone marrow failure, liver cirrhosis and problems with the nails and skin.
Drugs, known as PAPD5 inhibitors, are known to boost telomerase levels. In this 2020 study, Neha Nagpal and colleagues tested a PAPD5 inhibitor on cultured stem cells that came from patients with DC and found that it enhanced telomerase activity and increased telomere length.
Next, they wanted to see if the drugs would do the same for human stem cells, not in a dish but in an animal body. So, they tested a PAPD5 inhibitor in a mouse model of DC, where the animals’ bone marrow contains telomerase-deficient blood stem cells that come from humans. Just as they hoped, the treatment increased the length of the stem cells’ telomeres. The mice remained healthy, and their blood stem cells were able to make lots of new blood cells.
Scientists are concerned that telomerase-boosting drugs could have problematic side effects. Cancer cells have lots of telomerase, so the worry is that telomerase-boosting drugs could contribute to cancer. In this study, however, the effects of the PAPD5 inhibitor were confined to the animals’ stem cells. This is reassuring. Now, if further animal studies go well, the next step will be to set up clinical trials to test the effects of PAPD5 inhibitors in people with TBDs.
Inheritance patterns make a difference in telomere disorders – https://europepmc.org/article/MED/34852175
Telomere biology disorders (TBDs), such as dyskeratosis congenita (DC), are inherited. Faulty genes are passed down from parent to child. Mutations have been discovered in a variety of telomere-related genes, which can be inherited in different ways. In this 2022 study, Marena Niewisch and colleagues show that the pattern of inheritance has an effect on the way the disease unfolds.
TBDs can be inherited in one of three different ways:
Mutations in the DKC1 gene, for example, are inherited in an X-linked recessive manner (XLR). This means that the mutated gene is found on the X chromosome, and that males are more likely to be affected than females.
Mutations in the TERC gene are usually inherited in an autosomal dominant (AD) manner. This means that a person needs to inherit only one copy of the mutated gene to be affected. Males and females are affected equally.
Mutations in the PARN gene, meanwhile, are inherited in an autosomal recessive (AR) manner. This means that a person needs to inherit two copies of the mutated gene – one from each parent – to be affected. Males and females are affected equally.
Researcher studied 231 individuals, with a variety of TBDs, over time. They found that bone marrow failure, liver disease and cancer were more common in people with AR and XLR disease, whilst lung scarring was more common in adults with AD disease. There were differences in how long people lived for too. With the exception of one particular mutation, patients with AD disease tended to live longer than people with different inheritance patterns.
They also found that people with AD disease had longer telomeres than people with AR and XLR disease, which may explain the differences in survival between these groups.
Now that we know how inheritance affects the progression of TBDs, it may be possible for clinicians to tailor their care accordingly. Patients with AR or XLR disease, for example, might benefit from early surveillance, to catch signs of bone marrow failure and other issues before they become too much of a problem.
The evolving genetic landscape of DC – https://europepmc.org/article/MED/39198715
In 1995, UK researchers established an international registry of patients with dyskeratosis congenita (DC) and DC-like (DCL) conditions. From that day to this, they have been collecting samples and clinical information from the patients and families they have met, which they have used for research to improve the understanding and treatment of DC. The registry now incorporates the largest collection of DC and DCL families assembled to date, and in this 2024 study, researchers leverage it to shed new light on the genetics of this inherited disorder.
Although many different genes and mutations have been implicated in DC, 35% of people with the condition have mutations that are unknown. Using DNA from 2000 different families in the registry, Hemanth Tummala and colleagues identified several new genetic features. This included new mutations in two previously known DC genes, called POT1 and ZCCHC8, and also mutations in a gene called POLA1, which had not previously been linked to DC.
Like most of the genes that have previously been implicated in DC, POLA1 and POT1 play a role in telomere biology. Telomeres are the protective ends of chromosomes. POLA1 is involved in their protection and replication. POT1 is involved in their maintenance.
ZCCHC8, on the other hand, is not obviously linked to telomere biology, and instead appears to be involved in other processes, such as inflammation, gene activation and the production of the cell’s protein-making machinery.
Overall, the study confirms that DC and DC-like disorders are complex conditions, underpinned by diverse genetics. The newly discovered mutations add a growing list, which will help clinicians to better diagnose the condition and spur the development of new therapies