Dyskeratosis congenita is an inherited condition, which although rare (approximately one case per million population) is devastating for the families in which it occurs. The disease is characterised by many abnormalities (see box below), but the most common feature is bone marrow failure (aplastic anaemia), which affects approximately 80 per cent of patients. For 30-50 per cent of these, conventional treatment - medical therapy or bone marrow transplant - fails or is not available and the patient dies prematurely.

The variability in onset and symptoms makes diagnosis difficult - particularly without a definitive diagnostic test. During the 1990s, Drs Inderjeet Dokal, Philip Mason and Tom Vulliamy at the Department of Haematology at Imperial College decided to address this problem. The rarity of the disease and the lack of information about its biology made it difficult to devise a test based on metabolic or cellular abnormalities, but modern genetics supplied an answer.

"Because dyskeratosis congenita is an inherited form of bone marrow disease, we decided to try and find the gene or genes responsible," explains Dr Dokal. "To do that, we needed to compile a registry of families with the disease and scan the genomes of affected individuals for shared genetic mutations." In 1995, he set up a dyskeratosis congenita registry, locating 20 families in the UK. It rapidly became an international registry of the disease: currently 190 families from 38 different countries are registered.

The registry showed a clear preponderance of male patients, suggesting the disease was linked to a genetic mutation on the X chromosome. With a Wellcome Trust grant the team began the hunt for the disease-causing gene. In 1998, they published a paper in Nature Genetics announcing they had found a common gene mutation. DKC1, as suspected, was located on the X chromosome. The team was then immediately able to develop a diagnostic test to ascertain whether patients exhibiting symptoms of dyskeratosis congenita had this particular mutation.

But the story was far from over. Although a number of male patients tested positive for the mutation, not all of them did. Neither, unsurprisingly, did female patients, suggesting that there were other non-X-linked forms of the disease involving genetic mutations on one or more of the 22 pairs of non-sex chromosomes (autosomes).

In 2000, Dr Dokal visited a family in Iowa, USA, several of whose 47 members had features of dyskeratosis congenita. He identified six living patients, based on their symptoms, and through medical records discovered that two family members who had died without ever receiving a clear diagnosis had died of the disease. As both male and female family members were affected, it was not surprising that none had a mutation of the DKC1 gene.

Back in the UK, the team began a second gene hunt, in collaboration with the Human Genetic Mapping Project Resource Centre at Hinxton, Cambridge. This time a region on chromosome 3 emerged as the likely culprit. In 2001, the team identified a mutation in a gene known as hTR, a previously cloned gene but for which no mutations in humans had yet been described. The gene was also found to be abnormal in families with non-X-linked dyskeratosis congenita in France and Cincinnati.

Genes to biology

So, Dr Dokal's group knew that mutations in two unrelated genes, DKC1 or hTR, had the same effect. What was going on? The group began to explore what the genetic evidence might say about the biology of the disease. The team found that both DKC1 and hTR are active in all tissues of the body, indicating they have important housekeeping functions. The notion correlates well with the idea of a disease affecting many different bodily systems.

Then a key step forward occurred when it was discovered that both genes were important in the function of telomerase - the enzyme responsible for maintaining the ends of chromosomes (telomeres). RNA from the hTR gene is one of the essential components of the telomerase enzyme. Dyskerin, the protein encoded by DKC1, appears to play an important role in stabilising hTR. "This biological link between the X-linked and non-X-linked forms of the disease suggests what the principal biology of the disease is," says Dr Dokal. "It suggests that this might be a disease of defective telomere maintenance."

The involvement of telomeres began to make sense of the biology of dyskeratosis congenita. As cells divide, telomeres tend to get shorter. If the telomeres become too short, a cell dies - so most cells only divide a few times before dying, and the lengths of telomeres is a handy guide to the 'age' of a cell. Telomerase acts to maintain the lengths of telomeres and is particularly important in cells that are actively proliferating - such as bone marrow, gut or skin cells. If telomerase is not working properly, the telomeres of these cells will wear down quickly - in a sense tissues like bone marrow will suffer from premature ageing.

Since the most common symptoms of dyskeratosis congenita include abnormalities of precisely these cells - and a predisposition to premature ageing - the idea that the disease has its biological origins in defective telomerase production made a lot of sense. The theory was supported by the fact that patients with either X-linked or autosomal forms of dyskeratosis congenita had reduced concentrations of hTR and shorter telomeres than normal.

This new finding also provided an interesting twist to the story of telomerase and cancer. Previously, telomerase overactivity had been associated with various cancers. Since approximately ten per cent of dyskeratosis congenita patients also develop cancer, it now became apparent that defective telomerase also predisposes to an increased risk of cancer (because of chromosomal instability resulting from shorter telomeres). Thus, a tight regulation of telomerase appears to be essential in humans, both too much or too little being associated with an increased risk of cancer.

The future

The team has gone on to study the biology of the disease in mice, which has again produced surprising findings. Mice completely lacking functional mTR had many skin and other abnormalities reminiscent of the autosomal dominant form of dyskeratosis congenita. "These mice develop features similar to dyskeratosis congenita but, surprisingly, not until the sixth generation of mice," says Dr Dokal. "In humans a single defect on one chromosome 3 leads to significant disease in the very first generation. This shows that the enzyme clearly has similar but slightly different effects in humans and mice, which is something to be aware of. We now want to liaise with colleagues in the USA to make a mouse model of the X-linked form of dyskeratosis congenita to compare with the autosomal hTR model."

With diagnostic tests for two different genetic subtypes now available - and a biological link established between both genes giving clues to the primary biology of the disease - it looks as if the team is making inroads into understanding this rare condition. However, there is still a long way to go. "We're still getting patients with clear symptoms of the disease who don't test positive for either gene," says Dr Dokal. "This means there must be other genes responsible that we haven't yet found." The next step will be to identify the missing genes and undertake a more detailed analysis of the function of all these different genes in dyskeratosis congenita and other bone marrow diseases.

Work the team has achieved to date - in particular the identification of dyskerin and hTR and their link to telomerase - provides the basis for designing new treatments for dyskeratosis congenita. It also paves the way for greater understanding of other, far more common, conditions related to telomere length, such as ageing and cancer.

External links

• Department of Haematology at Imperial College: Affiliation of Drs Inderjeet Dokal, Philip Mason and Tom Vulliamy
• Human Genetic Mapping Project Resource Centre at Hinxton, Cambridge