By David N. Leff

One person in a million suffers from an exotic, unpleasant and eventually fatal syndrome called dyskeratosis congenita (DC).

While best known for kidney and bone marrow failure, DC attacks virtually every tissue in the human body where cells are dividing rapidly and often ¿ driven to constant renewal by stem cell activity. ¿A characteristic physical sign of DC,¿ said molecular geneticist Philip Mason at the Imperial College of Science, Technology & Medicine in London, ¿is atrophy of the nails. The fingernails and the toenails start off breaking and then disappear altogether. Another thing is whitish lesions of the tongue and mucosal membrane surfaces of the genitalia. Then there are pale patterns of abnormal skin pigmentation, similar to smokers¿ patches. When you see these three visible manifestations all together, along with anemia, it¿s almost invariably DC.¿

Then there¿s alopecia ¿ baldness ¿ and less visible DC stigmata, including lungs, liver, intestine and testes. Victims of dyskeratosis congenita usually die between the ages of 16 and 50 as a result of bone marrow and immune system failure. ¿Thus, death is often caused by pneumonia,¿ Mason said, ¿and DC is also associated with a higher risk of malignancy. I think its occurrence would be the same anywhere in the world, with no ethnic predilection. There are some rare forms for which we haven¿t found the genes yet. Because they¿re recessive, they¿ll be slightly more common in societies where consanguineous [first-cousin] marriages are common.¿

Mason¿s laboratory operates an international registry of DC patients. He is senior author of a paper in today¿s Nature, dated Sept, 27, 2001, titled: ¿The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenital.¿

¿Telomerase is a very well-investigated molecule,¿ he told BioWorld Today, ¿because of its suspected involvement in cancer and aging. [Telomerase attends to repair or preservation of telomeres, the tips of chromosomes. See BioWorld Today, April 18, 2001.] The telomerase enzyme is made up of a protein and an RNA component. In this very rare disease that we work on, we found that a still rarer subset of DC patients have mutations in the gene coding for the RNA component. That¿s quite unusual in itself ¿ disease-causing mutations coding for an RNA.¿

Two Payoffs: Scientific, Medical

¿The significance of this finding,¿ Mason pointed out, is twofold. ¿For science, one can see the effect of mutating this RNA in a completely in vivo situation. For medicine, the usual benefits you¿d expect for the patient suffering from this disease. It may indicate something about the qualities of slightly more common diseases that also involve failure of the bone marrow ¿ such as aplastic anemia.

¿Actually, it¿s very interesting to work on extremely rare diseases, such as DC,¿ Mason said, ¿because often they give you a clue to much more common ailments. In this disease, we discovered that the cause is purely genetic ¿ due to mutations in the telomerase RNA gene. A common form of DC is a mutation on the X chromosome¿s long arm, which we published in 1997.

¿So we¿re now using genetic linkage and positional cloning to try and find these other genes,¿ he said. ¿Obviously, we suspect that they¿re going to have something to do with telomerase. We are working on autosomal chromosome 3. In this Nature paper, we report on three families from our DC registry, in which we undertook gene linkage analysis: One is a large family from Iowa, with a mild form of DC and autosomal dominant inheritance. Our co-author, pediatrician Fred Goldman, at the University of Iowa, reported on this pedigree. The family¿s DC members displayed 821 base-pair deletions, which took away the last 74 bases of the gene that encodes telomerase RNA. In the two other families, one had a two-base-pair deletion; the other a single base-pair change. Our results in these three families¿ mutations in one allele of telomerase¿s RNA component sufficed to cause DC.¿

Turning from humans to knockout mice, Mason and his team explored the DC cancer connection in both of these in vivo subjects: ¿There¿s been a lot of work done on this KO mouse model,¿ Mason said, ¿which has none of the telomerase RNA at all. Both copies of that gene have been knocked out. These mice are perfectly normal for the first five or six generations. This is a very different situation to what we find in the DC human patients, where one mutation in one of the copies has immediate consequences. However, the mice in the sixth and subsequent generations have a lot of features in common with DC patients. Just like human sufferers, they are susceptible to an increased incidence of various malignancies, and display DC-like symptoms.

¿Now that we¿ve done this work,¿ he said, ¿there are other forms of the disease for which we haven¿t found the genes. They are mainly the recessive forms.¿

Gene Therapy For DC In Distant Future

Mason¿s paper in Nature suggests in closing: ¿If the genetic defect could be corrected, or the wild-type gene or gene product introduced into a hematopoietic stem cell, the severe effects of this disease could be improved, thereby making dyskeratosis congenita a good candidate for treatment by the emerging gene transfer methodologies.¿

To this, he added: ¿What we propose in that last paragraph is that this type of condition might lend itself to gene therapy, and here¿s why: Because these cells are in the patients with the PC disease, the blood cells are not proliferating very well; they¿re dying. So if one could introduce a good copy of the telomerase gene into only a few cells, those cells would start to thrive, and may gradually take over the entire blood system. In a sense, one¿s ability to get the gene into the cells doesn¿t have to be that efficient.

¿We¿re not working in this direction at this point,¿ he noted. ¿Obviously, gene therapy is a long-term aim of our group, but we¿re not doing anything toward that end at this moment ¿ apart from just studying DC. I would say it will be 10 to 20 years before this gene transfer starts to be worked on seriously.¿

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