The diagnostic features of dyskeratosis congenita are nail dystrophy, abnormal skin pigmentation and mucosal leukoplakia1. Bone marrow failure and pulmonary complications are the primary cause of death. There are multiple patterns of inheritance, and the autosomal dominant form (AD-DC) generally has a later age of onset. The X-linked form is due to mutations in the gene encoding dyskerin, which is involved in processing the template RNA component of telomerase (TERC). Individuals with X-linked dyskeratosis congenita have low levels of TERC (and less telomerase activity). Direct experimental evidence that dyskeratosis congenita is due to dysfunction of telomere maintenance comes from the observation that deletion or mutation of TERC itself is associated with AD-DC. It is thought that haploinsufficiency can cause dyskeratosis congenita (e.g., when one copy of TERC is mutated to an unstable form, it produces cells having less TERC and thus less telomerase activity to maintain highly proliferative stem-like cells)1,2,3,4,5. Because the telomerase RNP enzyme may be a functional dimer, mutations in one TERC allele may also result in a greater overall impact on telomerase activity by a dominant negative effect.

On page 447 of this issue, Tom Vulliamy and colleagues report3 disease anticipation (the onset of disease occurs at progressively younger ages in successive generations) in eight families with AD-DC, and this correlates with progressive telomere shortening in later generations (Fig. 1). Siblings that did not inherit a mutated copy of TERC did not have early-onset symptoms even though they inherited shorter telomeres from the affected parent. Thus, individuals with dyskeratosis congenita must both inherit short telomeres and be heterozygous with respect to TERC (TERC+/− ) to show anticipation. This is a new mechanism of disease anticipation. Instead of amplification of triplet repeats, as occurs in neurodegenerative disorders, there is a reduction of telomere repeats in dyskeratosis congenita.

Figure 1: In humans, telomeres progressively shorten with increased age.
figure 1

A parent with AD-DC provides all his children with shorter telomeres. But only children who inherit both the shorter telomeres and a TERC mutation will have accelerated disease. It is not yet known whether children who inherit shorter telomeres without the TERC mutation develop any symptoms very late in life due to normal age-associated telomere shortening.

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Repeat inheritance

The results of these new studies show that individuals with AD-DC in later generations inherit a set of chromosomes with short telomeres from the parent who carried the TERC mutation and that this is sufficient to cause anticipation. Studies in the telomerase-knockout mouse previously indicated that this could occur. Heterozygous mice derived from crossing TERC+/+ and TERC−/− mice did not fully elongate the shorter telomeres6. This suggests that haploinsufficiency with respect to TERC may reduce telomerase activity enough that telomeres cannot be fully elongated in one generation.

Reports based on twin studies show that telomere length is familial7,8. In one recent study telomere length was linked to the X chromosome9. The investigators found a correlation in telomere lengths of fathers and daughters and of mothers and daughters or sons but not of fathers and sons. Perhaps polymorphisms in the gene associated with dyskeratosis congenita on the X chromosome influence telomere maintenance. Thus, the X chromosome would influence telomere length heritability in a manner analogous to the anticipation phenomenon described by Vulliamy et al.3.

Several correlative studies support the idea that individuals with telomeres shorter than those of age-matched controls are prone to disease. For example, individuals with atherosclerotic heart disease have significantly shorter telomeres than healthy aged-matched controls10. Independent of age and mean arterial pressure, arterial stiffness and pulse pressure inversely correlate with TRF length in men11. In a retrospective study of archival cryopreserved white blood cells, telomere length was a primary independent predictor of overall mortality. In this study, mortality due to infectious disease was eight times greater in individuals (over the age of 60 y) whose blood-cell telomere length was in the lowest quartile (shortest telomeres) than in individuals whose telomeres were in the other quartiles12. Vulliamy et al.3 show that genetically inherited short telomeres in dyskeratosis congenita cause anticipation of disease. This supports the hypothesis that short telomeres due to a variety of causes (increased in cell turnover associated with chronic age-associated diseases, inflammatory processes, oxidative damage, genetic alterations in telomerase components) correlate with disease. Showing cause and effect will require showing that slowing down the rate of telomere loss or resetting the telomere clock reverses or delays the onset of disease13.

Because telomerase RNA is limiting in vivo in dyskeratosis congenita and telomeres are not maintained to age-appropriate lengths, is dyskeratosis congenita the perfect disease to test the therapeutic value of telomere rejuvenation?

Treatment options

One approach to test if telomere rejuvenation could affect the progression of disease in dyskeratosis congenita would be to isolate hematopoietic stem cells (CD34+) from individuals with dyskeratosis congenita, expand them in the laboratory while transiently overexpressing the catalytic protein (TERT) component of telomerase (perhaps using adenoviral TERT that does not integrate into nuclear DNA) until telomeres become sufficiently elongated, and then return the rejuvenated stem-like cells to the affected individual. The obvious advantage of this approach is that these are the person's own cells, which would avoid problems of rejection. In addition, this could be done without ablating the person's own bone marrow cells (skewing of X-chromosome inactivation in women carrying the X-linked form of dyskeratosis congenita shows that progressive overgrowth of cells with longer telomeres is likely to occur). The ectopic expression of TERT may be sufficient to maintain or elongate telomeres in a wide variety of cells14,15. Safety and efficacy standards, as well as quality and control assurances, will need to be carefully considered before initiating such studies. But if this strategy for engineering telomeres in cells improves the health and longevity of individuals with dyskeratosis congenita, then it could be considered for treatment of other telomere-based proliferative deficiencies produced by disease or aging.