Conclusion

DKC is a bone marrow failure syndrome with features of chromosomal instability, accelerated telomeric shortening, and premature aging. The identification of the DKC1 gene, and knowledge that dyskerin is a nucleolar protein involved in ribosomal biogenesis, has opened avenues for investigating the molecular mechanisms underlying the pathophysiology of DKC. In particular, yeast and Drosophila models have been invaluable in deciphering the more specific involvement of dyskerin in the pseudouridylation and cleavage of precuror rRNA. Further, dyskerin is either directly or indirectly involved in maintaining the lengths of chromosomes, although the mechanism remains unknown. Despite the significant shortening of telomeres in patients with DKC, there is no convincing evidence that this is associated with altered levels of telomerase expression. Another question that remains unanswered is why the majority of telomeric shorten ing has occurred at birth and does not progress with increasing age of the patients even though the disease itself is progressive. If it holds true that accelerated telom-eric shortening in DKC is largely complete at birth, it remains equally difficult to explain why cancers do not more consistently develop in patients with DKC, and why high cancer incidence and chromosomal instability occur largely in patients who survive longer. This is more analogous to the acquisition of cancers as an accompaniment of the slow but progressive process of normal aging. It also remains unresolved why a defect in telomeric maintenance should lead to such a severe phenotype and early death of children with HHS but not of patients with DKC who may share the same DKC1 mutation. In conclusion, it remains to be elucidated whether there are one or more mechanisms central to the pathophysiology of DKC. Similarly, it remains open whether DKC is a ribosomal biogenesis and/or a telomeric maintenance disorder. Mouse models of the disease should shed light on the functional connections between mutant dyskerin, rRNA biogenesis, telom-erase activity, and telomeric shortening. From a clinical point of view, although establishing phenotype-genotype correlations has not been possible largely because of the broad spectrum of phenotypes and mutations, the identification of the DKC1 gene is of great diagnostic value and has already improved counseling of affected families. Unfortunately, with rare exceptions of patients with DKC who have successfully undergone bone marrow transplantations, treatment of most individuals remains palliative. The identification and functional characterization of the DKC1 gene has immensely contributed toward a deeper understanding of the disease pathomechanism. In the future, this will greatly improve the chances of developing better treatment options for patients with DKC.

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