Abstract
Dyskeratosis congenita is a heterogeneous inherited bone marrow failure syndrome that is classically characterized by abnormal skin pigmentation, nail dystrophy and leukoplakia. X-linked recessive dyskeratosis congenita is due to mutations in DKC1, which encodes dyskerin. This protein is a key component in pseudouridylation and for telomere maintenance through the stabilization of the telomerase complex. Autosomal dominant dyskeratosis congenita has been found to be due to mutations in TERC and TERT that encode two key components (telomerase RNA component and reverse transcriptase) of the telomerase complex. These observations, together with the finding of shorter than expected telomeres in all dyskeratosis congenita patients, suggest that dyskeratosis congenita is primarily a disorder of telomerase deficiency. At present, it is unclear if defective pseudouridylation and/or rRNA processing plays any role in the pathophysiology of X-linked dyskeratosis congenita, but the clinical phenotype observed in highly proliferative tissues and stem cells of dyskeratosis congenita patients can be explained by telomerase dysfunction. The clinical features of dyskeratosis congenita overlap with several other bone marrow failure syndromes, as well as other premature aging and cancer syndromes. It is hypothesized that these different diseases all have a disrupted DNA maintenance and/or repair pathway in common. Further studies on dyskeratosis congenita, a monogenic disorder, can be expected to facilitate a better understanding of the more genetically complex diseases that result in bone marrow failure and cancer, as well as providing further information on these vitally important biological processes in normal physiology.