Dyskeratosis Congenita: A Disorder of Defective Telomere Maintenance?

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Abstract
Dyskeratosis congenita (DC) is a rare multisystem bone marrow failure syndrome that displays marked clinical and genetic heterogeneity. X-linked recessive, autosomal dominant and autosomal recessive forms of the disease are recognized. The gene that is mutated in the X-linked form of the disease is DKC1. The DKC1 -encoded protein, dyskerin, is a component of small nucleolar ribonucleoprotein particles, which are important in ribosomal RNA processing, and of the telomerase complex. The autosomal dominant form of DC is due to mutations in the gene for the RNA component of telomerase (TERC). Because both dyskerin and TERC are components of the telomerase complex and all patients with DC have short telomeres, the principal pathology of DC appears to relate to telomerase dysfunction, although defects in ribosomal processing via dyskerin’s involvement in pseudouridylation cannot be completely ruled out. The gene or genes involved in autosomal recessive DC remain elusive, although genes whose products are required for telomere maintenance remain strong candidates. The study of DC highlights the importance of telomerase in humans and how its deficiency results in multiple abnormalities, including premature aging, bone marrow failure, and cancer.