Telomerase Mutations and Premature Ageing in Humans

Hong-Yan Du, Monica Bessler, and Philip J. Mason(*)

Abstract Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome which gets its name from the classic diagnostic triad of abnormal skin pigmentation, nail dystrophy, and leukoplakia. Most DC patients have bone marrow failure, and this is the most common cause of premature death. DC is genetically heterogeneous. The most common X-linked form is due to mutations in the DKC1 gene encoding dyskerin. Autosomal-dominant DC is caused by mutations in either TERT or TERC; no genes have so far been identified that cause the Autosomal-dominant form of the disease. That all three known genes underlying DC are components of the telom-erase complex suggests strongly that DC is caused by defective telomerase, and this suggestion is supported by the fact that all DC patients have very short telomeres. Thus the study of DC offers a unique opportunity to observe the effects of defective telomerase and failure to maintain telomere length on the human organism. The tissues affected in DC, skin, blood, lung, and the gut lining are those which need to be constantly renewed by stem cell activity and can be considered to undergo a kind of tissue-specific accelerated ageing. In this chapter, we propose a model of the pathogenesis of DC. Mutations in the telomerase complex result in excessive telomere shortening either by decreasing the stability of telomerase complex, reducing the accumulation, or directly affecting the enzymatic activity of telomerase. Telomere shortening leads to cell cycle arrest (senescence) or cell death (apoptosis) in rapidly dividing cells, including bone marrow cells. To fulfill the requirement for normal function, these cells have to increase the recruitment of more quiescent stem cells into the cell cycle and subsequent proliferation, which in turn accelerates telomere shortening, senescence, and apoptosis. When the stem cell compartments are exhausted, clinical manifestations of bone marrow failure occur. Meanwhile, cells surviving the telomere crisis accumulate genomic instability and become potential malignant cells.

Philip J. Mason

Department of Internal Medicine, Washington University School of Medicine, 660 S Euclid Avenue, St. Louis, Missouri, United States. e-mail: [email protected]

K.L. Rudolph (ed.), Telomeres and Telomerase in Ageing, Disease, and Cancer. © 2008 Springer-Verlag Berlin Heidelberg

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