6 Telomerase Deficiency and Human Disease

Abstract

The critical importance of telomeres and telomerase in humans has been recently illustrated by studies on the rare multisystem disorder dyskeratosis congenita (DC). In this disease, two genetic subtypes have been found to be due to mutations in genes that encode components of the telomerase complex. This results in telomerase deficiency, accelerated telomere shortening, and the development of multisystem abnormalities including bone marrow failure and many features of premature aging.

DC and related disorders can now be regarded as disorders principally of telomerase deficiency. In this chapter, clinical and genetic features are described of classical DC as well as other diseases (the “occult/cryptic” and atypical forms of DC) that have been recently linked to DC. The genetic defects found in these patients and their effect on telomerase and telomeres are reviewed here. These developments have implications for the management of patients with DC and related disorders. They also provide new opportunities for exploring the role of telomeres and telomerase in more common processes such as aging and cancer. Some of the topics in this chapter have also been reviewed by Marciniak and Guarente (2001).

CLASSICAL DYSKERATOSIS CONGENITA
Clinical Aspects
Classical DC (also known as Zinsser–Engman–Cole syndrome) is an inherited bone-marrow-failure syndrome characterized by the mucocutaneous triad of abnormal skin pigmentation, nail dystrophy, and mucosal leukoplakia (Fig. 1) (Zinsser 1906; Engman 1926; Cole et al. 1930). A variety (dental, gastrointestinal, genitourinary, hair graying/loss, immunological, neurological, ophthalmic, pulmonary, and skeletal) of other somatic abnormalities have also been reported (Table 1)...