Dyskeratosis congenita as a disorder of telomere maintenance

Abstract

Since 1998, there have been great advances in our understanding of the pathogenesis of dyskeratosis congenita (DC), a rare inherited bone marrow failure and cancer predisposition syndrome with prominent mucocutaneous abnormalities and features of premature aging. DC is now characterized molecularly by the presence of short age-adjusted telomeres. Mutations in seven genes have been unequivocally associated with DC, each with a role in telomere length maintenance. These observations, combined with knowledge that progressive telomere shortening can impose a proliferative barrier on dividing cells and contribute to chromosome instability, have led to the understanding that extreme telomere shortening drives the clinical features of DC. However, some of the genes implicated in DC encode proteins that are also components of H/ACA-ribonucleoprotein enzymes, which are responsible for the post-translational modification of ribosomal and spliceosomal RNAs, raising the question whether alterations in these activities play a role in the pathogenesis of DC. In addition, recent reports suggest that some cases of DC may not be characterized by short age-adjusted telomeres. This review will highlight our current knowledge of the telomere length defects in DC and the factors involved in its development.

Figure 1

The affected proteins and/or RNA in DC, the associated modes of inheritance and relative frequencies. The implicated proteins in each form of inheritance are indicated in red, while the remainder of the complex is in grey. The secondary structure of hTR is diagrammed in black. XLR, X-linked recessive; AD, autosomal dominant; AR, autosomal recessive.

Figure 2

Structural organization of dyskerin with localization of disease-associated mutations. See the Telomerase Database for a periodically updated compilation of disease-associated DKC1 mutations [60, 105]. Abbreviations: Δ, deletion; DC, dyskeratosis congenita; fs?, putative frameshift; HH, Hoyeraal Hreidarsson syndrome.

Figure 3

Structural organization of TIN2 with localization of disease-associated mutations. See the Telomerase Database for a periodically updated compilation of disease-associated TINF2 mutations [60, 105]. Abbreviations: AA, aplastic anemia; BD, binding domain; BMF, bone marrow failure; DC, dyskeratosis congenita; fs, frameshift mutation; HH, Hoyeraal Hreidarsson syndrome; RS, Revesz syndrome; TIN2L-CTD, TIN2L C terminal domain; ↓WBC, decreased WBC; (X), nonsense mutation.

Figure 4

Localization of disease associated mutations on hTR secondary structure. Thick red and gray lines indicate areas of deletion in DC and other disorders, respectively. Locations of point mutations are noted. Although the disease(s) in which the mutation has been reported are specified, this does not imply that the mutation is necessarily restricted to that phenotype. The reader is referred to the Telomerase Database for a periodically updated compilation of disease-associated hTR mutations [60, 105]. Abbreviations: Δ, deletion; AA, aplastic anemia; BMF, bone marrow failure; DC, dyskeratosis congenita; ET, essential thrombocythemia; IPF, idiopathic pulmonary fibrosis; JMML, juvenile myelomonocytic leukemia; MDS, myelodysplastic syndrome; PNH, paroxysmal nocturnal hemoglobinuria; PF, pulmonary fibrosis.

Figure 5

Structural organization of TERT with localization of disease-associated mutations. See the Telomerase Database for a periodically updated compilation of disease-associated TERT mutations [60, 105]. As in Fig. 4, although the disease(s) in which the mutation has been reported are specified, this does not imply that the mutation is necessarily restricted to that phenotype. Abbreviations: Δ, deletion; AA, aplastic anemia; BMF, bone marrow failure; CTE, Cterminal extension; DC, dyskeratosis congenita; IPF, idiopathic pulmonary fibrosis; HH, Hoyeraal Hreidarsson syndrome; TEN, telomerase essential N terminal domain; TRBD, telomerase RNA binding domain; RT, reverse transcriptase domain.