More recently a different protein complex, shelterin, has been implicated in the pathology of DC. Shelterin has at least three effects on telomeres. It determines the structure of the telomeric terminus, it has been implicated in the generation of t-loops and it controls the synthesis of telomeric DNA by telomerase. Without the protective activity of shelterin, telomeres are no longer hidden from DNA damage repair mechanisms and so chromosome ends are incorrectly processed by the DNA repair pathways. The shelterin complex is comprised of six proteins: telomeric-repeat binding protein 1 (TERF1, TRF1), telomeric-repeat binding protein 2 (TERF2, TRF2), TRF1-interacting nuclear factor 2 (TINF2, TIN2), TERF2-interacting protein (TERF2IP, RAP1), TIN2-interacting protein 1 (ACD, protein names include TPP1, TINT1, PIP1 and PTOP) and protection of telomeres (POT1, POT1) (gene name, protein name abbreviation respectively) (de Lange, 2005). TRF1, TRF2 and POT1 of the shelterin complex (Fig 3) bind directly to the telomeric DNA: TRF1 and TRF2 bind to double stranded DNA and POT1 to the single stranded DNA overhang. The composition and protein interaction of the components of shelterin complex appears to be highly ordered with TIN2 playing a pivotal role (Kim et al, 1999; Ye et al, 2004; O’Connor et al, 2006; Chen et al, 2007; Gilson & Geli, 2007). Mutations have been identified in the TINF2 component of shelterin in patients with DC, HH, aplastic anaemia and Revesz syndrome (Savage et al, 2008; Walne et al, 2008). This discovery extends the range of the DC spectrum of diseases even further. Revesz syndrome is characterised by bilateral exudative retinopathy, bone marrow hypoplasia, nail dystrophy, fine hair, cerebellar hypoplasia and growth retardation and, from this brief description of the key clinical features, the overlap with DC is apparent (Revesz et al, 1992; Kajtar & Mehes, 1994). Patients with TINF2 mutations tend to have similar characteristics in terms of disease severity: all have severe disease and this is associated with very short telomere lengths. Interestingly, nearly all the patients had de novo mutations which gives rise to a different mechanism that causes the disease. In patients with heterozygous TERC mutations, studies have shown that the phenomenon of genetic anticipation is involved; a parent of an affected child has a particular mutation but no overt signs of disease. However in the child with the same heterozygous TERC mutation the disease manifests itself at a much younger age (Vulliamy et al, 2004). This adds another level of complexity to DC. Mutations in one gene (TERC) that take a generation to cause an obvious effect can cause the same disease as mutations in another gene (TINF2) that arise instantly.
Figure 3. Schematic representation of the telomerase and shelterin complexes involved in telomere maintenance. Protein names in bold are mutated in DC and associated disorders as listed. No human mutations have been described in the other components. AA, aplastic anaemia; AD-DC, autosomal dominant dyskeratosis congenita; AR-DC, autosomal recessive dyskeratosis congenita; ET, essential thrombocythaemia; HH, Hoyeraal Hreidarsson syndrome; PF, pulmonary fibrosis; MDS, myelodysplastic syndrome; PNH, paroxysmal nocturnal haemoglobinurea; RS, Revesz syndrome; S-DC, sporadic dyskeratosis congenita.
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