Dyskeratosis congenita, stem cells and telomeres

Abstract

Dyskeratosis congenita (DC) is a multi-system disorder which in its classical form is characterised by abnormalities of the skin, nails and mucous membranes. In approximately 80% of cases, it is associated with bone marrow dysfunction. A variety of other abnormalities (including bone, brain, cancer, dental, eye, gastrointestinal, immunological and lung) have also been reported. Although first described almost a century ago it is the last 10 years, following the identification of the first DC gene (DKC1) in 1998, in which there has been rapid progress in its understanding. Six genes have been identified, defects in which cause different genetic subtypes (X-linked recessive, autosomal dominant, autosomal recessive) of DC. The products of these genes encode components that are critical for telomere maintenance; either because they are core constituents of telomerase (dyskerin, TERC, TERT, NOP10 and NHP2) or are part of the shelterin complex that protects the telomeric end (TIN2). These advances have also highlighted the connection between the more "cryptic/atypical" forms of the disease including aplastic anaemia and idiopathic pulmonary fibrosis. Equally, studies on this disease have demonstrated the critical importance of telomeres in human cells (including stem cells) and the severe consequences of their dysfunction. In this context DC and related diseases can now be regarded as disorders of "telomere and stem cell dysfunction".

Fig. 1

Clinical features of dyskeratosis congenita. The three mucocutaneous features that classically characterise dyskeratosis congenita are shown: (A) abnormal skin pigmentation; (B) nail dystrophy; (C) oral leukoplakia.

Fig. 2

Histopathological features of dyskeratosis congenita (DC): (A) bone marrow slides show the loss of cells in an aplastic marrow, typical of dyskeratosis congenita; (B) fibroblasts grown from a patient with X-linked dyskeratosis congenita show a marked dysmorphism compared to those from a healthy individual.

Fig. 3

The telomerase and shelterin complexes. TERT, TERC, dyskerin, NOP10 and NHP2 in the telomerase complex and TIN2 in the shelterin complex have been shown to be mutated in cases of dyskeratosis congenita. Only around 50% of cases have been characterised at the molecular level and the other molecules shown (as well as other, unknown molecules) may yet prove to be implicated in the disease. Image derived from data in the telomerase database and Cristofari et al. .

Fig. 4

The defects in cellular proliferation and differentiation that give rise to dyskeratosis congenita. Stem cell replication is impaired and cell survival is compromised starting with the embryonic stem cell and continuing through to adult cells. This in turn drives excessive tissue-specific stem cell division, ultimately exhausting the stem cell reserve. This figure takes the haematopoietic system as an example but the principles apply equally to other tissues.

Fig. 5

A model of dyskeratosis congenita pathology. Mutations in telomerase and shelterin components cause excessive telomere attrition and may increase the response to normal DNA damage, a process which is exacerbated by environmental stresses. This leads to premature cell death and chromosome instability which eventually either exhausts the stem cell reserve or results in haematological or non-haematological cancers.