Dyskeratosis congenita

Dyskeratosis congenita (DC) is another rare, genetically heterogeneous, inherited disorder with BMF as a major feature. Lacy, reticulated skin, nail dystrophy, abnormal pigmentation, and mucosal leukoplakia in the first years of life and the later development of BMF classically define DC. Leukoplakia, particularly of the oral mucosa and also of the gastrointestinal and genital tracts, is common. Other clinical manifestations include developmental delay, short stature, ocular, dental and skeletal abnormalities, hyperhidrosis, hyperkeratinization of the palms and soles, bullae on minimal trauma, hair loss, sometimes gonadal failure, and features of premature ageing.

Molecular genetics and molecular pathogenesis. In the majority of cases (~85%) the mode of inheritance is X-linked recessive, and many cases are sporadic; in the remaining cases the mode of inheritance is either autosomal dominant or autosomal recessive.

The X-linked form of DC results mostly from missense mutations in the housekeeping gene DKC1. DKC1 maps to Xq28, consists of 15 exons, its cDNA is 2465 bp long and it encodes a protein (dyskerin) of 514 amino acids with a predicted molecular weight of 57.6 kDa. Mutations in the DKC1 gene account for ~40% of all cases. Hoyerall-Hreidarsson syndrome, a rare syndrome characterized by severe growth failure, immunodeficiency, cerebellar abnormalities and BMF, has been shown to be allelic to DC; indeed, in all cases tested mutations in DKC1 were identified.

Dyskerin is homologous to Cbf5p, a yeast protein that, in conjunction with the H/ACA class of small nucleolar RNAs, is involved in the pseudo-uridylation of preribosomal RNA (rRNA). However, one study addressing this issue failed to demonstrate any qualitative or quantitative defect of rRNA in DC patients. Instead, it was shown that dyskerin binds to a H/ACA domain of the human telomerase RNA (hTR); that is, the template used by the reverse transcriptase component of telomerase (TERT) for telomere lengthening. Telomerase is a ribonucleoprotein complex and dyskerin is among a number of proteins interacting, directly or indirectly, with hTR, ensuring its stability and ability to function as a template for TERT. Telomerase activity is highest in rapidly dividing cells (e.g. dividing HSCs), during organogenesis, in early life and also in tumor cells. The critical evidence that DC is a disease of telomere dysfunction was provided by the finding of monoallelic mutations in the 451 -nucelotide, intronless hTR gene in some families with the autosomal dominant form of DC (Figure 12.7). Thus, the current evidence links the X-linked and autosomal dominant types of DC in a common molecular pathogenetic pathway: namely, the maintenance of telomere length. In keeping with this notion, all types of blood cells in DC patients have significantly shorter telomeres than age-matched controls. Shortening of telomeres to a critical length can result either in growth arrest and apoptosis, hence the development of BMF, or, on some occasions, to neoplastic transformation; hence the increased propensity to epithelial tumors.

As for FA, there is no definitive treatment for DC and most patients die before the age of 30. The main causes of death are complications of BMF, opportunistic infections, pulmonary complications and malignancy. Few patients have had successful correction of BMF by HSCT.

CR4-CR5 domain

Hypervariable paired region

110-113 107-108

Pseudoknot domain

Hypervariable paired region

110-113 107-108

Pseudoknot domain

378-415 del

Box H/ACA domain

378-415 del

Box H/ACA domain

CR7 domain 408 C^-G

Fig 12.7 Model of secondary structure of the human hTR

Mutations identified in families with autosomal dominant dyskeratosis congenita are shown (courtesy of Dr T. Vulliamy).

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