Genetics of Dyskeratosis Congenita


Dyskeratosis congenita (DC) is a rare, inherited, skin and bone marrow failure disease. It is a multisystem disorder which is heterogeneous at the genetic and clinical levels. Genetically, nine genes have so far been identified whose mutation causes DC, and inheritance of the disease can be X linked, autosomal dominant or recessive. Clinically, the disease can present in childhood as classical DC with a characteristic triad of nail dystrophy, leukoplakia and abnormal skin pigmentation along with progressive bone marrow failure. More severe forms presenting in infancy and milder forms in adults, as aplastic anaemia or pulmonary fibrosis, exist. All forms of the disease with known pathogenesis are due to failure of telomere maintenance, often leading to stem cell exhaustion. Recent progress in the identification of mutations in human syndromes has revealed that DC overlaps clinically and genetically with a number of other rare syndromes.

Key Concepts:

  • The major cause of death in DC is bone marrow failure.

  • The most common form of DC is X linked.

  • In the X‐linked form, females are not, or very mildly, affected, but they show extremely skewed X‐inactivation, with cells expressing the mutated gene being outgrown by cells expressing the wild type gene.

  • Dyskeratosis congenita is a disease caused by defective telomere maintenance.

  • Nine genes have been discovered to cause dyskeratosis congenita when mutated, and their products are involved in telomerase and its assembly or as part of the telomere.

  • When the disease is caused by mutations in the core components of telomerase, TERT and TERC families show an increase in severity of the disease in later generations, a phenomenon known as genetic anticipation.

  • Genetic anticipation is due to shortening of telomeres from one generation to the next.

  • Some DC mutations are also known causes of pulmonary fibrosis, liver fibrosis and Coats retinopathy.

  • Now that genes responsible for rare syndromes are being discovered, it is becoming evident that there is overlap between DC and several other rare syndromes that have been described.

Keywords: telomerase; telomere; dyskerin; TERC; TIN2; Hoyeraal Hreidarsson; anticipation; pulmonary fibrosis; aplastic anaemia; telomere length

Figure 1.

Chromosomal location of genes involved in DC. In this diagram, the official symbols recommended by the HGNC:HUGO gene nomenclature committee are given. Thus, WRAP53 is used for TCAB1 and USB1 for C16orf57.

Figure 2.

DC patients have short telomeres. In this diagrammatical representation, the black lines show the distribution of telomere lengths in a healthy population. In red are the telomere lengths of DC patients. Note the decrease in telomere length with age in the healthy population and the fact that telomere lengths in DC patients are below the first percentile found in the healthy population and are relatively constant at presentation in patients with different ages.

Figure 3.

Pathogenic mutation clusters in dyskerin. Illustration of the clustering of X‐linked DC associated mutations in the DKC1 gene, encoding dyskerin. The majority of mutations, including the severe A353V mutation, are clustered in the PUA RNA‐binding domain and near the N‐terminus of the DKC1 gene. In the tertiary structure of the dyskerin ortholog from archaea, these domains are adjacent, implying that the mutations affect the same function of dyskerin. Arrows indicate clustering of mutations in the gene.

Figure 4.

The gene products known to be defective in DC. TERT, telomerase reverse transcriptase and TERC, the telomerase RNA containing the template for telomere synthesis, are core components of telomerase. Dyskerin, NOP10 and NHP2 are associated with telomerase in the telomerase RNP and are thought to be important for assembly and stability. Along with (GAR1), these three proteins are also found in H/ACA snoRNPs and scaRNPs. There are two copies of the H/ACA complex in each telomerase RNP (Egan and Collins, ). TCAB1 is important for the assembly of telomerase, its localisation in Cajal bodies and its translocation to its site of action at the telomere. TIN2 is one of the six proteins making up shelterin, a protein complex that protects telomeres from degradation by exonucleases and from the cell's DNA repair machinery. CTC1 is part of the CST complex, which may function in telomere replication. C16orf57 has recently been found to have a role in the biogenesis of U6snRNA – the mechanism by which mutations in C16orf57 cause disease is not known.

Figure 5.

The end replication problem. During DNA replication, synthesis of the lagging strand is fragmented, creating a gap at the 5′ ends of the newly synthesised DNA strands on removal of the RNA primers. This problem is corrected by telomerase, which adds TTAGGG repeats to the 3′ ends of the parent strands, allowing for the full extension of the daughter strands.

Figure 6.

DC as the tip of an iceberg. Hypothesis of the relationship between critically short telomeres and disease severity. It has been proposed that the time of disease onset is determined by the age telomeres become critically short. This model demonstrates that telomeres become critically short in severe DC during infancy. In classical DC, critically short telomeres occur in childhood and adolescence and in atypical DC, telomeres become critically short in adulthood. The asterisk on the C16orf57 mutation indicates that although this causes a severe disease phenotype, telomere lengths are normal. The double asterisk indicates genes in which compound heterozygous mutations result in DC.



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Further Reading

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Vulliamy TJ and Dokal I (2008) Dyskeratosis congenita: the diverse clinical presentation of mutations in the telomerase complex. Biochimie 90(1): 122–130.

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Mason, Philip J, Reeves, Dara, and Perdigones, Nieves(Feb 2013) Genetics of Dyskeratosis Congenita. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024269]