The genetics of dyskeratosis congenita

Abstract

Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome associated with characteristic mucocutaneous features and a variable series of other somatic abnormalities. The disease is heterogeneous at the genetic and clinical levels. Determination of the genetic basis of DC has established that the disease is caused by a number of genes, all of which encode products involved in telomere maintenance, either as part of telomerase or as part of the shelterin complex that caps and protects telomeres. There is overlap at the genetic and clinical levels with other, more common conditions, including aplastic anemia (AA), pulmonary fibrosis (PF), and liver cirrhosis. Although part of the spectrum of disorders known to be associated with DC, it has emerged that mutations in telomere maintenance genes can lead to the development of AA and PF in the absence of other DC features. Here we discuss the genetics of DC and its relationship to disease presentation.

Fig.1. DC patients have short telomeres

The graph shows telomere length in 24 DC patients at presentation and telomere length of healthy controls. All patients shown have dyskeratosis congenita and a mutation in a known DC gene. Telomere lengths were measured by flow cytometric fluorescence in situ hybridization in peripheral blood mononuclear cells. The 1st, 90^th, 25th, 50th, 75th, 90th, 99th percentiles of 243 healthy controls between the ages of 1 day and 94 years are shown.

Fig. 2. The gene products known to be defective in dyskeratosis congenita

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 2 copies of the H/ACA complex in each telomerase RNP (112, 113). TCAB1 is important for the assembly of telomerase, it’s localization in Cajal bodies and its translocation to its site of action at the telomere. TIN2 is one of 6 proteins making up shelterin, a protein complex that protects telomeres from degredation by exonucleases and from the cell’s DNA repair machinery. The estimates of the proportion of DC patients in each group is based on(111) and (93). The frequency of TERT and hTR are probably underestimated to ascertainment bias.

Fig.3. Schematic representation of age specific effects of mutations in different DC genes

The primary manifestation of DC differs with the age of disease onset and is dependent on the underlying gene mutation(s). This is a schematic presentation of the age dependent presentation of disease and the most frequent gene mutation responsible for this phenotype. The mutated genes are shown below and the presentation at disease onset is indicated above.