The short and long telomere syndromes: paired paradigms for molecular medicine

Abstract

Recent advances have defined a role for abnormally short telomeres in a broad spectrum of genetic disorders. They include rare conditions such as dyskeratosis congenita as well pulmonary fibrosis and emphysema. Now, there is new evidence that some familial cancers, such as melanoma, are caused by mutations that lengthen telomeres. Here, we examine the significance of these short and long telomere length extremes for understanding the molecular basis of age-related disease and cancer.

Figure 1. Telomere length extremes and their predominant clinical manifestations

Telogram showing the telomere length range across the age spectrum with percentile lines defining the normal range at every age. The short telomere syndromes have typical manifestations that are represented by the red circles at the typical age of onset. Familial melanoma and glioma have been linked to mutations that putatively cause long telomeres.

Figure 2. Telomerase and telomere components mutated in both short and long telomere syndromes

The ‘S’ subscript indicates a link to short telomere syndromes (n = 11 genes), while the ‘L’ superscript indicates a link to long telomere syndromes (n = 4 genes). Mutant components are shown in color and gray denotes telomere components not known to be linked to disease. These mutations affect telomerase catalytic activity or processivity (TERT and TR), telomerase biogenesis (dyskerin encoded by DKC1), NOP10 and NHP2, or telomerase trafficking (TCAB1 also known as WRAP53). Mutations in telomere syndromes may also fall in the shelterin components: TIN2 (encoded by TINF2), TPP1 (encoded by ACD), POT1, or RAP1 (encoded by TERF2IP). CTC1 and RTEL1 affect lagging strand synthesis and telomere replication, respectively. PARN is involved in RNA processing and deadenylation.

Figure 3. Genetic anticipation in the autosomal dominant short and long telomere syndromes

(a) In the short telomere syndromes, successive telomere shortening across generations manifests in disease that shows an earlier age of onset. There is also an evolving pattern with ancestors developing lung disease and their progeny having a higher incidence of high turnover phenotypes such as bone marrow failure. (b) Long telomere syndromes appear to also show genetic anticipation of the melanoma phenotype; this is presumably caused by inheritance of long telomeres (right panel). Mutations in TERT have been linked to both syndromes with short telomere syndromes being caused by loss-of-function mutations (a), while familial melanoma is caused by promoter gain-of-function mutations that turn on TERT transcription (b).