Syndromes of telomere shortening

Abstract

Telomeres and telomerase were initially discovered in pursuit of questions about how the ends of chromosomes are maintained. The implications of these discoveries to age-related disease have emerged in recent years with the recognition of a group of telomere-mediated syndromes. Telomere-mediated disease was initially identified in the context of dyskeratosis congenita, a rare syndrome of premature aging. More recently, mutations in telomerase components were identified in adults with idiopathic pulmonary fibrosis. These findings have revealed that the spectrum of telomere-mediated disease is broad and includes clinical presentations in both children and adults. We have previously proposed that these disorders be collectively considered as syndromes of telomere shortening. Here, the spectrum of these disorders and the unique telomere genetics that underlies them are reviewed. I also propose broader clinical criteria for defining telomere-mediated syndromes outside of dyskeratosis congenita, with the goal of facilitating their diagnosis and highlighting their pathophysiology.

Figure 1

Short telomeres activate a DNA-damage response that leads to apoptosis and senescence. As cells divide, short telomere accumulate because of the end-replication problem. Critically, short telomeres recruit DNA damage proteins that activate cellular programs of apoptosis or senescence. This cellular response manifests as organ failure in clinically recognizable syndromes of telomere shortening.

Figure 2

Mutations in telomerase and telomere components lead to syndromes of telomere shortening. (a) The essential telomerase components. hTERT utilizes the template provided by hTR to add new telomeres onto the ends of chromosomes. hTR is a 451 nucleotide RNA which contains a box H/ACA motif at its 3′ end. The box H/ACA motif is essential for hTR stability and for its assembly with hTERT. These functions are mediated by the presence of the box H/ACA-binding dyskerin complex, which is composed of four proteins: dyskerin, NOP10, NHP2 and GAR1. Loss-of-function mutations in hTR, hTERT, DKC1, and likely NOP10 and NHP2 lead to a decrease in available telomerase dose and accelerated telomere shortening. (b) The shelterin complex is composed of six specialized proteins that bind telomeric DNA. Mutations in the shelterin component TINF2 explain a subset of severe cases of dyskeratosis congenita. The mechanism by which TINF2 heterozygous mutations lead to telomere shortening is not known.

Figure 3

Telomere length is a unique heritable trait. In autosomal dominant syndromes of telomere shortening, in addition to a mutant hTERT or hTR allele, short telomeres are inherited across generations. The progressive telomere shortening leads to anticipation of phenotypes, as indicated by the darker shades of black in affected successive generations. Short telomeres can also be inherited in wild-type individuals; however, no telomere-associated phenotypes have been described in these individuals. Wild-type mice who inherit short telomeres have degenerative phenotypes similar to mTR^+/− mice (30).

Figure 4

Syndromes of telomere shortening lead to organ failure in the bone marrow, lung, and liver and define a distinct telomere-mediated entity in the absence of the classic features of DC. Bone marrow biopsy with normal cellularity shown in (a) is contrasted with marrow from patient with aplastic anemia in (b) where hematopoiesis is absent, and the marrow is replaced with fat. (c) Normal CAT scan of the chest with clear lung parenchyma is contrasted with (d) showing a CAT scan from a patient with idiopathic pulmonary fibrosis, a disorder classically marked by honeycombing in the peripheral and basilar portions of the lung as shown. (e) Normal CAT of the abdomen revealing a healthy liver size and structure. (f) CAT scan from a patient with cryptogenic liver cirrhosis due to telomere shortening. The liver is small and atrophic with nodular edges and secondary splenomegaly due to portal hypertension. This patient received a liver transplant after developing progressive symptoms of cirrhosis. Bone marrow micrographs were kindly provided by Dr. Kathleen Burns, Johns Hopkins Department of Pathology.

Figure 5

Short telomeres lead to stem cell failure in the bone marrow. (a) Normal hematopoiesis is hierarchical and relies on the intact capacity of a pleuripotent stem cell to self-renew and differentiate. When telomeres are short (b), stem cell function is impaired and the impairment leads to a progressive decline in the production of mature blood lineages in aplastic anemia.