Human diseases of telomerase dysfunction: insights into tissue aging

Abstract

There are at least three human diseases that are associated with germ-line mutations of the genes encoding the two essential components of telomerase, TERT and TERC. Heterozygous mutations of these genes have been described for patients with dyskeratosis congenita, bone marrow failure and idiopathic pulmonary fibrosis. In this review, we will detail the clinical similarities and difference of these diseases and review the molecular phenotypes observed. The spectrum of mutations in TERT and TERC varies for these diseases and may in part explain the clinical differences observed. Environmental insults and genetic modifiers that accelerate telomere shortening and increase cell turnover may exaggerate the effects of telomerase haploinsufficiency, contributing to the variability of age of onset as well as tissue-specific organ pathology. A central still unanswered question is whether telomerase dysfunction and short telomeres are a much more prominent factor than previously suspected in other adult-onset, age-related diseases. Understanding the biological effects of these mutations may ultimately lead to novel treatments for these patients.

Figure 1.

Schematic structure of the telomerase complex and diseases associated with mutations in the genes encoding each protein within the complex. TERT, hTR, dyskerin, NOP10, NHP2 and GAR1 constitute the telomerase ribonucleoprotein complex. Mutations in the genes TERT or TERC (encoding hTR) are associated with autosomal dominant pulmonary fibrosis, bone marrow failure syndromes and DKC. Mutations in DKC1, encoding dyskerin, cause X-linked recessive DKC. Autosomal recessive DKC has been described in one family with a homozygous mutation in NOLA3, encoding NOP10.

Figure 2.

Schematic representation of hTR (A) and TERT (B) and the location of mutations associated with DKC (red), bone marrow failure syndromes (orange) and pulmonary fibrosis (black). Mutations in TERC, encoding hTR and TERT have been described for patients with DKC (30,38,39,88) and bone marrow failure syndromes including aplastic anemia (30,43,54–58), myelodysplastic syndrome (56,59) and essential thrombocytemia (43). Rare mutations in TERC have been found in patients with familial pulmonary fibrosis (86,87). Mutations in TERT have been found in patients with DKC (30,41), familial pulmonary fibrosis (86,87) and aplastic anemia (42,58,61,62). Common genetic polymorphisms and promoter mutations are not shown. The schematic depiction of the predicted secondary structure of hTR is indicated (103); mutations in TERT are shown relative to conserved domains (3,104,105).

Figure 3.

A proposed model underlying the pathogenesis of inherited human diseases of telomere dysfunction. Inherited genetic effects and certain environmental effects can affect telomere lengths. With each round of cell division telomeres shorten until a critical telomere length is reached. Additional quiescent cells with replicative potential are then recruited into the cell cycle. These new stem cells proliferate and undergo further telomere shortening, followed by senescence.The premature exhaustion of the pool of stem cells leads to the clinical diseases of pulmonary fibrosis, bone marrow failure and failure of other organs associated with dyskeratosis congenita. If mutations in cell cycle checkpoint genes such as p53 have occurred, the senescent growth arrest is blocked, cells divide and telomeres continue to shorten until they lose their ability to protect the ends of chromosomes. These can initiate breakage-fusion-bridge cycles and generate genomic instability, which can lead to cancer.