Components for which mutations have been identified in telomere syndromes are indicated in bold type and shaded in blue. Shelterin complex components are made up of six component proteins — telomere repeat-binding factor 1 (TRF1), TRF2, repressor/activator protein 1 (RAP1), TRF1-interacting nuclear protein 2 (TIN2), TIN2-interacting protein 1 (TPP1) and protection of telomeres 1 (POT1) — which are essential for telomere protection and for regulating telomere elongation. The telomerase enzyme complex is comprised of TERT (the reverse transcriptase) and TR (the essential RNA component that contains a template for telomere repeat addition). TR contains a 3′H/ACA box motif that binds the dyskerin protein, which is part of a larger dyskerin complex that also consists of NHP2, NOP10 and GAR1. Note that for simplicity, one dyskerin complex is shown per TR molecule, although two copies are now thought to bind each TR. Telomerase Cajal body protein 1 (TCAB1) binds a Cajal body localization motif in TR and has a role in TR trafficking and biogenesis. In the Cajal body, TR and TERT assemble into a functional holoenzyme complex. The CST complex has three components — conserved telomere protection component 1 (CTC1), suppressor of cdc thirteen 1 (STN1) and telomeric pathway with STN1 (TEN1) — which are thought to function in part in telomere lagging-strand synthesis. Figure adapted, with permission, from Ref. © (2009) Annual Reviews.

A schematic drawing that illustrates the typical range of telomere lengths by age in, for example, peripheral blood lymphocytes. At every age, telomere length displays a normal distribution that is defined by the percentile lines labelled on the right. Telomere length in individuals with four different clinical presentations across the age range is indicated. The dashed lines represent a typical age range in which these disorders may first manifest, and ‘G_n’, ‘G_{n + 1}’ and ‘G_{n + 2}’ designate three successive generations manifesting with earlier-onset and evolving disease type owing to progressive telomere shortening.

a | Schema of a typical autosomal-dominant family with an inherited mutation in TERT (the reverse transcriptase) or TR (the telomerase RNA) showing earlier-onset disease with each generation, as illustrated by the darkening shades of purple. b | Disease type evolves in autosomal-dominant families from lung-predominant, which commonly manifests as idiopathic pulmonary fibrosis (IPF), to bone-marrow-failure-predominant, which presents as aplastic anaemia or dyskeratosis congenita. c | In mouse and human families, progeny of telomerase mutation carriers inherit the short telomeres even when they do not carry the mutant telomerase gene and are designated wt*. Mice with the wt* genotype have mild telomere-mediated phenotypes, but it remains unclear whether this is the situation for human cases (as represented by the question mark). The telomere length in human families is restored in progeny of these individuals. Figure adapted, with permission, from Ref. © (2012) Elsevier.

a | Simplified schema of the haematopoiesis hierarchy with intact telomere length (left panel) and in the presence of telomere dysfunction (right panel). Telomere dysfunction causes both quantitative and qualitative defects in haematopoietic stem cells, which cause a decrease in mature blood forms. Defects in lymphopoiesis also cause immune defects. b | Histopathology of normal bone marrow biopsy shows intact marrow cellularity and haematopoietic cellular elements (left panel). In the right panel, a photomicrograph of a bone marrow biopsy from an individual with aplastic anaemia shows acellular marrow and replacement of the marrow parenchyma by fat. Panel b reproduced, with permission, from Ref. © (2009) Annual Reviews.

a | Telomere length lowers the threshold to endogenous and exogenous damage, which is hypothesized to precipitate disease in slow-turnover tissues. b | A schematic of an insulin-producing β-cell showing the mechanism of a telomere-mediated insulin exocytosis defect. Glucose passively enters β-cells through the glucose transporter type 2 (GLUT2; also known as SLC2A2). Following glycolysis, ATP is generated by oxidative phosphorylation in the mitochondria. The net cytosolic change of the ATP/ADP ratio leads to closure of ATP-dependent K⁺ channels and opening of Ca²⁺ channels. The influx of extracellular Ca²⁺ results in an increase in the concentration of free, intracellular Ca²⁺ ([Ca²⁺]_i), which triggers the release of insulin from both reserve and back-up pools. Short telomeres cause gene expression changes in pancreatic islets, which are associated with global metabolic dysregulation, mitochondrial dysfunction and concurrent defects in glucose-dependent and glucose-independent Ca²⁺ handling.