Mutations in telomerase and telomere gene components manifest as diverse clinical syndromes that vary in severity but share a single common molecular defect of shortened telomeres.
Telomere length determines disease severity and type in the monogenic telomere syndromes. This is most evidently seen in the pattern of genetic anticipation in families with autosomal-dominant inheritance because mutant telomerase genes cause haploinsufficiency and progressive telomere shortening across generations.
Telomere length is a heritable genetic trait even when the telomerase genes are wild-type. Because it is polymorphic, it may influence disease risk across populations.
Short telomere length limits the replicative potential of stem cells in high-turnover tissues, such as the bone marrow. This is seen clinically in a failure of haematopoiesis known as aplastic anaemia, which is a common complication of telomere syndromes.
Even in tissues of slow turnover, short telomere length causes degenerative disease, as seen in the high prevalence of pulmonary disease in telomerase mutation carriers. In these tissues, short telomere length lowers the threshold to acquired injuries, such as cigarette smoke in the lung.
There has been mounting evidence of a causal role for telomere dysfunction in a number of degenerative disorders. Their manifestations encompass common disease states such as idiopathic pulmonary fibrosis and bone marrow failure. Although these disorders seem to be clinically diverse, collectively they comprise a single syndrome spectrum defined by the short telomere defect. Here we review the manifestations and unique genetics of telomere syndromes. We also discuss their underlying molecular mechanisms and significance for understanding common age-related disease processes.
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Much of the basic biology that is relevant to disease and that is discussed in this Review has been studied in a number of model organisms, and we acknowledge that owing to space limitations we could not reference that important work comprehensively. We are grateful to several colleagues and laboratory members for helpful discussions and comments on the manuscript. M.A. acknowledges research support from the US National Institutes of Health Heart, Lung and Blood Institute (NHLBI), the US National Cancer Institute (NCI) and the Maryland Stem Cell and Flight Attendants Medical Research Foundations. E.H.B. acknowledges support from the US National Institute of General Medical Sciences (NIGMS) and the NCI.
Elizabeth H. Blackburn is a co-founder and shareholder of Telome Health, a company that specializes in telomere length measurement. Mary Armanios declares no competing financial interests.
Classically defined as a permanent arrest in the cell cycle in G0.
- Pulmonary fibrosis
A scarring disorder of the lung in which alveolar structures are replaced with extracellular matrix components such as collagen.
- Cajal body
A small subnuclear organelle that contains the telomerase ribonucleoprotein complex, as well as other newly assembled ribonucleoproteins.
A state in a diploid organism whereby one normal gene copy is insufficient for normal function.
- Oral leukoplakia
White patches in the mucosa of the mouth; this is often considered to be a precancerous state.
- Nail dystrophy
Abnormal or absent finger nails.
- Exudative retinopathy
A condition in which white–yellow spots are seen in the retina, indicating damage to retina blood vessels. When it is an isolated finding, it is often referred to as Coats disease.
- Coats plus syndrome
A syndrome defined by multiple congenital anomalies that are beyond the retinal abnormalities of Coats disease patients.
- Aplastic anaemia
A bone marrow failure state characterized by low blood counts and a paucity of haematopoietic cells in the bone marrow.
- Genetic anticipation
A pattern by which a certain phenotype manifests at an earlier age and with increasing severity with successive generations in autosomal-dominant disorders.
A quantification of the genetic component contributing to a specific trait.
- Missing heritability
The state in which the specific genotypes underlying the inheritance of a certain trait are not known.
- Allogeneic stem cell transplant
Transplant of stem cells, most frequently bone-marrow-derived, from an alternative donor to replace a failed organ.
An effect that is intrinsic to a specific cell type and not to an independent factor beyond that cell type.
- Crypt stem cells
Cells in the intestinal crypt that are responsible for the regenerative capacity of the epithelial protective barrier in the intestine.
- Tissue remodelling
The process by which tissue structures change, often in the setting of recovery from injury or healing.
- Senescence-associated secretory phenotype
(SASP). The phenomenon by which cultured senescent cells secrete growth factors, cytokines and proteases.
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