The telomere syndromes

Abstract

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.

Telomerase mutations in smokers with severe emphysema

“…Four families carried known deleterious mutations in telomerase (12, 14, 22), including our originally reported family with the mutant TR, and (25). Moreover, in addition to TERT and TR, a number of other telomerase and telomere genes have been implicated in the monogenic telomere disorders (26,27). It is therefore possible that although the telomerase genes may account for a small subset, other mutant telomere pathway genes will collectively explain a larger proportion of susceptibility.…”

“…Identifying telomere syndrome patients at the bedside is particularly important in the setting of lung transplant, since some of these patients may be at increased risk for serious toxicities of immunosuppressive medications because of limited reserves in the bone marrow, gastrointestinal tract, and elsewhere (13). Relatives of telomerase mutation carriers may also be at risk for telomere syndrome complications, which may occur at an earlier age in successive generations because of genetic anticipation (26). Given the public health burden of COPD, our report suggests that emphysema may be a recurrent manifestation of telomere syndromes in populations where smoking remains prevalent.…”

Telomerase and the Genetics of Emphysema Susceptibility. Implications for Pathogenesis Paradigms and Patient Care

“…Telomere length shortens with cell division, and abnormally short telomeres signal senescence and apoptosis (reviewed in Reference 13). The role of telomere maintenance defects in mediating agerelated disease has become evident in recent years through studies of human telomerase mutation carriers (13). These individuals have abnormally short telomere length for their age (14), and develop a disease spectrum known as the short telomere syndromes (15).…”

Risk of multiple myeloma is associated with polymorphisms within telomerase genes and telomere length

“…Even moderate changes in TERT and TERC activity could profoundly affect telomere homeostasis. 26,27 Telomeres are highly specialized structures that have a key role in various cellular processes such as chromosomal stability and cell growth [28][29][30] and in the proper segregation of chromosomes to daughter cells. 31 There is overwhelming evidence suggesting telomere dysfunction, mediated by telomerase activation, as a driving force in cancer development.…”