The genetics and clinical manifestations of telomere biology disorders

Abstract

Telomere biology disorders are a complex set of illnesses defined by the presence of very short telomeres. Individuals with classic dyskeratosis congenita have the most severe phenotype, characterized by the triad of nail dystrophy, abnormal skin pigmentation, and oral leukoplakia. More significantly, these individuals are at very high risk of bone marrow failure, cancer, and pulmonary fibrosis. A mutation in one of six different telomere biology genes can be identified in 50–60% of these individuals. DKC1, TERC, TERT, NOP10 and NHP2 encode components of telomerase or a telomerase-associated factor, and TINF2, a telomeric protein. Progressively shorter telomeres are inherited from generation to generation in autosomal dominant dyskeratosis congenita, resulting in disease anticipation. Up to 10% of individuals with apparently acquired aplastic anemia or idiopathic pulmonary fibrosis also have short telomeres and mutations in TERC or TERT. Similar findings have been seen in individuals with liver fibrosis or acute myelogenous leukemia. This report reviews basic aspects of telomere biology and telomere length measurement, and the clinical and genetic features of those disorders that constitute our current understanding of the spectrum of illness caused by defects in telomere biology. We also suggest a grouping schema for the telomere disorders.

Telomerase promoter mutations in cancer: an emerging molecular biomarker?

“…Like in the aforementioned disorders, IPF patients also have shorter telomeres than age-matched controls [17]. TERT and TERC telomerase component mutations have been found in familial forms of IPF [107]. The human diseases associated with telomerase or telomere dysfunction encompass mainly the above-referred three disorders (and some related syndromes) but there are other rare diseases reported in the literature [35].…”

Children of the Sun, Children of the Moon—A Mini-Panel for Assessment of Inter-Individual Variation Between the Capacity of Healthy Individuals to Repair Everyday Genotoxic Insults

“…longer-than-normal telomeres often seen in transformed cells usually indicate an increased capacity for uncontrolled proliferation, whereas shorter telomeres support the genomic instability of neoplastic cells, thereby promoting their potential for genomic rearrangements which may eventually boost their malignant potential (11,45). in myelodysplastic syndrome (MSD), accelerated telomere attrition is a typical feature, preceding the development of leukemia with years and sometimes with decades (46,51). the process of neoplastic transformation of skin cells is greatly enhanced by UVirradiation, especially in individuals devoid of natural melanin protection (Fitzpatrick skin types I-III).…”

Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus

“…Dyskeratosis congenita-associated mutations have been identified in the genes encoding DKC1, TERC, TERT, NOP10, NHP2 and TCAB1, which belong to the telomerase holoenzyme responsible for maintaining telomere length, and a member of the shelterin protein complex TINF2, which is responsible for maintaining the structural integrity of the telomere. Thus, dyskeratosis congenita is a disorder of telomere maintenance and is associated with shortened telomeres 2,3 .…”

“…These latter Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus features are also observed in dyskeratosis congenita. Furthermore, individuals with Hoyeraal Hreidarsson or Revesz syndrome, both of which are associated with telomeric shortening, can have intracranial calcification and, in the case of Revesz syndrome, an exudative retinopathy 2 .…”