Haploinsufficiency of t e lomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita

Abstract

Dyskeratosis congenita is a rare inherited disorder characterized by abnormal skin manifestations. Morbidity and mortality from this disease is usually due to bone marrow failure, but idiopathic pulmonary fibrosis and an increased cancer predisposition also occur. Families with autosomal dominant dyskeratosis congenita display anticipation and have mutations in the telomerase RNA gene. We identified a three-generation pedigree with autosomal dominant dyskeratosis congenita, anticipation, and telomere shortening. We show that a null mutation in motif D of the reverse transcriptase domain of the protein component of telomerase, hTERT, is associated with this phenotype. This mutation leads to haploinsufficiency of telomerase, and telomere shortening occurs despite the presence of telomerase. This finding emphasizes the importance of telomere maintenance and telomerase dosage for maintaining tissue proliferative capacity and has relevance for understanding mechanisms of age-related changes.telomere ͉ aplastic anemia ͉ hTERT

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

“…In this family, the IPF phenotype was most common (21). Mutations in TERT are now recognized to be the most prevalent cause of familial pulmonary fibrosis (16).…”

“…The role of telomerase genetics in familial lung disease came first from a study of a three-generation family that was found to carry a deleterious mutation in the telomerase reverse transcriptase gene, TERT (21). In this family, the IPF phenotype was most common (21).…”

“…To date, mutations in seven telomerase and telomere genes have been shown to cause familial lung disease; together, they explain one-third of the inheritance in familial pulmonary fibrosis. They include genes that encode the essential telomerase components: TERT, the catalytic component, and TR, the telomerase RNA (21)(22)(23). Three other genes when mutated disrupt TR stability, processing, and biogenesis: DKC1, PARN, and NAF1, respectively (24)(25)(26)(27).…”

Dyskerin Is a Component of the Arabidopsis Telomerase RNP Required for Telomere Maintenance

“…Heterozygous mutations in hTR, which reduce its accumulation and perturb its structure, lead to an autosomal dominant form of DC through haploinsufficiency of the RNA subunit (5,14,45). Similarly, haploinsufficiency of TERT has been implicated in DC and in aplastic anemia (1,47,51). Limiting abundance of telomerase subunits may help to facilitate the fine balance of telomerase repression and activation associated with differentiated cells and their stem cell progenitors (15).…”

TCAB1: Driving telomerase to Cajal bodies

“…11,12 Autosomal dominant forms of DC are caused by mutations in TERT, TERC or the telomere binding protein TIN2, providing a clear link between telomere shortening and the pathophysiology of DC. [13][14][15][16] Several dedicated cofactors associate with dyskerin and are required for telomerase RNP assembly and function. Many of these, such as NAF1, pontin and reptin, aid in RNP assembly but do not remain associated with the mature telomerase enzyme.…”