TERT

Two extremes of the same gene

TERT exemplifies the telomerase trade-off: too little drives stem- cell exhaustion and premature aging; too much drives cancer.

Loss-of-function: telomere syndromes

• Dyskeratosis congenita: classic triad of nail dystrophy, leukoplakia, skin pigmentation; bone marrow failure; high cancer risk.
• Hoyeraal-Hreidarsson syndrome: severe variant with cerebellar hypoplasia.
• Idiopathic pulmonary fibrosis (IPF): TERT variants explain a meaningful fraction of familial IPF; sometimes present as isolated lung disease in adults.
• Aplastic anaemia in adults: occasional TERT variant cause.

Hyperactivation: cancer

~85% of human cancers reactivate telomerase (often via TERT-promoter mutations C228T, C250T) to bypass replicative senescence. TERT promoter mutations are particularly common in melanoma, glioblastoma, bladder cancer, and hepatocellular carcinoma.

Therapeutic implications

• AAV-TERT gene therapy extended mouse lifespan in Maria Blasco’s lab. Human translation raises cancer concerns.
• TERT-promoter mutation testing is part of standard glioblastoma workup.
• Telomerase inhibitors (e.g. imetelstat) are in haematological cancer development.

Practical clinical use

TERT germline testing is part of investigation for:

• Unexplained adult-onset cytopenias.
• Familial IPF.
• Cryptogenic liver cirrhosis (hepatopulmonary syndrome).

Predictive testing in unaffected family members carries significant psychological and management considerations.

Related entries

Telomerase, Telomere attrition, Telomere length, Maria Blasco.