TERT and TERC mutations detected in cryptic dyskeratosis congenita suppress telomerase activity.

Introduction: A cryptic form of dyskeratosis congenita (cDKC) has a gradual onset without the characteristic physical findings of DKC. cDKC is distinguished from other forms of bone marrow failure (BMF) through analysis of telomere shortening and gene mutations. Mutations in the telomerase reverse transcriptase (TERT) and telomere RNA component (TERC) genes have been detected in most Japanese cDKC patients. Therefore, we investigated the impact of each TERT and TERC mutation on telomerase activity.

Methods: TERT and TERC mutants observed in DKC or cDKC patients were transfected into Saos-2 or VA13+TERT (TERT-expressing VA13 cells) cells to measure telomerase activity.

Results: Telomerase activity in cells expressing a mutant detected in cDKC patients was significantly lower (P < .0001) than in cells expressing the wild-type genes. In addition, some TERT mutations seen in cDKC (p.P632R, p.T726M) caused weaker (P = .0013) suppression of telomerase activity than others (p.G106W and p.G682D). In contrast, telomerase activity in cells expressing a TERT or TERC mutant detected in DKC patients did not significantly differ from cells expressing the wild-type genes.

Conclusion: These findings suggest that TERT and TERC mutations detected in cDKC patients could potentially contribute to the pathogenesis of cDKC by blocking telomerase activity. However, TERT and TERC mutations detected in DKC patients did not affect telomerase activities, which means studying the telomerase activity of mutants are not always useful for the diagnosis of DKC.