Functional characterization of mutations in the promoter proximal region of the telomerase hTERC gene identified in patients with hematological disorders

Telomerase RNA gene (hTERC) mutations have been identified in a subset of patients with bone-marrow failure syndromes (BMFS). While most of the mutations were found in the coding region of hTERC, some rare disease-associated mutations as well as polymorphic sequence changes were found in the promoter proximal region of the gene, including the -99C/G sequence change that was thought to modulate hTERC gene expression by disrupting Sp1 transcriptional factor binding [1]. We and other researchers recently identified, in addition to the -99C/G mutation, several other sequence variations (-240delCT, -714+C insertion, and -771A/G) in the hTERC promoter in other cohorts of patients with blood disorders. Using a convenient telomerase reconstitution assay coupled with the hTERC-promoter driven luciferase reporter assay, we characterized each of the hTERC's promoter sequence variants and found that these rare sequence changes did not negatively affect telomerase gene expression or function. We therefore conclude that all known mutations in the promoter proximal region of the hTERC gene to date do not necessarily contribute to the pathogenesis of hematological disorders by directly affecting telomerase transcriptional activity and/or its enzymatic function.