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Exp Gerontol 2004 Apr;39(4):461-7.
Hutchinson-Gilford progeria (HGP) is a genetic disorder in which individuals prematurely display features of ageing. Mutations in LMNA (lamin A) have recently been shown to underlie HGP, although how such mutations lead to the complex phenotype seen in the disease remains unclear. HGP is often associated with the premature replicative senescence of dermal fibroblasts. Normally dermal fibroblast senescence is initiated by erosion of chromosomal ends (telomeres) resulting from sustained cell division. Since ectopic expression of telomerase reproducibly immortalises human dermal fibroblasts, it is of interest to determine whether HGP fibroblasts immortalise via the same route, and at the same frequency. Three strains of HGP fibroblasts (AGO6917A, AGO6297B and AGO8466) were infected with a retroviral vector expressing the catalytic subunit of telomerase (hTERT). Here we report that fibroblast clones derived from HGP donors frequently fail to immortalise with telomerase. Of the 15 independently isolated clones from the three donors, five failed to immortalise despite the restoration of telomerase activity and the stabilisation of telomere length. In contrast, out of four clones isolated from a culture of hTERT transduced control fibroblasts, no failures to immortalise were detected. This suggests a novel cellular phenotype in HGP, one whereby the HGP mutation confers resistance to 'telomerisation'.