Molecular cytogenetic insights into the ageing syndrome Hutchinson-Gilford Progeria (HGPS)

Abstract

Hutchinson-Gilford Progeria Syndrome (HGPS) is an extremely rare genetic disorder characterized by premature ageing in childhood and serves as a valuable model for the human ageing process in general. Most recently, point mutations in the lamin A (LMNA) gene on chromosome 1q have been associated with the disease, however how these mutations relate to the complex phenotype of HGPS remains to be established. It has been shown that fibroblasts from HGPS patients are frequently resistant to immortalization with telomerase (hTERT), consistent with the idea that the loss of a dominant acting HGPS gene is a pre-requisite for immortalization. In this study we report the first detailed cytogenetic analysis of hTERT-immortalised HGPS cell lines from three patients and one corresponding primary fibroblast culture. Our results provide evidence for a cytogenetic mosaicism in HGPS with a distinctive pattern of chromosome aberrations in all the HGP clones. Chromosome 11 alterations were observed at a high frequency in each immortalised HGPS cell line but were also present at a lower frequency in the corresponding primary cells. Moreover, we were able to identify the 11q13→q23 region as a potential site of breakage. Our results are therefore consistent with a role of chromosome 11 alterations in the escape from senescence observed in HGPS cells. In addition to this defined rearrangement, we consistently observed complex chromosomal rearrangements, suggesting that HGPS displays features of chromosomal instability.

Suppression of Proliferative Defects Associated with Processing-defective Lamin A Mutants by hTERT or Inactivation of p53

“…Suppression of proliferation defects associated with progerin expression has not been reported previously, although investigators have found that hTERT expression will immortalize HGPS fibroblasts (Wallis et al, 2004;Corso et al, 2005;Huang et al, 2005). Because the suppressive effects of hTERT are apparent immediately after hTERT expression, we disfavor a model whereby enhanced telomere length is a primary determinant.…”

Progerin-Induced Replication Stress Facilitates Premature Senescence in Hutchinson-Gilford Progeria Syndrome

“…Some reports indicate that hTERT-mediated cellular immortalization is possible in certain HGPS strains (34,44,45), while others have found that HGPS fibroblasts are resistant to hTERT immortalization (46,47). Moreover, hTERT does not protect against progerin-induced aberrant nuclear shape and DNA damage (48).…”

Increased mechanosensitivity and nuclear stiffness in Hutchinson–Gilford progeria cells: effects of farnesyltransferase inhibitors

“…Mechanical weakening of vascular endothelial and smooth muscle cells could be the initiating pathological event that leads to arteriosclerosis (Davies, 1995;Mounkes & Stewart, 2004) or at least add to other cellular defects seen in HGPS such as genetic instability and premature cellular senescence (Mounkes & Stewart, 2004;Corso et al, 2005;Liu et al, 2005;Varela et al, 2005;Kudlow et al, 2007). Since vascular smooth muscle cells (VSCM) and endothelial cells were shown to be the primary targets of progerin build-up (McClintock et al, 2006) and are constantly exposed to fluid shear stress and strain in the vessel wall, increased cellular sensitivity to mechanical stress and impaired cell cycle activation may predominantly affect vascular cells and, therefore, contribute to arteriosclerosis.…”