Figure 2

Potential mechanisms of disease. A range of molecular and cellular mechanisms are likely to contribute to the diverse phenotypes that are seen in the laminopathies, and these mechanisms probably vary depending on the specific mutation. Here, as an example, we show a range of putative disease-causing mechanisms for the case of HGPS, in which lamin A is permanently farnesylated in the form of progerin. We predict that progerin becomes entrapped in the nuclear membrane as a result of permanent farnesylation, resulting in a multitude of downstream effects. Disruption of the normal lamina architecture leads to fragility, vulnerability to mechanical stresses and nuclear blebbing. Other consequences include disrupted interactions with other nuclear envelope proteins – such as nesprin, emerin and laminaassociated protein 2 (LAP2) – which leads to their mislocalization (that is, emerin is relocalized to the cytoplasm in Lmna -/- mice)74 and clustering of nuclear pores. Disorganization and loss of peripheral heterochromatin is also seen, with heterochromatin becoming detached from the nuclear envelope, and disrupted interactions with RNA polymerase II, RNA splicing factors and transcription factors such as the retinoblastoma transcriptional regulator (RB) and sterol response element binding protein (SREBP1), which leads to misregulation of gene expression. GCL, germ cell-less [9].