Transcriptional profiling of Hutchinson-Gilford progeria patients identifies primary target pathways of progerin

Hutchinson Gilford Progeria Syndrome (HGPS) is an ultra-rare pediatric premature aging disorder. It is caused by a point mutation in the <i>LMNA</i> gene leading to the production of the dominant-negative progerin isoform of the nuclear envelope protein lamin A. Most of the mechanistic insights into the disease have come from studies using cellular or mouse models of HGPS. To probe the clinical relevance of previously implicated cellular pathways and to address the extent of gene expression heterogeneity between patients, we performed transcriptomic analysis of a comprehensive set of HGPS patients. We find misexpression of several cellular pathways, including multiple signaling pathways, the Unfolded Protein Response (UPR) and mesodermal cell fate specification. Variability amongst individual patients was limited, with misregulation of the major pathways observed in most patients. Comparing the transcriptome of patients with an inducible HGPS cell model, we also identified the primary target pathways of the disease-causing progerin protein.