Transcriptional profiling of Hutchinson-Gilford Progeria patients identifies primary target pathways of the disease-causing progerin protein

Hutchinson Gilford Progeria Syndrome (HGPS) is an ultra-rare pediatric premature aging disorder. The disease is caused by a point mutation in the LMNA gene leading to the production of the dominant-negative progerin isoform of the nuclear envelope protein lamin A. Disease severity and progression amongst the population of ~140 known patients is variable. Numerous cellular pathways have been implicated in the disease mechanism, including mTOR signaling, stem cell differentiation and the oxidative stress response. Most of 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 have performed transcriptomic analysis of a comprehensive set of HGPS patients. We find misexpression of several of the major HGPS-associated cellular pathways across the patient population, particularly of multiple signaling pathways as well as 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 distinguished immediate-early cellular response pathways from secondary adaptive pathways and identify mTOR, the UPR, UV response, apoptosis and TNFa signaling via NFkB as primary targets of the disease-causing progerin protein. Overall design: RNA-seq profiling of primary human HGPS fibroblasts and primary human wild type control fibroblats, as well as hTERT-immortalized GFP-progerin doxycycline inducible dermal fibroblast cell line where progerin was expressed for 0 or 6 days.