Abstract
Hutchinson–Gilford progeria syndrome (HGPS) is a deadly childhood disorder, which is considered a very rare disease. It is caused by an autosomal dominant mutation on the LMNA gene, and it is characterized by accelerated aging. Human cell lines from HGPS patients and healthy parental controls were studied in parallel using next-generation sequencing (NGS) to unravel new non-previously altered molecular pathways. Nine hundred and eleven transcripts were differentially expressed when comparing healthy versus HGPS cell lines from a total of 21,872 transcripts; ITPR1, ITPR3, CACNA2D1, and CAMK2N1 stood out among them due to their links with calcium signaling, and these were validated by Western blot analysis. It was observed that the basal concentration of intracellular Ca2+ was statistically higher in HGPS cell lines compared to healthy ones. The relationship between genes involved in Ca2+ signaling and mitochondria-associated membranes (MAM) was demonstrated through cytosolic calcium handling by means of an automated fluorescent plate reading system (FlexStation 3, Molecular Devices), and apoptosis and mitochondrial ROS production were examined by means of flow cytometry analysis. Altogether, our data suggest that the Ca2+ signaling pathway is altered in HGPS at least in part due to the overproduction of reactive oxygen species (ROS). Our results unravel a new therapeutic window for the treatment of this rare disease and open new strategies to study pathologies involving both accelerated and healthy aging.
Highlights
Hutchinson–Gilford progeria syndrome (HGPS) is a deadly childhood genetic disorder caused by an autosomal dominant mutation on the LMNA gene and is a very rare disease [1]
These results suggest that HGPS is a complex metabolic syndrome, as pointed by other authors [17] and, it must be treated
Our data show that HGPS, caused by an autosomal dominant mutation on the LMNA
Summary
Hutchinson–Gilford progeria syndrome (HGPS) is a deadly childhood genetic disorder caused by an autosomal dominant mutation on the LMNA gene and is a very rare disease [1]. HGPS belongs to a group of diseases called laminopathies, all of them sharing mutations in the LMNA gene as the causal agent. HGPS is characterized by premature aging of the organism and accelerated senescence at the cellular level [3], and patients die at a mean age of 13 years old, mainly due to cardiovascular complications. The LMNA point mutation most frequently associated with HGPS promotes the processing and accumulation of a deleterious lamin A isoform, called progerin or lamin A ∆50 [4], which remains permanently farnesylated [5]. Therapeutic strategies have focused on reverting the action of progerin, mainly through the use of farnesyltransferase inhibitors [6].
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