PhD Student/junior Researcher Institute of Cytology Russian Academy of Science, Russia
Abstract: Singleton-Merten syndrome (SMS) is a dominant autosomal orphan disease classified as an interferonopathy. Patients with SMS experience severe pathologies, including dental dysplasia, early-onset osteoporosis, psoriasis, and calcification of heart valves, vessels, and organs. The syndrome is linked to mutations in DDX58 and IFIH1. Despite its genetic basis, the molecular mechanisms of calcification and the role of endothelial cells remain unclear. We derived and characterized the first induced pluripotent stem cell (iPSC) line, SMS-DDX58, from a patient with SMS. Reprogrammed from peripheral blood mononuclear cells (PBMs) using viral vectors, SMS-DDX58 retains the patient-specific c.902C>G mutation in DDX58, confirmed by Sanger sequencing, while STR analysis verified its identity with the original PBMCs. SMS-DDX58 displays stem cell characteristics, expressing pluripotency markers OCT4, NANOG, and SSEA4. mRNA analysis confirmed POU5F1, SOX2, and NANOG expression. The cells differentiate into derivatives of all three germ layers under spontaneous and directed conditions, expressing lineage-specific markers. To investigate endothelial involvement in calcification, SMS-DDX58 cells were directed towards the endothelial lineage, expressing endothelial markers CD31 and vWF. Analysis of these derivatives demonstrated their potential to serve as a cellular model for studying the mechanisms of endothelial calcification in SMS. This iPSC line represents a promising model to study SMS pathogenesis and the role of endothelial cells in calcification. Beyond SMS, it offers a valuable tool for exploring mechanisms underlying interferonopathies, providing insights that could inform therapeutic strategies for related conditions.
Funding Source: This study was supported by the Ministry of Science and Higher Education of the Russian Federation (Agreement No. 075-15-2022-301, dated 04/20/2022)
