Omics Profiling of S2P Mutant Fibroblasts as a Mean to Unravel the Pathomechanism and Molecular Signatures of X-Linked MBTPS2 Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is an inherited skeletal dysplasia characterized by low bone density, fragility and recurrent fractures. The characterization of its heterogeneous genetic basis has allowed the identification novel players in development. In 2016, we described first X-linked recessive form OI caused hemizygous MBTPS2 missense variants resulting moderate to severe phenotypes. encodes site-2 protease (S2P), which activates transcription factors involved (OASIS) cartilage development (BBF2H7), ER stress response (ATF6) lipid metabolism (SREBP) via regulated intramembrane proteolysis. times or sterol deficiency, aforementioned are sequentially cleaved site-1 (S1P) S2P. Their N-terminal fragments shuttle nucleus activate gene transcription. Intriguingly, mutations at other positions cause dermatological spectrum condition Ichthyosis Follicularis, Atrichia Photophobia (IFAP) Keratosis Follicularis Spinulosa Decalvans (KFSD) without clinical overlap with despite proximity some pathogenic variants. To understand how single amino acid substitutions S2P can lead non-overlapping phenotypes, aimed compare molecular features -OI -IFAP/KFSD, ultimate goal unravel pathomechanisms underlying -OI. RNA-sequencing-based transcriptome profiling primary skin fibroblasts from healthy controls ( n = 4), 3), MBTPS2- IFAP/KFSD 2) patients was performed identify genes that differentially expressed individuals compared controls. We observed SREBP-dependent more downregulated than IFAP/KFSD. This coupled alterations relative abundance fatty acids vitro , while no consistent profile were observed. Few OASIS-dependent suppressed -OI, BBF2H7- ATF6-dependent comparable between control fibroblasts. Importantly, identified physiology but not -IFAP/KFSD conclusion, our data provide clues deformities altered may affect development, mineralization endochondral ossification.