MBTPS2 encodes a zinc metalloprotease that catalyzes intramembrane proteolysis of membrane-bound transcription factors, most notably the sterol regulatory element-binding proteins (SREBPs) and ATF6. The enzyme cleaves substrates within their transmembrane segments; for SREBPs, this second cleavage step releases their N-terminal domains, which translocate to the nucleus to activate genes governing cholesterol and lipid biosynthesis 12. MBTPS2 similarly processes ATF6 during endoplasmic reticulum (ER) stress responses 3. The protease also participates in bone formation and regulates the transcription factor CREB3L1 during DNA damage and ER stress in osteoblasts. Pathogenic MBTPS2 variants cause X-linked disorders with overlapping but distinct phenotypes. Mutations underlie ichthyosis follicularis, atrichia, and photophobia (IFAP) syndrome, and the more severe BRESHECK syndrome, which adds intellectual disability and congenital anomalies to the IFAP triad 4. A recent variant impaired both SREBP pathway activation and ER stress response, manifesting with cytopenias and bone marrow fibrosis 4. MBTPS2 mutations also cause keratosis follicularis spinulosa decalvans and osteogenesis imperfecta type XIX, highlighting the protease's critical role in skin barrier function and osteoblast differentiation 5. The clinical heterogeneity suggests that different mutations produce variable pathway impairment. No disease-specific therapeutics targeting MBTPS2 dysfunction have been established.