NCSTN (nicastrin) encodes an essential scaffolding subunit of the gamma-secretase complex, a multiprotein endoprotease that catalyzes intramembrane cleavage of integral membrane proteins including Notch receptors and amyloid-beta precursor protein (APP) 12. Through its role in this complex, NCSTN regulates Notch and Wnt/β-catenin signaling cascades critical for epidermal keratinization and hair follicle development 34. Mechanistically, NCSTN functions as a membrane-anchored adaptor protein within gamma-secretase, facilitating substrate recognition and catalytic processing. Loss-of-function NCSTN mutations impair hair follicle structure and keratinocyte differentiation, reducing expression of hair cortex cytokeatin and trichohyalin 4. Clinically, NCSTN mutations are associated with hidradenitis suppurativa (HS)/acne inversa, a chr1 inflammatory skin disease characterized by follicular occlusion and destructive lesions 53. NCSTN variants account for a subset of familial HS cases, with carriers showing earlier disease onset and distinctive phenotypes involving atypical sites (scalp, neck, torso) 6. NCSTN mutations also cause Dowling Degos disease, a reticulated pigmentation disorder, often comorbid with HS 7. These findings establish NCSTN as a major genetic determinant in dermatologic disease pathogenesis through disrupted epidermal differentiation pathways.