Analysis of Hidradenitis Suppurativa-Linked Mutations in Four Genes and the Effects of PSEN1-P242LfsX11 on Cytokine and Chemokine Expression in Macrophages

The document analyzed 34 mutations linked to hidradenitis suppurativa (HS) in the genes NCSTN, PSEN1, PSENEN, and POGLUT1, and particularly focused on the effects of the PSEN1-P242LfsX11 mutation on cytokine and chemokine expression in macrophages. The study found that NCSTN mutations are likely loss-of-function and affect protein structure and function, while the PSEN1-P242LfsX11 mutation increases and prolongs TNFα production in macrophages in response to LPS stimulation. This suggests a role for the PSEN1-P242LfsX11 mutation in the inflammatory processes of HS. The study also indicates that mutations in POGLUT1 and PSENEN are linked to dysregulation of Notch signaling, potentially contributing to small vessel disease and vascular cognitive impairment. The findings support the use of TNFα inhibiting agents for treating HS patients with PSEN1 mutations and propose iPSC therapy as a potential treatment, with further studies recommended to understand the role of these genetic mutations in HS pathogenesis.