Analysis of hidradenitis suppurativa-linked mutations in four genes and the effects of PSEN1-P242LfsX11 on cytokine and chemokine expression in macrophages

Hum Mol Genet. 2019 Apr 1;28(7):1173-1182. doi: 10.1093/hmg/ddy414.


Hidradenitis suppurativa (HS), or acne inversa, is a chronic inflammatory skin disorder characterized clinically with acne-like lesions in apocrine gland-bearing skin, follicular occlusion and recurrent inflammation. Thirty-four unique mutations in patients with HS have been found in three genes encoding the γ-secretase complex: nicastrin (NCSTN), presenilin 1 (PSEN1), presenilin enhancer 2 (PSENEN) and in POGLUT1, an endoplasmic reticulum O-glucosyltransferase involved in Notch signaling. We have carried out a system review and have performed a functional analysis of the 34 unique reported HS-linked mutations in NCSTN, PSEN1, PSENEN and POGLUT1. We have also examined the effects of the HS-linked PSEN1-P242LfsX11 mutation on cytokine and chemokine expression in macrophages. Mutations in NCSTN are predicted to cause loss of function, to result in loss of transmembrane (TM) domain, to affect NCSTN substrate recruitment sites, to cause loss or creation of new ligand binging sites and to alter post-translational modifications and disulfide bonds. PSEN1-P242LfsX11 occurs at the opposite side of TM5 from Alzheimer's disease-linked PSEN1 mutations. All of the PSENEN mutations occur on TM regions that are predicted to disrupt membrane function. POGLUT1 mutations lead to an early termination of protein synthesis and are predicted to affect ligand binding function. In addition, PSEN1-P242LfsX11 mediates cytokine and chemokine expression and prolongs tumor necrosis factor α production on the inflammatory processes in THP-1 cells and phorbol-12-myristate-13-acetate-differentiated macrophages in response to lipopolysaccharide stimulation. These in silico analyses are instructive for functional studies of the HS-linked mutations. The PSEN1-P242LfsX11 mutation mediates cytokine and chemokine expression in macrophages.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Systematic Review

MeSH terms

  • Amyloid Precursor Protein Secretases / genetics
  • Chemokines / genetics
  • Chemokines / metabolism
  • Cytokines / genetics
  • Cytokines / metabolism
  • Gene Expression / genetics
  • Glucosyltransferases / genetics
  • Hidradenitis Suppurativa / genetics*
  • Hidradenitis Suppurativa / physiopathology
  • Humans
  • Macrophages / metabolism
  • Macrophages / physiology
  • Membrane Glycoproteins / genetics
  • Membrane Proteins / genetics
  • Mutation / genetics
  • Presenilin-1 / genetics
  • Presenilin-2 / genetics


  • Chemokines
  • Cytokines
  • Membrane Glycoproteins
  • Membrane Proteins
  • PSEN1 protein, human
  • PSENEN protein, human
  • Presenilin-1
  • Presenilin-2
  • nicastrin protein
  • Glucosyltransferases
  • POGLUT1 protein, human
  • Amyloid Precursor Protein Secretases