SERCA2 dysfunction in Darier disease causes endoplasmic reticulum stress and impaired cell-to-cell adhesion strength: rescue by Miglustat

J Invest Dermatol. 2014 Jul;134(7):1961-1970. doi: 10.1038/jid.2014.8. Epub 2014 Jan 3.


Darier disease (DD) is a severe dominant genetic skin disorder characterized by the loss of cell-to-cell adhesion and abnormal keratinization. The defective gene, ATP2A2, encodes sarco/endoplasmic reticulum (ER) Ca2+ -ATPase isoform 2 (SERCA2), a Ca2+ -ATPase pump of the ER. Here we show that Darier keratinocytes (DKs) display biochemical and morphological hallmarks of constitutive ER stress with increased sensitivity to ER stressors. Desmosome and adherens junctions (AJs) displayed features of immature adhesion complexes: expression of desmosomal cadherins (desmoglein 3 (Dsg3) and desmocollin 3 (Dsc3)) and desmoplakin was impaired at the plasma membrane, as well as E-cadherin, β-, α-, and p120-catenin staining. Dsg3, Dsc3, and E-cadherin showed perinuclear staining and co-immunostaining with ER markers, indicative of ER retention. Consistent with these abnormalities, intercellular adhesion strength was reduced as shown by a dispase mechanical dissociation assay. Exposure of normal keratinocytes to the SERCA2 inhibitor thapsigargin recapitulated these abnormalities, supporting the role of loss of SERCA2 function in impaired desmosome and AJ formation. Remarkably, treatment of DKs with the orphan drug Miglustat, a pharmacological chaperone, restored mature AJ and desmosome formation, and improved adhesion strength. These results point to an important contribution of ER stress in DD pathogenesis and provide the basis for future clinical evaluation of Miglustat in Darier patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Deoxynojirimycin / analogs & derivatives*
  • 1-Deoxynojirimycin / pharmacology
  • Adherens Junctions / drug effects
  • Adherens Junctions / metabolism
  • Cadherins / metabolism
  • Calcium / metabolism
  • Cell Adhesion / drug effects
  • Cell Adhesion / physiology*
  • Cells, Cultured
  • Darier Disease* / drug therapy
  • Darier Disease* / metabolism
  • Darier Disease* / pathology
  • Desmosomes / drug effects
  • Desmosomes / metabolism
  • Endoplasmic Reticulum Stress / drug effects
  • Endoplasmic Reticulum Stress / physiology*
  • Enzyme Inhibitors / pharmacology
  • Female
  • Humans
  • Keratinocytes / cytology
  • Keratinocytes / metabolism
  • Keratinocytes / pathology
  • Male
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism*
  • Thapsigargin / pharmacology
  • beta Catenin / metabolism


  • CTNNB1 protein, human
  • Cadherins
  • Enzyme Inhibitors
  • beta Catenin
  • 1-Deoxynojirimycin
  • Thapsigargin
  • miglustat
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • ATP2A2 protein, human
  • Calcium