Filaggrin 2 Deficiency Results in Abnormal Cell-Cell Adhesion in the Cornified Cell Layers and Causes Peeling Skin Syndrome Type A

J Invest Dermatol. 2018 Aug;138(8):1736-1743. doi: 10.1016/j.jid.2018.04.032. Epub 2018 Jun 27.

Abstract

Peeling skin syndromes form a large and heterogeneous group of inherited disorders characterized by superficial detachment of the epidermal cornified cell layers, often associated with inflammatory features. Here we report on a consanguineous family featuring noninflammatory peeling of the skin exacerbated by exposure to heat and mechanical stress. Whole exome sequencing revealed a homozygous nonsense mutation in FLG2, encoding filaggrin 2, which cosegregated with the disease phenotype in the family. The mutation was found to result in decreased FLG2 RNA levels as well as almost total absence of filaggrin 2 in the patient epidermis. Filaggrin 2 was found to be expressed throughout the cornified cell layers and to colocalize with corneodesmosin that plays a crucial role in maintaining cell-cell adhesion in this region of the epidermis. The absence of filaggrin 2 in the patient skin was associated with markedly decreased corneodesmosin expression, which may contribute to the peeling phenotype displayed by the patients. Accordingly, using the dispase dissociation assay, we showed that FLG2 downregulation interferes with keratinocyte cell-cell adhesion. Of particular interest, this effect was aggravated by temperature elevation, consistent with the clinical phenotype. Restoration of corneodesmosin levels by ectopic expression rescued cell-cell adhesion. Taken together, the present data suggest that filaggrin 2 is essential for normal cell-cell adhesion in the cornified cell layers.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Arabs / genetics
  • Biopsy
  • Cell Adhesion / genetics*
  • Cells, Cultured
  • Codon, Nonsense
  • Consanguinity
  • Dermatitis, Exfoliative / genetics*
  • Dermatitis, Exfoliative / pathology
  • Epidermis / pathology*
  • Epidermis / ultrastructure
  • Female
  • Homozygote
  • Humans
  • Keratinocytes / pathology
  • Male
  • Microscopy, Electron
  • Primary Cell Culture
  • S100 Proteins / genetics*
  • Skin Diseases, Genetic / genetics*
  • Skin Diseases, Genetic / pathology
  • Whole Exome Sequencing

Substances

  • Codon, Nonsense
  • S100 Proteins
  • filaggrin-2 protein, human

Supplementary concepts

  • Peeling Skin Syndrome