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

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.
Janan Mohamad 1,  Ofer Sarig 2,  Lisa M Godsel 3,  Alon Peled 1,  Natalia Malchin 2,  Ron Bochner 2,  Dan Vodo 1,  Tom Rabinowitz 4,  Mor Pavlovsky 2,  Shahar Taiber 1,  Maya Fried 1,  Marina Eskin-Schwartz 1,  Siwar Assi 5,  Noam Shomron 6,  Jouni Uitto 7,  Jennifer L Koetsier 3,  Reuven Bergman 8,  Kathleen J Green 9,  Eli Sprecher 10
Affiliations

Affiliations

  • 1 Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • 2 Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
  • 3 Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
  • 4 Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • 5 Research Center for Digestive Disease, Sourasky Medical Center and Sackler Faculty of Medicine, Tel-Aviv, Israel.
  • 6 Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Variantyx, Ltd, Framingham, Massachusetts, USA.
  • 7 Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
  • 8 Department of Dermatology, Rambam Health Care Campus, Haifa, Israel; Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
  • 9 Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA; Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
  • 10 Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: [email protected].
PMID: 29758285 DOI: 10.1016/j.jid.2018.04.032
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.

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