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

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.

Autosomal recessive congenital ichthyosis: Genomic landscape and phenotypic spectrum in a cohort of 125 consanguineous families

“…Bathing‐suit ichthyosis (BSI), a condition in which arms and legs are not affected, has been defined as a minor variant of ichthyosis (Marukian et al., ). Other forms of ichthyosis include erythrokeratoderma variabilis, loricrin keratoderma, congenital reticular ichthyosiform erythroderma, and peeling skin syndrome (Mohamad et al., ; Oji et al., ; Youssefian, Touati, et al., ).…”

Peeling Skin Disorders: A Paradigm for Skin Desquamation

“…Two independent groups report that FLG2 deficiency due to biallelic lossof-function mutations causes generalized noninflammatory skin peeling (Bolling, et al 2018;Mohamad et al, 2018). Affected individuals displayed erythroderma at birth, as well as trauma-and heat-aggravated generalized skin peeling that improved during childhood.…”

Differential stromal reprogramming in benign and malignant naturally occurring canine mammary tumours identifies disease-promoting stromal components

“…using single cell methods to simultaneously characterise changes in composition and state of CAS at the single cell resolution between benign and malignant tumours would help elucidating such changes further. Identification of the hub genes ( Figure 4) SPINK5, DSG1, FLG2, KRT1, and DMKN the turquoise module, which is strongly decreased in CAS from mCA compared to adenoma, is highly interesting, since all of these genes have been strongly linked to maintenance of epithelial differentiation and integrity (Deraison et al, 2007;Hammers and Stanley, 2013;Leclerc et al, 2014;Mohamad et al, 2018;Roth et al, 2013). This suggests an important function of stromal reprogramming in destabilization of epithelial differentiation and integrity.…”