Loss of Corneodesmosin Leads to Severe Skin Barrier Defect, Pruritus, and Atopy: Unraveling the Peeling Skin Disease

Abstract

Generalized peeling skin disease is an autosomal-recessive ichthyosiform erythroderma characterized by lifelong patchy peeling of the skin. After genome-wide linkage analysis, we have identified a homozygous nonsense mutation in CDSN in a large consanguineous family with generalized peeling skin, pruritus, and food allergies, which leads to a complete loss of corneodesmosin. In contrast to hypotrichosis simplex, which can be associated with specific dominant CDSN mutations, peeling skin disease is characterized by a complete loss of CDSN expression. The skin phenotype is consistent with a recent murine Cdsn knockout model. Using three-dimensional human skin models, we demonstrate that lack of corneodesmosin causes an epidermal barrier defect supposed to account for the predisposition to atopic diseases, and we confirm the role of corneodesmosin as a decisive epidermal adhesion molecule. Therefore, peeling skin disease will represent a new model disorder for atopic diseases, similarly to Netherton syndrome and ichthyosis vulgaris in the recent past.

Inherited ichthyoses/generalized Mendelian disorders of cornification

“…These include proteins of structural importance for corneocyte formation (eg, cornified envelope proteins), cell-cell junction proteins and enzymes required for the proteolysis of cell junctions, for lipid metabolism and for DNA repair (Table 1). 2,[12][13][14][15][16][17][18][19][20][21] In the revised classification, MeDOC entities are listed using the term for the clinical entity referenced with the causative gene in parenthesis. The major clinicogenetic categories of the current MeDOC classification are summarized in Table 2 (also see Oji et al) 2 .…”

Alu‐mediated large deletion of the CDSN gene as a cause of peeling skin disease

“…The CDSN gene was amplified from genomic DNA using specific primers (2). Array CGH and breakpoint analysis were performed as described previously (3).…”

“…Peeling skin disease (PSD), a generalized inflammatory form of peeling skin syndrome, is an autosomal recessive skin disorder caused by mutations in CDSN and is characterized by superficial peeling of the upper epidermis (1,2). Patients with PDS have been reported to carry nonsense or frameshift mutations resulting in complete loss of expression of corneodesmosin (CDSN), a major component of corneodesmosomes that plays an important role in maintaining epidermis integrity.…”

State-of-the-art of 3D cultures (organs-on-a-chip) in safety testing and pathophysiology

“…this is in accordance with the enhanced transepidermal water loss in atopic patients presenting filaggrin abnormalities (Winge et al, 2011). Moreover, the model of peeling skin disease is also based on gene silencing, i.e., of transglutaminase (Oji et al, 2010).…”