Targeted deletion of the murine corneodesmosin gene delineates its essential role in skin and hair physiology

Abstract

Controlled proteolytic degradation of specialized junctional structures, corneodesmosomes, by epidermal proteases is an essential process for physiological desquamation of the skin. Corneodesmosin (CDSN) is an extracellular component of corneodesmosomes and, although considerable debate still exists, genetic studies have suggested that the CDSN gene in the major psoriasis-susceptibility locus (PSORS1) may be responsible for susceptibility to psoriasis, a human skin disorder characterized by excessive growth and aberrant differentiation of keratinocytes. CDSN is also expressed in the inner root sheath of hair follicles, and a heterozygous nonsense mutation of the CDSN gene in humans is associated with scalpspecific hair loss of poorly defined etiology. Here, we have investigated the pathogenetic roles of CDSN loss of function in the development of skin diseases by generating a mouse strain with targeted deletion of the Cdsn gene. Cdsn-deficient mouse skin showed detachment of the stratum corneum from the underlying granular layer and/or detachment within the upper granular layers due to the disrupted integrity of the corneodesmosomes. When grafted onto immunodeficient mice, Cdsn-deficient skin showed rapid hair loss together with epidermal abnormalities resembling psoriasis. These results underscore the essential roles of CDSN in hair physiology and suggest functional relevance of CDSN gene polymorphisms to psoriasis susceptibility.corneodesmosome ͉ hypotrichosis simplex of the scalp ͉ keratinocyte ͉ psoriasis

Corneodesmosin: Structure, Function and Involvement in Pathophysiology

“…before appearance of the macroscopic phenotype) observed by transmission electron microscopy revealed a similar organization and thickness of the granular layer and the SC than WT skin. In particular, we did not detect any significant differences in the number of transitional desmosomes between WT and KO neonates, unlike Matsumoto and coworkers' published data [30]. Moreover, the electron density of the corneodesmosomes appeared unchanged, suggesting no premature degradation of these structures.…”

“…In particular, they did not develop any hair phenotype up to 8 months. This reinforced the hypothesis that HSS is not caused by Cdsn haploinsufficiency [30,31]. Given our previous finding that a recombinant truncated form of CDSN is able to bind the entire CDSN [13,14], a dominant negative interaction between the mutant and wild-type proteins may account for the loss of cohesion in the inner root sheath of the hair follicles.…”

“…Analysis of mouse models with an inactivated Cdsn gene is of particular interest to answer these questions. The first publication of Cdsn inactivation in mice, obtained by insertional mutation, concluded that Cdsn is necessary for corneodesmosome formation [30]. We also realized conditional ablation of Cdsn using the K14-driven Cremediated recombination.…”

Genetic skin diseases related to desmosomes and corneodesmosomes

“…Importance of CDSN in the epidermal cell-cell adhesion was first discovered by lethal phenotypes of mice lacking CDSN expression [28]. In the skin of these mice, corneodesmosomes were structurally abnormal and the stratum corneum was detached from the granular layer.…”

Rarely occurring genodermatosis (acral peeling skin syndrome) – case report. Literature review of localized and generalized variants

“…CDSN jest zlokalizowany w rdzeniu korneodesmosomów i jest kowalencyjnie związany ze skeratynizowaną otoczką korneocytów. Brak CDSN powoduje cięż-kie uszkodzenie bariery naskórkowej, co objawia się odklejeniem warstwy rogowej od warstwy ziarnistej oraz brakiem integralności górnych partii warstwy ziarnistej [20]. Podobieństwo zespołu Nethertona do APSS wynika z bliskiej zależności funkcjonalnej SPINK5 i CDSN.…”