Identification of six novel polymorphisms in the human corneodesmosin gene

Abstract

Psoriatic epidermis is characterised by a defective differentiation program leading to an abnormal permeability barrier and impaired desquamation. The corneodesmosin gene (CDSN) or "S" gene is a strong candidate in psoriasis susceptibility, due first to its genomic position ("S" gene, 160 kb telomeric to HLA-C) and second to its expression and function in the epidermis. Moreover, an association between CDSN and psoriasis vulgaris was recently shown in Caucasian populations. In order to pursue the CDSN polymorphism analysis, we determined the sequence of its alleles in 14 HLA-Cw6-positive individuals. A 4.6 kb genomic fragment encompassing the first exon, the unique intron and the coding sequence of the second exon was amplified from 8 psoriatic patients and 6 controls. Allelic discrimination was performed by restriction fragment length polymorphism analysis. The entire coding sequence and the intron boundaries of 27 alleles were sequenced. A total of 26 dimorphic sites were found, 23 consisting in single nucleotide polymorphisms (SNPs) and 3 in triplet modifications. Five out of the 23 SNPs have not been previously reported, and among them, one causes amino-acid exchange leading to the suppression of a potential chymotrypsin site. Among the triplet modifications, one leads to deletion of one out of five consecutive valines in the protein. The high polymorphism of the gene allowed the identification of 13 different alleles. These haplotypes will permit additional family-based studies that could provide new genetic support for the involvement of CDSN in psoriasis susceptibility. Moreover, the establishment of an extensive catalogue of CDSN alleles will allow functional analyses of the different protein isoforms.

Refined Characterization of Corneodesmosin Proteolysis during Terminal Differentiation of Human Epidermis and Its Relationship to Desquamation

“…Psoriasis is a human multifactorial skin disease characterized by T-cell infiltration, keratinocyte hyperproliferation, and epidermal differentiation abnormalities resulting in impaired desquamation. The involvement of Cdsn in the pathogenesis of the disease has been suggested based on its putative function and on genetic studies including association of various forms of psoriasis with a particular allele of CDSN (31)(32)(33)(34). Therefore, it appears of particular importance to determine the primary substrate specificity of SCCE and SCTE.…”

Psoriasis: genetic associations and immune system changes

“…CDSN is expressed in terminally differentiated keratinocytes and in the inner root sheath of hair follicles. [43][44][45] It localizes to the modified desmosomes of keratinocytes in the stratum granulosum and stratum corneum. The serine and glycine-rich terminal domains of CDSN that are essential for cell adhesion are sequentially cleaved during skin desquamation.…”

Genetic basis of psoriasis vulgaris and its pharmacogenetic potential

“…The CDSN gene is highly polymorphic, a feature shared with other MHC-located genes. CDSN polymorphism occurs at a frequency of at least 1 per 65 bp [69] and as with other genes the CDSN SNPs are approximately equally divided between synonymous and non-synonymous changes [70]. Non-synonymous SNPs inducing amino acid changes may modify sites for epidermal proteases giving rise to the characteristic epidermal features of psoriasis.…”

“…Non-synonymous SNPs inducing amino acid changes may modify sites for epidermal proteases giving rise to the characteristic epidermal features of psoriasis. Alternatively, changes in amino acid charges may alter CDSN structure thereby interfering with function [70].…”