Corneodesmosin gene polymorphism demonstrates strong linkage disequilibrium with HLA and association with psoriasis vulgaris

Abstract

Corneodesmosin (CD) is thought to play a key role in corneocyte cohesion, and its proteolysis appears to be a major event in the process of desquamation. Recently it was shown that CD is encoded by the S-gene, which is located approximately 160 kb telomeric of HLA-C. In the present study, the role of CD in the genetics of psoriasis vulgaris was studied in greater detail. The second exon of the CD gene was sequenced in 86 HLA-typed individuals from 13 psoriasis multiplex families. A total of 11 silent dimorphisms and 7 variants resulting in amino acid substitutions were found. Pedigree analysis showed that these variants could be grouped into 7 alleles, encoding 6 different amino acid sequences. These alleles are in strong linkage disequilibrium with HLA-B and -C, indicating that the polymorphism of the CD gene is ancient and well conserved rather than sporadic. One allele at the CD locus, designated CD2, displayed strong linkage disequilibrium with HLA-Cw6, the HLA allele most prominently associated with psoriasis. CD2 demonstrated a greater relative risk than Cw6 (3.4 vs. 2.5, not significant) and higher significant transmission disequilibrium with psoriasis than any of the investigated HLA-alleles. Due to its biologic function, cellular location and disease association, the CD gene appears to be an excellent candidate gene for PSORS1, the HLA-linked determinant of psoriasis vulgaris.

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.…”

Analysis of protein–protein interaction between late cornified envelope proteins and corneodesmosin

“…Polymorphisms identified within the coding sequence of CDSN have been grouped in several haplotypes (7), resulting in six different protein variants. Association studies have shown strong linkage disequilibrium (LD) between certain haplotypes of the CDSN gene and HLA-C locus (7,8). In general, HLA-C*06 is considered to be the most likely 'psoriasis gene', but CDSN cannot be ruled out as the causative gene (9).…”

Corneodesmosin Expression in Psoriasis Vulgaris Differs from Normal Skin and Other Inflammatory Skin Disorders

“…However, the major histocompatibility complex contains many non-HLA genes and HLA-C may simply be acting as a genetic marker for the psoriasissusceptibility gene(s) in close linkage disequilibrium with HLA-C. One such gene is the Cdsn gene, which, because of its genomic position and biological function, is a good potential candidate for psoriasis susceptibility. Strong association has been demonstrated between alleles of the Cdsn gene and psoriasis (Allen et al, 1999;Jenisch et al, 1999;Tazi Ahnini et al, 1999). A characteristic feature of psoriasis is hyperkeratosis and increased shedding of epidermal scale, suggesting a possible abnormality of keratinocyte adhesion.…”