Corneodesmosin Research Articles

Corneodesmosin (CDSN) gene association with psoriasis vulgaris in Caucasian but not in Japanese populations.

PSORS1 on chromosome 6p21.3, which contains the MHC, is a major susceptibility locus for psoriasis vulgaris. This region is characterized by strong linkage disequilibrium and contains the corneodesmosin (CSDN) gene, an attractive candidate for psoriasis susceptibility based on its putative biological function in keratinocyte adhesion, and HLA-Cw6, an established marker for psoriasis susceptibility. We compared two genetically independent populations in order to define the major psoriasis susceptibility gene, a British Caucasian population comprising parent-offspring trios analysed by the transmission disequilibrium test (TDT) and a Japanese case-control population. All individuals were investigated for CDSN polymorphism (+619, +1236, +1240 and +1243) and HLA-C association. Our data confirms strong association with HLA-Cw6 and CDSN allele 5 (+619T, +1240G, +1243C) in the Caucasian cohort (TDT, P = 5.4 x 10(-6)) and in addition defines this region further by identifying a high-risk CDSN haplotype (allele 5 and +1236T, P = 8.5 x 10(-8)). In contrast no association was observed in the Japanese cohort for any HLA-C or CDSN alleles. This data supports a role for the CDSN gene in Caucasian populations with psoriasis. However the lack of association with HLA-Cw6 and CDSN alleles in Japanese psoriasis patients may be because Japanese patients exhibit a form of psoriasis similar to late onset or Type II psoriasis vulgaris in contrast to early onset or Type I disease characterizing our Caucasian population.

The Major Psoriasis Susceptibility Locus PSORS1 Is not a Risk Factor for Late-Onset Psoriasis

PSORS1 is the major susceptibility locus for psoriasis vulgaris (PV) and lies within an approximately 200 kb segment of the major histocompatibility complex on chromosome 6p21.3. Alleles of candidate genes in this region including human leukocyte antigen (HLA)-C, alpha-helical coiled coil rod (HCR), and corneodesmosin (CDSN) show association with early-onset PV. Late-onset psoriasis (LOP) is defined as a disease with onset after 40 y of age and is typically sporadic. We assessed the role of PSORS1 in genetic susceptibility to LOP. Genotyping for HLA-C alleles and seven single nucleotide polymorphisms (SNP) within the genes HCR and CDSN was performed in LOP (n=145) and normal controls (n=309). Statistical analysis of allelic frequencies included calculation of odds ratio and chi2 comparisons. LOP demonstrated only a weak association to PSORS1 alleles HLA-Cw*6 (p=0.037), CDSN*5 (p=0.041), HCR*WC (p=0.013), and HCR SNP +325 (p=0.038). Patients with age of onset for psoriasis of 50 y or above provided no evidence of association with any of these alleles. These data suggest that the study cohort may include a number of subjects who harbor PSORS1 predisposition to early-onset psoriasis and yet do not present with disease by the age of 40 y. Thus this study demonstrates that PSORS1 is not a major inherited risk factor in the pathogenesis of LOP. These data suggest that the exclusion of LOP subjects from case-control studies will aid further delineation of the PSORS1 locus. Future genome-wide studies will be required to identify loci conferring risk for late-onset disease.

Degradation of Corneodesmosome Proteins by Two Serine Proteases of the Kallikrein Family, SCTE/KLK5/hK5 and SCCE/KLK7/hK7

Corneodesmosin (CDSN), desmoglein 1 (DSG1), and desmocollin 1 (DSC1) are adhesive proteins of the extracellular part of the corneodesmosomes, the junctional structures that mediate corneocyte cohesion. The degradation of these proteins at the epidermis surface is necessary for desquamation. Two serine proteases of the kallikrein family synthesized as inactive precursors have been implicated in this process: the stratum corneum chymotryptic enzyme (SCCE/KLK7/hK7) and the stratum corneum tryptic enzyme (SCTE/KLK5/hK5). Here, we analyzed the capacity of these enzymes to cleave DSG1, DSC1, and epidermal or recombinant forms of CDSN, at an acidic pH close to that of the stratum corneum. SCCE directly cleaved CDSN and DSC1 but was unable to degrade DSG1. But incubation with SCTE induced degradation of the three corneodesmosomal components. Using the recombinant form of CDSN, either with its N-glycan chain or enzymatically deglycosylated, we also demonstrated that oligosaccharide residues do not protect CDSN against proteolysis by SCCE. Moreover, our results suggest that SCTE is able to activate the proform of SCCE. These results strongly suggest that the two kalikreins are involved in desquamation. A model is proposed for desquamation that could be regulated by a precisely controlled protease-protease inhibitor balance.

Homo-Oligomerization of Human Corneodesmosin Is Mediated by Its N-Terminal Glycine Loop Domain

Corneodesmosin (CDSN), a glycoprotein expressed during the late stages of epidermal differentiation, localizes in the extracellular core of upper desmosomes and of corneodesmosomes. Since it displays homophilic adhesive properties, CDSN is thought to reinforce cell-cell cohesion within the upper layers of the epidermis. CDSN presents two serine- and glycine-rich domains in its N- and C-terminus that may fold into highly flexible and adhesive secondary structures called glycine loops. We analyzed the importance of these domains in CDSN homophilic adhesion by producing full-length and truncated recombinant forms of the protein deleted of the N- and/or the C-terminal domain. The adhesive properties of the various proteins were then tested in vitro by overlay binding assays and surface plasmon resonance quantitative analysis. Experiments evidenced the homophilic adhesive properties of the N-terminal glycine loop domain, confirming its involvement in CDSN-CDSN interactions. They further indicated that most of the C-terminal domain is not necessary for the adhesive properties of the protein. The dissociation constant (K(D)) was calculated to be 1.3x10(-5) M. This interaction strength might allow dynamic regulation of the CDSN-CDSN association to occur in vivo. Moreover, molecular filtration analyses demonstrated for the first time that non-glycosylated CDSN is able to spontaneously form large homo-oligomers in vitro and that the N-terminal glycine loop domain is necessary for the formation of these macromolecular complexes.

A 4.2 kb Upstream Region of the Human Corneodesmosin Gene Directs Site-Specific Expression in Hair Follicles and Hyperkeratotic Epidermis of Transgenic Mice

Corneodesmosin (CDSN) is a desmosomal protein expressed in the epidermis during the late stages of differentiation and in the inner root sheath of hair follicles. The homophilic adhesive properties of the protein suggest that it reinforces keratinocyte cohesion in the upper layers of the epidermis (stratum granulosum and stratum corneum). In this study, we analyzed the expression of the CDSN gene in 16 human tissues. We confirmed the closely restricted expression pattern of CSDN. Indeed, apart from the skin, the mRNA was significantly detected only in the placenta and the thymus. As a step in elucidating the mechanisms of tissue-specific expression, transgenic mice bearing a 4.2 kb fragment of the human CSDN gene promoter linked to the LacZ gene were generated. The reporter-gene expression was detected in special areas of the inner root sheath of the hair follicles and the hair medulla but not in the epidermis. Induction of epidermis hyperproliferation however either by pharmacological agents or by wounding led to strong expression of the reporter gene in the keratinocytes of the stratum granulosum and the parakeratotic corneocytes of the stratum corneum. The data suggest that the genomic sequences and/or regulating factors responsible for the cell-specific expression of the human CDSN gene in the normal hair follicle as well as in the hyperproliferative epidermis are different from those necessary for expression in the normal epidermis.

Investigation on the polymorphisms of corneodesmosin (CDSN) gene in Korean psoriasis patients

Investigation on the polymorphisms of corneodesmosin (CDSN) gene in Korean psoriasis patients

Corneodesmosin gene: no evidence for PSORS 1 gene in North-eastern Thai psoriasis patients.

Psoriasis vulgaris, a common inflammatory skin disorder, is known to be associated with the HLA-Cw*06 allele. It has been recently suggested by microsatellite mapping that a real susceptible gene for psoriasis resides in the approximately 100-kb genomic region telomeric of the HLA-C gene. In this respect, the corneodesmosin (CDSN) gene 160-kb telomeric of HLA-C is a strong candidate because of its location and its functional role in corneocyte cohesion and desquamation. In fact, a significant association between CDSN polymorphism and psoriasis was recently recognized in Caucasian populations. However, this association has not been replicated in other studies, being still controversial. In this study, we investigated the genetic polymorphism of the CDSN gene in 139 psoriasis patients and 144 healthy controls in the North-eastern Thai population. By direct sequencing technique, a total of 28 polymorphic sites were found, consisting of 26 single nucleotide polymorphisms (SNPs) and two indels (insertion/deletion). Among them, six SNPs have not been previously reported. Through this analysis, as many as 28 different SNP/indel haplotypes within the CDSN gene were identified. Seven SNPs and one indel, namely 9C, 614 A, 722T, 971T, 1215G, 1243C, 1331G and 1606AAG (deletion), revealed significant deviation in the allelic frequencies of the patients from those of the healthy controls. However, none of them are likely to be responsible for controlling the susceptibility of psoriasis, but these associations can be explained by a linkage disequilibrium to a real pathogenic allele of a nearby gene. Further, the large variations between the CDSN SNP/indel haplotypes and the psoriatic major histocompatibility complex (MHC) haplotypes also make it unlikely that CDSN is a major psoriasis-susceptible gene.

Dimorphic Alu element located between the TFIIH and CDSN genes within the major histocompatibility complex.

Most Alu members of the large SINE family are fixed within the human genome but some younger mobile members are dimorphic, that is, they are either present or absent in the genome. Four different dimorphic Alu insertions have been identified and characterized previously within the class I region of the major histocompatibility complex (MHC). Here we report on (i) the identification and characterization of a new dimorphic Alu insertion, AluyTF, located between the transcription factor II H (TFIIH) and corneodesmosin (CDSN) genes within a region of the MHC that is telomeric of the human leukocyte antigen type B (HLA-B) locus and centromeric of the HLA-A locus, (ii) the haplotypic relationships between the AluyTF dimorphism and the HLA-A and -B loci within a panel of 48 IHW cell-lines representing at least 36 different HLA class I haplotypes, (iii) the AluyTF genotype, allele and haplotype frequencies present in the Australian caucasian and Japanese populations, and (iv) the frequency of association between the AluTF dimorphisms and HLA-A and -B alleles in 108 Australian caucasians and 99 Japanese. The AluyTF insertion was present at 27% in the IHW cell lines, and the gene frequency was 0.107 and 0.083 in the Australian caucasian and Japanese population, respectively. The Alu haplotype frequencies constructed from four different dimorphic Alu loci including AluyTF within the MHC were not significantly different (p > 0.05) between the two populations. There were no significant associations between the Alu insertion and either the HLA-A or -B alleles except for a moderately strong association with HLA-A29 in the Australians (71.7%). This polymorphic AluyTF element, along with the four other previously described polymorphic Alu elements within the class I region of the MHC, will be useful lineage and linkage markers in human population studies and for elucidating the evolution of HLA class I haplotypes.

Genotyping Psoriasis

Genotyping Psoriasis

A study of candidate genes for psoriasis near HLA-C in Chinese patients with psoriasis

Genetic analyses have identified the HLA-Cw6 allele as the major risk allele for psoriasis in many racial groups. However, by serological typing, HLA-Cw6 is not considered a risk factor in Chinese psoriatics. There are several susceptibility genes for psoriasis residing in chromosome 6p near the HLA-C locus, including the corneodesmosin (CDSN) gene, the octamer transcription factor-3 (POU5F1) gene, the major histocompatibility complex class I chain-related gene A (MICA), and the gene for tumour necrosis factor (TNF)-alpha. However, the information about their role in psoriasis in Chinese patients is limited. We aimed to determine whether Cw6 and the genetic polymorphism of the CDSN gene, POU5F1 gene, MICA gene and the gene for TNF-alpha promoter region were associated with an increased risk of psoriasis in Chinese patients. We conducted a case-control association study in 105 Chinese patients with psoriasis vulgaris and 160 control subjects of similar ages. Genotypes of Cw6, the CDSN gene, the POU5F1 gene, and the gene for the TNF-alpha promoter region were determined by polymerase chain reaction (PCR) followed by restriction enzyme digestion. Genotyping of MICA was determined by PCR combined with fluorescent-based automated fragment detection technology. Results The allele frequencies showed no differences between patients and controls for the POU5F1 gene, MICA gene and the gene for TNF-alpha promoter region. The frequency of the HLA-Cw6 allele in the psoriasis group was significantly higher than that in the control group (18.6% vs. 6.56%, P < 0.00005). For the CDSN gene, patients were more likely to have C allele at position +619 (P = 0.006) and C allele at position +1243 (P = 0.007), but the significance disappeared after correction for multiple testing (Pc > 0.05). HLA-Cw6 remains the most significant susceptibility gene in Chinese patients with psoriasis. However, the role of the CDSN gene in the pathogenesis of psoriasis deserves further scrutiny.

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

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.