Alternative titles; symbols
HGNC Approved Gene Symbol: CDSN
SNOMEDCT: 717256009, 724838009;
Cytogenetic location: 6p21.33 Genomic coordinates (GRCh38): 6:31,115,087-31,120,446 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p21.33 | Hypotrichosis 2 | 146520 | Autosomal dominant | 3 |
| Peeling skin syndrome 1 | 270300 | Autosomal recessive | 3 |
Corneodesmosin is an extracellular glycoprotein essential for maintaining desmosome integrity in the epidermal upper layers, proper development and function of the skin barrier in adult skin, and normal hair follicle formation (summary by Telem et al., 2012).
Corneodesmosomes are intercellular structures that are involved in desquamation, the shedding of superficial corneocytes from the skin surface. Corneocytes are anucleated cells derived from keratinocytes during the late stages of terminal differentiation of cornified squamous epithelia such as the epidermis. Using monoclonal antibodies raised against plantar stratum corneum, Serre et al. (1991) identified corneodesmosin, a protein in corneodesmosomes. Simon et al. (1997) found that corneodesmosin has an isoelectric point higher than 8 and migrates as a 52- to 56-kD protein on Western blots.
During an analysis of the class I region of the HLA complex (see 142800), Zhou and Chaplin (1993) identified a gene that is located approximately 160 kb telomeric to HLA-C (142840) at 6p21.3 (see PSORS1; 177900). Since the gene was expressed only in skin, they designated it the 'S gene.' In situ hybridization showed that S gene expression is restricted to the differentiating keratinocytes in the granular layer of the epidermis. By Northern blotting, the S gene is expressed as 2.2- and 2.6-kb mRNAs. The S gene contains 2 exons which encode a predicted 486-amino acid protein, including a putative 16-amino acid signal sequence. The S protein shows homology to loricrin (152445), keratin-1 (139350), and keratin-10 (148080), all major components of the granular layer. Partial amino acid sequencing of corneodesmosin indicated that it is probably encoded by the S gene (Simon et al., 1997).
Holm et al. (2003) determined that the CDSN gene contains 2 exons and spans 4.5 kb.
The CDSN gene is located approximately 160 kb telomeric to HLA-C on chromosome 6p21.3 (Zhou and Chaplin, 1993).
Holm et al. (2003) reported that both exons of the CDSN gene are located within intron 1 of the SEEK1 gene (613525), which lies on the opposite strand.
Psoriasis
Psoriasis is an inflammatory skin disease of unknown origin, but with a clear genetic component. The strongest genetic association is with the major histocompatibility complex (MHC) region, and specifically between susceptibility to familial early-onset psoriasis and HLA-Cw6 (PSORS1; 177900). The basis of this association of HLA-C was not clear, and it was possible that other genes, or a combination of genes, in the HLA region are of functional importance. The CDSN gene is expressed specifically in keratinocyte differentiation and, being located 160 kb telomeric of HLA-C, was a plausible candidate gene. Tazi Ahnini et al. (1999) analyzed the allelic distribution of 2 polymorphisms in the CDSN gene (at +619 and +1243) in a case-control association study. They confirmed a significant association between psoriasis and HLA-Cw6 (odds ratio = 7.75). No association was found between disease (or any subtype) and the CDSN gene polymorphism at position +619, despite its close proximity to HLA-C and the strong linkage disequilibrium between the loci. However, a significant trend with the rarer allele at CDSN (+1243) and psoriasis was detected in the overall data set (odds ratio = 2.66). This effect was most pronounced in type 1a (early-onset) psoriasis (odds ratio = 3.43). Furthermore, homozygosity for the +1243 allele associated with psoriasis increased the risk of disease over that for carriage of HLA-Cw6 alone (odds ratio = 9.38), suggesting that allele 2 of CDSN provides an additional risk in psoriasis susceptibility. The strong association found by Tazi Ahnini et al. (1999), coupled with the biologic involvement of the CDSN gene product, corneodesmosin, in skin physiology, implicated this locus (or a haplotype across HLA-C and CDSN) in the impaired desquamation characteristic of psoriasis.
Asumalahti et al. (2000) used association and haplotype analysis to study a cohort of 142 Finnish psoriasis patients within 100 families. The HLA-Cw*0602 allele was associated with a strong relative risk, but association analysis did not support CDSN*5 (defined by +619T and +1243C) as a psoriasis susceptibility allele in their sample.
In 52 Caucasian nuclear families with chronic stable early-onset psoriasis, each with 1 affected child, Schmitt-Egenolf et al. (2001) tested for locus interaction using the HLA haplotype EH-57.1/I and the CDSN haplotype formed by 3 intragenic variant sites at nucleotides 619 (T), 1236 (T), and 1243 (C). On direct comparison of their contributions, the corneodesmosin TTC haplotype was more closely associated with psoriasis than EH-57.1/I by 1 order of magnitude, and there was no higher order interaction between psoriasis, HLA, and CDSN. Schmitt-Egenolf et al. (2001) suggested that there are 2 independent genetic contributions to psoriasis within the MHC.
Capon et al. (2004) showed that mRNAs transcribed from a CDSN risk haplotype presented a 2-fold increase in stability compared with mRNAs transcribed from a neutral haplotype (P = 0.004). Site-directed mutagenesis revealed that a single synonymous SNP (CDSN*971T) accounted for the observed increase in RNA stability. CDSN*971T mapped to an RNA stability motif, and UV crosslinking analysis demonstrated that the SNP affected the transcript affinity for a 39-kD RNA-binding protein. Association analyses show that haplotypes bearing CDSN*971T conferred psoriasis susceptibility in a wide range of ethnic groups.
Orru et al. (2005) undertook fine mapping of the PSORS1 locus (177900) in the major histocompatibility complex at 6p21.3. They set up a study using 17 polymorphic markers in a 525-kb interval around the HLA-C locus. The results uncovered 5 loci with alleles strongly associated with psoriasis, all structured in a psoriasis-susceptibility haplotype (PSH). Subsequent analysis of extended haplotypes showed that the PSH was not only present in the traditional psoriasis-susceptibility extended haplotypes but also on a haplotype of Sardinian origin found to be associated with psoriasis because of an ancestral recombination with one of the susceptibility haplotypes carrying a particular HLA-C allele. Comparisons of the regions identical by descent among associated and nonassociated haplotypes highlighted a minimum region of 70 kb not recombinant with PSORS1, surrounding the CDSN gene.
Hypotrichosis Simplex of Scalp
In 3 families with autosomal dominant hypotrichosis simplex of the scalp (HYPT2; 146520) in which the disorder had been mapped to chromosome 6p21.3 (Betz et al., 2000; Kohn and Metzker, 1987; Levy-Nissenbaum et al., 2003), Levy-Nissenbaum et al. (2003) identified heterozygous mutations in the CDSN gene (602593.0001-602593.0002). Relative to the possibility that corneodesmosin may be involved in the pathogenesis of psoriasis, Levy-Nissenbaum et al. (2003) pointed out that none of the individuals with HYPT2 showed clinical signs of psoriasis or any other skin abnormalities.
Peeling Skin Syndrome 1
In a large consanguineous Roma family from Germany with generalized skin peeling, pruritus, and atopy mapping to chromosome 6p21 (PSS1; 270300), Oji et al. (2010) analyzed the functional candidate gene CDSN and identified homozygosity for a nonsense mutation (K59X; 602593.0003). The mutation segregated with disease in the family and was not found in 220 ethnically matched chromosomes. Oji et al. (2010) generated 3-dimensional skin models and demonstrated that lack of corneodesmosin causes an epidermal barrier defect, which they suggested accounted for the predisposition to atopic disease.
In a Jewish man with generalized pruritic skin peeling, Israeli et al. (2011) sequenced the CDSN gene and identified homozygosity for a 1-bp deletion (c.746delG; 602593.0004).
In a 10-month-old Ashkenazi Jewish boy with widespread patchy peeling of the skin, Telem et al. (2012) identified homozygosity for a 4-bp duplication in the CDSN gene (c.164dupGCCT; 602593.0005); his unaffected parents were heterozygous for the mutation.
In a 50-year-old Caucasian woman with widespread skin peeling and erythema, Mallet et al. (2013) identified homozygosity for a nonsense mutation in the CDSN gene (G142X; 602593.0006); her 2 healthy children were heterozygous for the mutation.
Matsumoto et al. (2008) found that while Cdsn +/- mice showed no hair or skin phenotypes, Cdsn -/- mice died within several hours after birth with skin defects consistent with dehydration caused by defective skin barrier function. Cdsn-null mouse skin showed detachment of the stratum corneum from the underlying granular layer and/or detachment within the upper granular layers due to disrupted integrity of corneodesmosomes. When grafted onto immunodeficient mice, Cdsn-null skin showed rapid hair loss together with epidermal abnormalities resembling psoriasis.
In 2 families with hypotrichosis simplex of the scalp (HYPT2; 146520), a Spanish family reported by Betz et al. (2000) and an Israeli family of Yemenite origin reported by Kohn and Metzker (1987), Levy-Nissenbaum et al. (2003) identified a heterozygous gln215-to-ter (Q215X) mutation in the CDSN gene. Haplotype analysis showed that the mutation arose on a different genetic background in each family.
In a Dutch family with hypotrichosis simplex of the scalp (HYPT2; 146520) reported by Betz et al. (2000), Levy-Nissenbaum et al. (2003) identified a heterozygous gln200-to-ter (Q200X) mutation in the CDSN gene.
In 2 brothers and a distantly related boy and girl with generalized skin peeling and pruritus (PSS1; 270300) from a large consanguineous Roma family from Germany, Oji et al. (2010) identified homozygosity for a 175A-T transversion in exon 2 of the CDSN gene, resulting in a lys59-to-ter (K59X) substitution. family members who were heterozygous carriers of the K59X mutation showed no skin or hair phenotype. Analysis of primary keratinocytes from 1 of the brothers showed a 75% reduction of CDSN mRNA, indicative of nonsense-mediated decay, and immunoblot analysis confirmed the absence of corneodesmosin in that patient's primary keratinocytes. Antigen mapping of corneodesmosin was negative for all patient skin biopsies.
In a 32-year-old Jewish man with generalized pruritic skin peeling (PSS1; 270300), Israeli et al. (2011) identified homozygosity for a 1-bp deletion (c.746delG) in exon 2 of the CDSN gene, causing a frameshift predicted to result in a premature termination codon (Gly249ValfsTer40). The mutation was not found in 50 population-matched controls; the mutation status of his unaffected first-cousin parents and an affected sister was not reported.
In a 10-month-old Ashkenazi Jewish boy with widespread patchy peeling of the skin (PSS1; 270300), Telem et al. (2012) identified homozygosity for a 4-bp duplication (c.164dupGCCT) in the CDSN gene, causing a frameshift predicted to result in a premature termination codon (Thr57ProfsTer6). His unaffected parents were heterozygous for the duplication, which was not found in 50 Ashkenazi Jewish controls. A patient skin biopsy showed absence of corneodesmosin expression in the granular layers, in contrast to control skin. Haplotype analysis revealed that the disease-associated maternal and paternal haplotypes were identical, suggesting that the parents may have inherited the duplication from a common ancestor.
In a 50-year-old Caucasian woman with widespread skin peeling and erythema (PSS1; 270300), who was originally described by Mevorah et al. (1987), Mallet et al. (2013) identified homozygosity for a c.424G-T transversion in exon 2 of the CDSN gene, resulting in a gly142-to-ter (G142X) substitution within the N-terminal glycine loop domain. Her 2 healthy children were heterozygous for the mutation. Quantitative RT-PCR analysis revealed that not only was mutant mRNA not degraded in patient skin, it was also 2-fold more abundant than wildtype CDSN mRNA in control skin. Western blot analysis showed that the truncated protein was present in patient skin, but was 22-fold less abundant than full-length corneodesmosin in control skin; full-length protein was not detected in patient skin.
Asumalahti, K., Laitinen, T., Itkonen-Vatjus, R., Lokki, M.-L., Suomela, S., Snellman, E., Saarialho-Kere, U., Kere, J. A candidate gene for psoriasis near HLA-C, HCR (Pg8), is highly polymorphic with a disease-associated susceptibility allele. Hum. Molec. Genet. 9: 1533-1542, 2000. Note: Erratum: Hum. Molec. Genet. 10: 301 only, 2001. [PubMed: 10888604] [Full Text: https://doi.org/10.1093/hmg/9.10.1533]
Betz, R. C., Lee, Y.-A., Bygum, A., Brandrup, F., Bernal, A. I., Toribio, J., Alvarez, J. I., Kukuk, G. M., Ibsen, H. H. W., Rasmussen, H. B., Wienker, T. F., Reis, A., Propping, P., Kruse, R., Cichon, S., Nothen, M. M. A gene for hypotrichosis simplex of the scalp maps to chromosome 6p21.3. Am. J. Hum. Genet. 66: 1979-1983, 2000. [PubMed: 10793007] [Full Text: https://doi.org/10.1086/302934]
Capon, F., Allen, M. H., Ameen, M., Burden, A. D., Tillman, D., Barker, J. N., Trembath, R. C. A synonymous SNP of the corneodesmosin gene leads to increased mRNA stability and demonstrates association with psoriasis across diverse ethnic groups. Hum. Molec. Genet. 13: 2361-2368, 2004. [PubMed: 15333584] [Full Text: https://doi.org/10.1093/hmg/ddh273]
Holm, S. J., Carlen, L. M., Mallbris, L., Stahle-Backdahl, M., O'Brien, K. P. Polymorphisms in the SEEK1 and SPR1 genes on 6p21.3 associate with psoriasis in the Swedish population. Exp. Derm. 12: 435-444, 2003. [PubMed: 12930300] [Full Text: https://doi.org/10.1034/j.1600-0625.2003.00048.x]
Israeli, S., Zamir, H., Sarig, O., Bergman, R., Sprecher, E. Inflammatory peeling skin syndrome caused by a mutation in CDSN encoding corneodesmosin. (Letter) J. Invest. Derm. 131: 779-781, 2011. [PubMed: 21191406] [Full Text: https://doi.org/10.1038/jid.2010.363]
Kohn, G., Metzker, A. Hereditary hypotrichosis simplex of the scalp. Clin. Genet. 32: 120-124, 1987. [PubMed: 3652491] [Full Text: https://doi.org/10.1111/j.1399-0004.1987.tb03338.x]
Levy-Nissenbaum, E., Betz, R. C., Frydman, M., Simon, M., Lahat, H., Bakhan, T., Goldman, B., Bygum, A., Pierick, M., Hillmer, A. M., Jonca, N., Toribio, J., Kruse, R., Dewald, G., Cichon, S., Kubisch, C., Guerrin, M., Serre, G., Nothen, M. M., Pras, E. Hypotrichosis simplex of the scalp is associated with nonsense mutations in CDSN encoding corneodesmosin. Nature Genet. 34: 151-153, 2003. [PubMed: 12754508] [Full Text: https://doi.org/10.1038/ng1163]
Mallet, A., Kypriotou, M., George, K., Leclerc, E., Rivero, D., Mazereeuw-Hautier, J., Serre, G., Huber, M., Jonca, N., Hohl, D. Identification of the first nonsense CDSN mutation with expression of a truncated protein causing peeling skin syndrome type B. Brit. J. Derm. 169: 1322-1325, 2013. [PubMed: 23957618] [Full Text: https://doi.org/10.1111/bjd.12593]
Matsumoto, M., Zhou, Y., Matsuo, S., Nakanishi, H., Hirose, K., Oura, H., Arase, S., Ishida-Yamamoto, A., Bando, Y., Izumi, K., Kiyonari, H., Oshima, N., Nakayama, R., Matsushima, A., Hirota, F., Mouri, Y., Kuroda, N., Sano, S., Chaplin, D. D. Targeted deletion of the murine corneodesmosin gene delineates its essential role in skin and hair physiology. Proc. Nat. Acad. Sci. 105: 6720-6724, 2008. [PubMed: 18436651] [Full Text: https://doi.org/10.1073/pnas.0709345105]
Mevorah, B., Frenk, E., Saurat, J. H., Siegenthaler, G. Peeling skin syndrome: a clinical, ultrastructural and biochemical study. Brit. J. Derm. 116: 117-125, 1987. [PubMed: 2434123] [Full Text: https://doi.org/10.1111/j.1365-2133.1987.tb05799.x]
Oji, V., Eckl, K.-M., Aufenvenne, K., Natebus, M., Tarinski, T., Ackermann, K., Seller, N., Metze, D., Nurnberg, G., Folster-Holst, R., Schafer-Korting, M., Hausser, I., Traupe, H., Hennies, H. C. Loss of corneodesmosin leads to severe skin barrier defect, pruritus, and atopy: unraveling the peeling skin disease. Am. J. Hum. Genet. 87: 274-281, 2010. [PubMed: 20691404] [Full Text: https://doi.org/10.1016/j.ajhg.2010.07.005]
Orru, S., Giuressi, E., Carcassi, C., Casula, M., Contu, L. Mapping of the major psoriasis-susceptibility locus (PSORS1) in a 70-kb interval around the corneodesmosin gene (CDSN). Am. J. Hum. Genet. 76: 164-171, 2005. [PubMed: 15529278] [Full Text: https://doi.org/10.1086/426948]
Schmitt-Egenolf, M., Windemuth, C., Hennies, H. C., Albis-Camps, M., von Engelhardt, B., Wienker, T., Reis, A., Traupe, H., Blasczyk, R. Comparative association analysis reveals that corneodesmosin is more closely associated with psoriasis than HLA-Cw*0602-B*5701 in German families. Tissue Antigens 57: 440-446, 2001. [PubMed: 11556968] [Full Text: https://doi.org/10.1034/j.1399-0039.2001.057005440.x]
Serre, G., Mils, V., Haftek, M., Vincent, C., Croute, F., Reano, A., Ouhayoun, J.-P., Bettinger, S., Soleilhavoup, J.-P. Identification of late differentiation antigens of human cornified epithelia, expressed in re-organized desmosomes and bound to cross-linked envelope. J. Invest. Derm. 97: 1061-1072, 1991. [PubMed: 1748816] [Full Text: https://doi.org/10.1111/1523-1747.ep12492589]
Simon, M., Montezin, M., Guerrin, M., Durieux, J.-J., Serre, G. Characterization and purification of human corneodesmosin, an epidermal basic glycoprotein associated with corneocyte-specific modified desmosomes. J. Biol. Chem. 272: 31770-31776, 1997. [PubMed: 9395522] [Full Text: https://doi.org/10.1074/jbc.272.50.31770]
Tazi Ahnini, R. T., Camp, N. J., Cork, M. J., Mee, J. B., Keohane, S. G., Duff, G. W., di Giovine, F. S. Novel genetic association between the corneodesmosin (MHC S) gene and susceptibility to psoriasis. Hum. Molec. Genet. 8: 1135-1140, 1999. Note: Erratum: Hum. Molec. Genet. 9: 659 only, 2000. [PubMed: 10332047] [Full Text: https://doi.org/10.1093/hmg/8.6.1135]
Telem, D. F., Israeli, S., Sarig, O., Sprecher, E. Inflammatory peeling skin syndrome caused a novel mutation in CDSN. Arch. Derm. Res. 304: 251-255, 2012. [PubMed: 22146835] [Full Text: https://doi.org/10.1007/s00403-011-1195-z]
Zhou, Y., Chaplin, D. D. Identification in the HLA class I region of a gene expressed late in keratinocyte differentiation. Proc. Nat. Acad. Sci. 90: 9470-9474, 1993. [PubMed: 8415725] [Full Text: https://doi.org/10.1073/pnas.90.20.9470]