Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Desmoglein 1 deficiency results in severe dermatitis, multiple allergies and metabolic wasting

Nature Genetics volume 45, pages 1244–1248 (2013)Cite this article

Subjects

Abstract

The relative contribution of immunological dysregulation and impaired epithelial barrier function to allergic diseases is still a matter of debate. Here we describe a new syndrome featuring severe dermatitis, multiple allergies and metabolic wasting (SAM syndrome) caused by homozygous mutations in DSG1. DSG1 encodes desmoglein 1, a major constituent of desmosomes, which connect the cell surface to the keratin cytoskeleton and have a crucial role in maintaining epidermal integrity and barrier function. Mutations causing SAM syndrome resulted in lack of membrane expression of DSG1, leading to loss of cell-cell adhesion. In addition, DSG1 deficiency was associated with increased expression of a number of genes encoding allergy-related cytokines. Our deciphering of the pathogenesis of SAM syndrome substantiates the notion that allergy may result from a primary structural epidermal defect.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Clinical and pathological features.
Figure 2: Molecular and immunohistochemical analysis.
Figure 3: DSG1 and DSP expression in skin from affected individuals.
Figure 4: Electron microscopy.
Figure 5: Cytokine gene expression.

Similar content being viewed by others

Accession codes

Primary accessions

NCBI Reference Sequence

References

  1. Menon, G.K., Cleary, G.W. & Lane, M.E. The structure and function of the stratum corneum. Int. J. Pharm. 435, 3–9 (2012).

    Article  CAS  Google Scholar 

  2. Kubo, A., Nagao, K. & Amagai, M. Epidermal barrier dysfunction and cutaneous sensitization in atopic diseases. J. Clin. Invest. 122, 440–447 (2012).

    Article  CAS  Google Scholar 

  3. Simpson, C.L., Patel, D.M. & Green, K.J. Deconstructing the skin: cytoarchitectural determinants of epidermal morphogenesis. Nat. Rev. Mol. Cell Biol. 12, 565–580 (2011).

    Article  CAS  Google Scholar 

  4. Desai, B.V., Harmon, R.M. & Green, K.J. Desmosomes at a glance. J. Cell Sci. 122, 4401–4407 (2009).

    Article  CAS  Google Scholar 

  5. Amagai, M. & Stanley, J.R. Desmoglein as a target in skin disease and beyond. J. Invest. Dermatol. 132, 776–784 (2012).

    Article  CAS  Google Scholar 

  6. Oji, V. et al. Revised nomenclature and classification of inherited ichthyoses: results of the First Ichthyosis Consensus Conference in Soreze 2009. J. Am. Acad. Dermatol. 63, 607–641 (2010).

    Article  Google Scholar 

  7. Milingou, M., Wood, P., Masouye, I., McLean, W.H. & Borradori, L. Focal palmoplantar keratoderma caused by an autosomal dominant inherited mutation in the desmoglein 1 gene. Dermatology 212, 117–122 (2006).

    Article  CAS  Google Scholar 

  8. Rickman, L. et al. N-terminal deletion in a desmosomal cadherin causes the autosomal dominant skin disease striate palmoplantar keratoderma. Hum. Mol. Genet. 8, 971–976 (1999).

    Article  CAS  Google Scholar 

  9. Keren, H., Bergman, R., Mizrachi, M., Kashi, Y. & Sprecher, E. Diffuse nonepidermolytic palmoplantar keratoderma caused by a recurrent nonsense mutation in DSG1. Arch. Dermatol. 141, 625–628 (2005).

    Article  CAS  Google Scholar 

  10. Hershkovitz, D., Lugassy, J., Indelman, M., Bergman, R. & Sprecher, E. Novel mutations in DSG1 causing striate palmoplantar keratoderma. Clin. Exp. Dermatol. 34, 224–228 (2009).

    Article  CAS  Google Scholar 

  11. Bergman, R. et al. Disadhesion of epidermal keratinocytes: a histologic clue to palmoplantar keratodermas caused by DSG1 mutations. J. Am. Acad. Dermatol. 62, 107–113 (2010).

    Article  Google Scholar 

  12. Amagai, M., Ishii, K., Takayanagi, A., Nishikawa, T. & Shimizu, N. Transport to endoplasmic reticulum by signal peptide, but not proteolytic processing, is required for formation of conformational epitopes of pemphigus vulgaris antigen (Dsg3). J. Invest. Dermatol. 107, 539–542 (1996).

    Article  CAS  Google Scholar 

  13. Hanifin, J.M., Butler, J.M. & Chan, S.C. Immunopharmacology of the atopic diseases. J. Invest. Dermatol. 85, (suppl. 1) 161s–164s (1985).

    Article  CAS  Google Scholar 

  14. Sandilands, A. et al. Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema. Nat. Genet. 39, 650–654 (2007).

    Article  CAS  Google Scholar 

  15. Schuttelaar, M.L. et al. Filaggrin mutations in the onset of eczema, sensitization, asthma, hay fever and the interaction with cat exposure. Allergy 64, 1758–1765 (2009).

    Article  CAS  Google Scholar 

  16. Brown, S.J. et al. Filaggrin haploinsufficiency is highly penetrant and is associated with increased severity of eczema: further delineation of the skin phenotype in a prospective epidemiological study of 792 school children. Br. J. Dermatol. 161, 884–889 (2009).

    Article  CAS  Google Scholar 

  17. Chavanas, S. et al. Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome. Nat. Genet. 25, 141–142 (2000).

    Article  CAS  Google Scholar 

  18. Oji, V. et al. 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).

    Article  CAS  Google Scholar 

  19. Ishida-Yamamoto, A., Igawa, S. & Kishibe, M. Order and disorder in corneocyte adhesion. J. Dermatol. 38, 645–654 (2011).

    Article  Google Scholar 

  20. Hovnanian, A. Netherton syndrome: skin inflammation and allergy by loss of protease inhibition. Cell Tissue Res. 351, 289–300 (2013).

    Article  CAS  Google Scholar 

  21. Descargues, P. et al. Corneodesmosomal cadherins are preferential targets of stratum corneum trypsin- and chymotrypsin-like hyperactivity in Netherton syndrome. J. Invest. Dermatol. 126, 1622–1632 (2006).

    Article  CAS  Google Scholar 

  22. Descargues, P. et al. Spink5-deficient mice mimic Netherton syndrome through degradation of desmoglein 1 by epidermal protease hyperactivity. Nat. Genet. 37, 56–65 (2005).

    Article  CAS  Google Scholar 

  23. Getsios, S. et al. Desmoglein 1–dependent suppression of EGFR signaling promotes epidermal differentiation and morphogenesis. J. Cell Biol. 185, 1243–1258 (2009).

    Article  CAS  Google Scholar 

  24. Strid, J., Sobolev, O., Zafirova, B., Polic, B. & Hayday, A. The intraepithelial T cell response to NKG2D-ligands links lymphoid stress surveillance to atopy. Science 334, 1293–1297 (2011).

    Article  CAS  Google Scholar 

  25. Bonnart, C. et al. Elastase 2 is expressed in human and mouse epidermis and impairs skin barrier function in Netherton syndrome through filaggrin and lipid misprocessing. J. Clin. Invest. 120, 871–882 (2010).

    Article  CAS  Google Scholar 

  26. Incorvaia, C. et al. Allergy and the skin. Clin. Exp. Immunol. 153 (suppl. 1), 27–29 (2008).

    Article  CAS  Google Scholar 

  27. Leyva-Castillo, J.M., Hener, P., Jiang, H. & Li, M. TSLP produced by keratinocytes promotes allergen sensitization through skin and thereby triggers atopic march in mice. J. Invest. Dermatol. 133, 154–163 (2013).

    Article  CAS  Google Scholar 

  28. Petrof, G., Mellerio, J.E. & McGrath, J.A. Desmosomal genodermatoses. Br. J. Dermatol. 166, 36–45 (2012).

    Article  CAS  Google Scholar 

  29. Moskowitz, D.G. et al. Pathophysiologic basis for growth failure in children with ichthyosis: an evaluation of cutaneous ultrastructure, epidermal permeability barrier function, and energy expenditure. J. Pediatr. 145, 82–92 (2004).

    Article  CAS  Google Scholar 

  30. Fowler, A.J. et al. Nutritional status and gastrointestinal structure and function in children with ichthyosis and growth failure. J. Pediatr. Gastroenterol. Nutr. 38, 164–169 (2004).

    Article  Google Scholar 

  31. Sprecher, E. et al. The spectrum of pathogenic mutations in SPINK5 in 19 families with Netherton syndrome: implications for mutation detection and first case of prenatal diagnosis. J. Invest. Dermatol. 117, 179–187 (2001).

    Article  CAS  Google Scholar 

  32. Omori-Miyake, M. & Ziegler, S.F. Mouse models of allergic diseases: TSLP and its functional roles. Allergol. Int. 61, 27–34 (2012).

    Article  CAS  Google Scholar 

  33. Li, H. & Durbin, R. Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics 26, 589–595 (2010).

    Article  Google Scholar 

  34. McKenna, A. et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20, 1297–1303 (2010).

    Article  CAS  Google Scholar 

  35. Adzhubei, I.A. et al. A method and server for predicting damaging missense mutations. Nat. Methods 7, 248–249 (2010).

    Article  CAS  Google Scholar 

  36. Kumar, P., Henikoff, S. & Ng, P.C. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat. Protoc. 4, 1073–1081 (2009).

    Article  CAS  Google Scholar 

  37. Dusek, R.L. et al. The differentiation-dependent desmosomal cadherin desmoglein 1 is a novel caspase-3 target that regulates apoptosis in keratinocytes. J. Biol. Chem. 281, 3614–3624 (2006).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank S. Getsios for the use of the Zeiss Apotome. We thank D. Garrod (University of Manchester) for the kind gift of 11-5F antibody to DSP. We thank K. Stone (King's College London) for technical assistance in whole-exome sequencing. This work was supported by a generous donation of the Ram family to E.S.; US National Institutes of Health (NIH) grant RO1 AR041836 and the Joseph L. Mayberry Senior Endowment to K.J.G.; JSPS (Japan Society for the Promotion of Science) Kakenhi grant 24591620 and a grant from the Ministry of Health, Labor and Welfare of Japan to A.I.-Y.; DebRA (Dystrophic Epidermolysis Bullosa Research Association) UK to J.A.M.; the Wellcome Trust (programme grant 092530/Z/10/Z to W.H.I.M. and A.D.I. and bioresources grant 090066/B/09/Z to A.D.I. and W.H.I.M.); the National Children's Research Centre to A.D.I.; and the Pachyonychia Congenita Project to F.J.D.S. Some control sections were obtained from the Pathology Core of the Northwestern University Skin Disease Research Center (NIH grant P30AR057216). The Centre for Dermatology and Genetic Medicine at the University of Dundee is supported by a Wellcome Trust Strategic Award (098439/Z/12/Z to W.H.I.M.). L.S. is the recipient of an Excellence Award from the Tel Aviv Sourasky Medical Center.

Author information

Author notes

  1. Liat Samuelov, Ofer Sarig and Robert M Harmon: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

    Liat Samuelov, Ofer Sarig, Ilan Goldberg, Ori Eytan, Shamir Geller & Eli Sprecher

  2. Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

    Robert M Harmon, Jennifer L Koetsier & Kathleen J Green

  3. Department of Cell Research and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel

    Debora Rapaport & Mia Horowitz

  4. Department of Dermatology, Asahikawa Medical University, Asahikawa, Japan

    Akemi Ishida-Yamamoto

  5. Department of Cell and Developmental Biology, Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel

    Ofer Isakov & Noam Shomron

  6. Department of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

    Andrea Gat

  7. Department of Dermatology, Rambam Health Care Campus, Haifa, Israel

    Reuven Bergman

  8. Rappaport Faculty of Medicine, Technion–Israel Institute of Technology, Haifa, Israel

    Reuven Bergman, Ronen Spiegel & Sarit Peleg

  9. Institute of Human Genetics, Haemek Medical Center, Afula, Israel

    Ronen Spiegel

  10. Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel

    Ori Eytan & Eli Sprecher

  11. Pediatric Department B, Haemek Medical Center, Afula, Israel

    Sarit Peleg

  12. Pediatric Gastroenterology Unit, Haemek Medical Center, Afula, Israel

    Sarit Peleg

  13. Centre for Dermatology and Genetic Medicine, University of Dundee, Dundee, UK

    Christabelle S M Goh, Neil J Wilson, Frances J D Smith, Elizabeth Pohler & W H Irwin McLean

  14. Division of Genetics and Molecular Medicine, King's College London (Guy's Campus), London, UK

    Michael A Simpson

  15. Paediatric Dermatology, Our Lady's Children's Hospital Crumlin, Dublin, Ireland

    Alan D Irvine

  16. National Children's Research Centre, Our Lady's Children's Hospital Crumlin, Dublin, Ireland

    Alan D Irvine

  17. Clinical Medicine, Trinity College Dublin, Dublin, Ireland

    Alan D Irvine

  18. St. John's Institute of Dermatology, King's College London (Guy's Campus), London, UK

    John A McGrath

  19. Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

    Kathleen J Green

Authors
  1. Liat Samuelov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ofer Sarig
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Robert M Harmon
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Debora Rapaport
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Akemi Ishida-Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ofer Isakov
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jennifer L Koetsier
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Andrea Gat
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ilan Goldberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Reuven Bergman
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ronen Spiegel
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ori Eytan
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Shamir Geller
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Sarit Peleg
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Noam Shomron
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Christabelle S M Goh
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Neil J Wilson
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Frances J D Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Elizabeth Pohler
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Michael A Simpson
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. W H Irwin McLean
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Alan D Irvine
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Mia Horowitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. John A McGrath
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Kathleen J Green
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Eli Sprecher
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

K.J.G. and E.S. jointly supervised the project and conceived and designed the experiments. L.S., O.S., R.M.H., D.R., A.I.-Y., J.L.K., W.H.I.M. and A.D.I. participated in the design of the experiments. L.S., I.G., R.S., S.G. and S.P. contributed to the phenotypic characterization of the syndrome. R.S., O.E., S.G. and S.P. contributed to biological sample collection. J.A.M. conceived and designed the exome sequencing experiments. M.A.S. carried out exome sequencing. O.S., O.I. and N.S. performed variant calling and biostatistical analysis of the exome sequencing data with contributions from M.A.S. L.S., O.S., C.S.M.G., N.J.W., F.J.D.S. and E.P. performed direct sequencing with assistance from O.E. L.S. performed PCR-RFLP. L.S. and O.S. performed RT-PCR experiments. M.H. conceived and designed the cell culture immunostaining experiments. L.S. and O.S. generated cell lines from affected individuals. L.S., R.M.H., D.R. and J.L.K. performed immunostaining of skin biopsies. A.I.-Y. performed the electron microscopic analysis of skin biopsies. A.G. performed the histopathological analysis of skin biopsies with contributions from I.G. and R.B. L.S., O.S., R.M.H., D.R., R.B., C.S.M.G., N.J.W., F.J.D.S., E.P., W.H.I.M., A.D.I., M.H., J.A.M., K.J.G. and E.S. analyzed the data. L.S., O.S., R.M.H., W.H.I.M., A.D.I., J.A.M., K.J.G. and E.S. participated in the writing of the manuscript. O.S., F.J.D.S., W.H.I.M., A.D.I., M.H., J.A.M., K.J.G. and E.S. supervised the research program.

Corresponding authors

Correspondence to Kathleen J Green or Eli Sprecher.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4, Supplementary Tables 1–3 and Supplementary Note (PDF 793 kb)

Supplementary Data 1

Supplementary data set for Supplementary Figure 4 (XLSX 9 kb)

Source data

Rights and permissions

Reprints and permissions

About this article

Cite this article

Samuelov, L., Sarig, O., Harmon, R. et al. Desmoglein 1 deficiency results in severe dermatitis, multiple allergies and metabolic wasting. Nat Genet 45, 1244–1248 (2013). https://doi.org/10.1038/ng.2739

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.2739

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing