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

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

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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.

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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.

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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

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  1. Liat Samuelov
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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.

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The authors declare no competing financial interests.

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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

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