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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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

    • Liat Samuelov
    • , Ofer Sarig
    •  & Robert M Harmon

    These authors contributed equally to this work.

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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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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Kathleen J Green or Eli Sprecher.

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DOI

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

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