Epithelial barrier dysfunction in desmoglein-1 deficiency

Laura Polivka¹, Smail Hadj-Rabia¹, Elodie Bal², Stéphanie Leclerc-Mercier³, Marine Madrange², Yamina Hamel², Damien Bonnet⁴, Stéphanie Mallet⁵, Hubert Lepidi⁶, Caroline Ovaert⁷, Patrick Barbet⁸, Christophe Dupont⁹, Bénédicte Neven¹⁰, Arnold Munnich¹¹, Lisa M Godsel¹², Florence Campeotto¹³, Robert Weil¹⁴, Emmanuel Laplantine¹⁴, Sylvie Marchetto¹⁵, Jean-Paul Borg¹⁵, William I Weis¹⁶, Jean-Laurent Casanova¹⁷, Anne Puel¹⁸, Kathleen J Green¹², Christine Bodemer¹⁹, Asma Smahi²⁰

Affiliations

¹ Department of Dermatology, Reference Center for Genodermatoses (MAGEC), Necker-Enfants Malades Hospital (AP-HP), Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Laboratory of Genetics of Monogenic Auto-inflammatory Diseases, Necker Branch, U1163, Necker-Enfants Malades Hospital (AP-HP), Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
² Laboratory of Genetics of Monogenic Auto-inflammatory Diseases, Necker Branch, U1163, Necker-Enfants Malades Hospital (AP-HP), Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
³ Department of Dermatology, Reference Center for Genodermatoses (MAGEC), Necker-Enfants Malades Hospital (AP-HP), Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Department of Pathology, Necker-Enfants Malades Hospital (AP-HP), Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
⁴ M3C-Necker, Pediatric Reference Center for Inherited Cardiac Diseases, Necker-Enfants Malades Hospital (AP-HP), Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
⁵ Department of Dermatology, La Timone Hospital (AP-HM), Aix Marseille University, Marseille, France.
⁶ Department of Pathology, La Timone Hospital (AP-HM), Aix Marseille University, Marseille, France.
⁷ Department of Pediatric Cardiology, La Timone Hospital (AP-HM), Aix Marseille University, Marseille, France.
⁸ Department of Pathology, Necker-Enfants Malades Hospital (AP-HP), Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
⁹ Department of Pediatric Gastroenterology, Hepatology and Nutrition, Necker-Enfants Malades Hospital (AP-HP), Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
¹⁰ Department of Pediatric Immunology and Hematology, Necker-Enfants Malades Hospital (AP-HP), Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
¹¹ Laboratory of Molecular and Pathophysiological Basis of Cognitive Disorders, U1163, Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Necker-Enfants Malades Hospital, Paris, France.
¹² Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Ill; Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Ill.
¹³ Department of Paediatric Gastroenterology, Necker-Enfants Malades Hospital (AP-HP), Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
¹⁴ Laboratory of Signaling and Pathogenesis, Centre National de la Recherche Scientifique, UMR3691, Pasteur Institute, Paris, France.
¹⁵ Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille University, UM105, Inst Paoli-Calmettes, CNRS, UMR7258, Inserm, U1068, "Cell Polarity, Cell Signalling, and Cancer-Equipe Labellisée Ligue Contre le Cancer," Marseille, France.
¹⁶ Departments of Structural Biology, Molecular & Cellular Physiology and Photon Science, Stanford University, Stanford, Calif.
¹⁷ Department of Pediatric Immunology and Hematology, Necker-Enfants Malades Hospital (AP-HP), Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France; Paris Descartes University, Imagine Institute, Paris, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY; Howard Hughes Medical Institute, New York, NY.
¹⁸ Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France; Paris Descartes University, Imagine Institute, Paris, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY; Howard Hughes Medical Institute, New York, NY.
¹⁹ Department of Dermatology, Reference Center for Genodermatoses (MAGEC), Necker-Enfants Malades Hospital (AP-HP), Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Laboratory of Genetics of Monogenic Auto-inflammatory Diseases, Necker Branch, U1163, Necker-Enfants Malades Hospital (AP-HP), Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France. Electronic address: christine.bodemer@aphp.fr.
²⁰ Laboratory of Genetics of Monogenic Auto-inflammatory Diseases, Necker Branch, U1163, Necker-Enfants Malades Hospital (AP-HP), Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France. Electronic address: asma.smahi@inserm.fr.

PMID: 29705242
PMCID: PMC6078820
DOI: 10.1016/j.jaci.2018.04.007

Case Reports

Epithelial barrier dysfunction in desmoglein-1 deficiency

Laura Polivka et al. J Allergy Clin Immunol. 2018 Aug.

. 2018 Aug;142(2):702-706.e7.

doi: 10.1016/j.jaci.2018.04.007. Epub 2018 Apr 27.

Authors

Affiliations

¹ Department of Dermatology, Reference Center for Genodermatoses (MAGEC), Necker-Enfants Malades Hospital (AP-HP), Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Laboratory of Genetics of Monogenic Auto-inflammatory Diseases, Necker Branch, U1163, Necker-Enfants Malades Hospital (AP-HP), Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
² Laboratory of Genetics of Monogenic Auto-inflammatory Diseases, Necker Branch, U1163, Necker-Enfants Malades Hospital (AP-HP), Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
³ Department of Dermatology, Reference Center for Genodermatoses (MAGEC), Necker-Enfants Malades Hospital (AP-HP), Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Department of Pathology, Necker-Enfants Malades Hospital (AP-HP), Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
⁴ M3C-Necker, Pediatric Reference Center for Inherited Cardiac Diseases, Necker-Enfants Malades Hospital (AP-HP), Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
⁵ Department of Dermatology, La Timone Hospital (AP-HM), Aix Marseille University, Marseille, France.
⁶ Department of Pathology, La Timone Hospital (AP-HM), Aix Marseille University, Marseille, France.
⁷ Department of Pediatric Cardiology, La Timone Hospital (AP-HM), Aix Marseille University, Marseille, France.
⁸ Department of Pathology, Necker-Enfants Malades Hospital (AP-HP), Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
⁹ Department of Pediatric Gastroenterology, Hepatology and Nutrition, Necker-Enfants Malades Hospital (AP-HP), Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
¹⁰ Department of Pediatric Immunology and Hematology, Necker-Enfants Malades Hospital (AP-HP), Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
¹¹ Laboratory of Molecular and Pathophysiological Basis of Cognitive Disorders, U1163, Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Necker-Enfants Malades Hospital, Paris, France.
¹² Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Ill; Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Ill.
¹³ Department of Paediatric Gastroenterology, Necker-Enfants Malades Hospital (AP-HP), Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
¹⁴ Laboratory of Signaling and Pathogenesis, Centre National de la Recherche Scientifique, UMR3691, Pasteur Institute, Paris, France.
¹⁵ Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille University, UM105, Inst Paoli-Calmettes, CNRS, UMR7258, Inserm, U1068, "Cell Polarity, Cell Signalling, and Cancer-Equipe Labellisée Ligue Contre le Cancer," Marseille, France.
¹⁶ Departments of Structural Biology, Molecular & Cellular Physiology and Photon Science, Stanford University, Stanford, Calif.
¹⁷ Department of Pediatric Immunology and Hematology, Necker-Enfants Malades Hospital (AP-HP), Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France; Paris Descartes University, Imagine Institute, Paris, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY; Howard Hughes Medical Institute, New York, NY.
¹⁸ Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France; Paris Descartes University, Imagine Institute, Paris, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY; Howard Hughes Medical Institute, New York, NY.
¹⁹ Department of Dermatology, Reference Center for Genodermatoses (MAGEC), Necker-Enfants Malades Hospital (AP-HP), Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Laboratory of Genetics of Monogenic Auto-inflammatory Diseases, Necker Branch, U1163, Necker-Enfants Malades Hospital (AP-HP), Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France. Electronic address: christine.bodemer@aphp.fr.
²⁰ Laboratory of Genetics of Monogenic Auto-inflammatory Diseases, Necker Branch, U1163, Necker-Enfants Malades Hospital (AP-HP), Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France. Electronic address: asma.smahi@inserm.fr.

PMID: 29705242
PMCID: PMC6078820
DOI: 10.1016/j.jaci.2018.04.007

No abstract available

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Conflict of interest statement

Disclosure of potential conflict of interest: J.-L. Casanova reports personal fees from Genentech, Sanofi, Novartis, Pfizer, Bioaster, Regeneron, BiogenIdec, and Merck outside the submitted work. The rest of the authors declare that they have no relevant conflicts of interest.

Figures

**FIG 1**
Clinical and histopathologic features of patients 1 and 2. A, Clinical phenotype of patient 1: desquamative erythroderma, thickening of the skin *(a–e)*, sparse hair *(a)*, diffuse palmoplantar keratoderma (*PPK; b* and c), and thickening of the nail plate (d and e). B, Clinical phenotype of patient 2: desquamative erythroderma *(a)*, sparse hair (a and b), onycholysis *(c)*, and plantar keratoderma *(d)*. C, Skin histology (patient 1) showing epidermal acanthosis, hyperorthokeratosis, extensive acantholysis *(inset)*, and inflammation in the superficial dermis (lymphocytes; ×100 magnification for Fig 1, C, and ×200 magnification for the *inset* of Fig 1, C). D, Ultrastructural features of a skin biopsy specimen from patient 1 (a, b, and d) and a healthy control subject *(c). a*, Many desmosomes clustered in the upper epidermis *(arrows)*. Keratin filaments strongly aggregated to the desmosome *(inset). b*, Complete absence of desmosomes and widened spaces between keratinocytes (cell membrane features filipodium-like processes; *inset*) in the lower epidermis. d, Patient 1’s desmosome lacks the inner plaque compared with a control subject (*arrow*, c). Scale bar = 2 μm for Fig 1, D, a and b. Scale bar = 500 nm for the *inset* of Fig 1, D, a, and 1 μm for the *inset* of Fig 1, D, b. E, Immunofluorescence on skin sections from a healthy control subject *(a–c)*, patient 1 *(d–f)*, and patient 2 *(g–i)* showed drastic reduction and mislocalization in staining of DSP and DSG1 in both patients. Scale bar =20 μM. F, Immunofluorescence on esophageal sections from a healthy control subject *(a–c)* and patient 1 *(d–f)*, showing low levels of DSP staining and absence of DSG1 staining in patient 1. Scale bar = 20 μM.

**FIG 2**
Role of DSG1 and ERBIN in NF-κB–mediated epithelial inflammation. A, Relative mRNA expression levels of proinflammatory cytokines in primary keratinocytes (patient 1). B, NF-κB luciferase reporter assay in HEK293T cells transfected with DSG1 vector or with an empty vector and stimulated with IL-1β or TNF-α. AU, Arbitrary units. *Inset*, Western blot of DSG1 expression in HEK293T cells transfected with DSG1 vector. C, Relative mRNA expression of *IL8 (a)*, *IL6 (b)*, *IL1B (c)*, *TNFA (d)*, and *TSLP (e)* in control *(ctrl)* keratinocytes infected with a lentivirus-expressing short hairpin RNA against *DSG1* and stimulated or not stimulated *(NS)* with IL-1β. D, Relative mRNA expression of patient 1’s keratinocytes infected with a retrovirus expressing FLAG *DSG1. Inset*, Western blot of DSG1 and FLAG expression in patient 1’s keratinocytes after transduction. E, NF-κB luciferase reporter assay in HEK293T cells transfected with ERBIN or empty vector and stimulated with IL-1β. *Inset*, Western blot of *ERBIN* expression in HEK293T cells transfected with the ERBIN vector. F, Relative mRNA expression levels of *IL1B* and *IL6* in nonstimulated *Erbin*^+/+ and *Erbin*^−/− keratinocytes. G, Relative mRNA expression levels of *IL1B* in *Erbin*^+/+ and *Erbin*^−/− MEFs before/after stimulation with LPS. H, Immunoblot assays showing degradation of IκBα proteins in *Erbin*^+/+ and *Erbin*^−/− MEFs induced by IL-1β stimulation. *P < .05, **P < .01, and ***P < .001.

See this image and copyright information in PMC

References

1. Samuelov L, Sarig O, Harmon RM, Rapaport D, Ishida-Yamamoto A, Isakov O, et al. Desmoglein 1 deficiency results in severe dermatitis, multiple allergies and metabolic wasting. Nat Genet. 2013;45:1244–8. - PMC - PubMed
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Epithelial barrier dysfunction in desmoglein-1 deficiency

Affiliations

Epithelial barrier dysfunction in desmoglein-1 deficiency

Authors

Affiliations

Conflict of interest statement

Figures

References

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MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

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