Severe dermatitis, multiple allergies, and metabolic wasting syndrome caused by a novel mutation in the N-terminal plakin domain of desmoplakin

Maeve A. McAleer, Elizabeth Pohler, Frances J.D. Smith, Neil J. Wilson, Christian Cole, Stuart Macgowan, Jennifer L. Koetsier, Lisa M. Godsel, Robert M. Harmon, Robert Gruber, Debra Crumrine, Peter M. Elias, Michael McDermott, Karina Butler, Annemarie Broderick, Ofer Sarig, Eli Sprecher, Kathleen J. Green, W. H.Irwin McLean, Alan D. Irvine*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

Abstract

Background Severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome is a recently recognized syndrome caused by mutations in the desmoglein 1 gene (DSG1). To date, only 3 families have been reported. Objective We studied a new case of SAM syndrome known to have no mutations in DSG1 to detail the clinical, histopathologic, immunofluorescent, and ultrastructural phenotype and to identify the underlying molecular mechanisms in this rare genodermatosis. Methods Histopathologic, electron microscopy, and immunofluorescent studies were performed. Whole-exome sequencing data were interrogated for mutations in desmosomal and other skin structural genes, followed by Sanger sequencing of candidate genes in the patient and his parents. Results No mutations were identified in DSG1; however, a novel de novo heterozygous missense c.1757A>C mutation in the desmoplakin gene (DSP) was identified in the patient, predicting the amino acid substitution p.His586Pro in the desmoplakin polypeptide. Conclusions SAM syndrome can be caused by mutations in both DSG1 and DSP. Knowledge of this genetic heterogeneity is important for both analysis of patients and genetic counseling of families. This condition and these observations reinforce the importance of heritable skin barrier defects, in this case desmosomal proteins, in the pathogenesis of atopic disease.

Original languageEnglish (US)
Pages (from-to)1268-1276
Number of pages9
JournalJournal of Allergy and Clinical Immunology
Volume136
Issue number5
DOIs
StatePublished - Mar 4 2015

Keywords

  • Atopy
  • atopic dermatitis
  • atopic sensitization
  • desmoplakin
  • desmosome
  • eosinophilic esophagitis
  • skin barrier

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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