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

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• 作者：Maeve A. McAleer ; MB ; MRCP^a ; ^b ; ^c ; Elizabeth Pohler ; PhD^d ; Frances J.D. Smith ; PhD^d ; Neil J. Wilson ; MSc^d ; Christian Cole ; PhD^e ; Stuart MacGowan ; PhD^e ; Jennifer L. Koetsier ; BS^f ; Lisa M. Godsel ; PhD^f ; ^g ; Robert M. Harmon ; PhD^f ; Robert Gruber ; MD^h ; Debra Crumrine ; BSⁱ ; Peter M. Elias ; MDⁱ ; Michael McDermott ; FRCPath^c ; Karina Butler ; FRCPI^j ; Annemarie Broderick ; MRCPI^k ; Ofer Sarig ; PhD^l ; ^m ; Eli Sprecher ; MD ; PhD^k ; ^l ; ^m ; Kathleen J. Green ; PhD^f ; ^g ; W.H. Irwin McLean ; PhD ; DSc ; FRS ; FRSE ; FMedSci^d ; Alan D. Irvine ; MD^a ; ^b ; ^c ; ^{irvinea@tcd.ie" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Atopy ; skin barrier ; atopic dermatitis ; desmosome ; desmoplakin ; atopic sensitization ; eosinophilic esophagitis
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2015
• 出版时间：November 2015
• 年：2015
• 卷：136
• 期：5
• 页码：1268-1276
• 全文大小：4599 K

文摘

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.