DSG3 Deficiency in a Patient with Suprabasal Acantholytic Blisters in Oral and Laryngeal Mucosa

Jong Hoon Kim1, Song-Ee Kim1, Hae Seok Park1, Si-Hyung Lee1, Sang Eun Lee1, Soo-Chan Kim1*
1Department of Dermatology and Cutaneous Biology Research Institute, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
kimsc@yuhs.ac


Introduction : Desmoglein (DSG) 3, encoded by DSG3 gene, is the major component of desmosomes which contribute to cell-cell adhesion in epidermis. Development of autoimmunity against DSG3 causes mucosal type of pemphigus vulgaris which is characterized by suprabasal acantholytic blisters limited to the mucosa, however, mutations in DSG3 gene to cause human disorder have not been found so far. 

Objective : Here, we report a novel DSG3 mutation as a cause of inherited blistering disease affecting oral mucosa.

Methods : A 1 year-old female baby presented with recurrent erosions in the oral and laryngeal mucosa since birth. Whole genome sequencing (WGS) was performed using the blood sample of the patient. Mutation and restriction fragment length polymorphisms (RFLP) analysis was conducted with the genomic DNA of her and her family. Enzyme-linked immunosorbent assay (ELISA) was examined with her serum. H&E staining, immunofluorescence (IF) staining, and electron microscopic examination were analyzed using her skin and mucosal tissues. Immunoblotting was performed using primary keratinocyte from her skin and mucosa.

Results : Her conjunctival and genital mucosa is spared and her hair was normally growing. Histological examination of skin biopsy showed suprabasal acantholytic blisters. Direct and indirect IF and ELISA for DSG1 and DSG3 were negative. WGS from her DNA identified a homozygous nonsense c.859C>T DSG3 mutation which is expected to result in premature termination of protein translation in the third extracellular cadherin domain of DSG3 (p.R287*). Direct sequencing and RFLP analysis of affected family revealed that the mutation is hereditary. In the IF studies using the skin and oral mucosa and immunoblotting studies using primary cultured keratinocytes, loss of DSG3 was detected in the epidermis of the skin and oral mucosa. 

Conclusion : We describe a new hereditary disease caused by an autosomal-recessive homozygous nonsense mutation in DSG3.