The present invention relates to methods and pharmaceutical composition for the treatment of inflammatory skin diseases associated with desmoglein-1 deficiency. The inventors show, for the first time, that the structural protein DSG1 directly acts as a novel and unexpected inhibitor of epithelial inflammation via the inhibition of NF-κB signaling pathway. In particular, the present invention relates to a method of treating an inflammatory skin disease associated with desmoglein-1 deficiency in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an agent capable of restoring the expression of desmogelin-1. Particularly, the inventors carried out the whole exome sequencing, histopathological, electron microscopy, immunofluorescence and immunological analyses in two unrelated patients presenting with SAMEC syndrome.