Mutations in desmoglein 1 cause diverse inherited palmoplantar keratoderma phenotypes: implications for genetic screening

Summary The inherited palmoplantar keratodermas (PPKs) are a heterogeneous group of genodermatoses, characterized by thickening of the epidermis of the palms and soles. No classification system satisfactorily unites clinical presentation, pathology and molecular pathogenesis. There are four patterns of hyperkeratosis – striate, focal, diffuse and punctate. Mutations in the desmoglein 1 gene (DSG1), a transmembrane glycoprotein, have been reported primarily in striate, but also in focal and diffuse PPKs. We report seven unrelated pedigrees with dominantly inherited PPK owing to mutations in the DSG1 gene, with marked phenotypic variation. Genomic DNA from each family was isolated, and individual exons amplified by polymerase chain reaction. Sanger sequencing was employed to identify mutations. Mutation analysis identified novel mutations in five families (p.Tyr126Hisfs*2, p.Ser521Tyrfs*2, p.Trp3*, p.Asp591Phefs*9 and p.Met249Ilefs*6) with striate palmar involvement and varying focal or diffuse plantar disease, and the recurrent mutation c.76C>T, p.Arg26*, in two families with variable PPK patterns. We report one recurrent and five novel DSG1 mutations, causing varying patterns of PPK, highlighting the clinical heterogeneity arising from mutations in this gene. What's already known about this topic? Twenty‐three mutations in the desmoglein 1 gene (DSG1) have been described in 25 families with palmoplantar keratoderma (PPK). The majority have striate palmar involvement with focal plantar keratoderma, but isolated focal and diffuse PPKs have been reported. What does this study add? DSG1 mutations can present with variable phenotype within the same family. Environmental factors, such as manual labour, may alter the clinical appearance of PPK. A lower threshold should be considered for DSG1 screening in nonstriate PPK where an underlying keratin mutation has not been identified.