Palmoplantar keratoderma caused by a missense variant in CTSB encoding cathepsin B

BACKGROUND Palmoplantar keratoderma (PPK) refers to a large group of disorders characterized by extensive genetic and phenotypic heterogeneity. PPK diagnosis therefore increasingly relies upon genetic analysis. AIM We aimed at delineating the genetic defect underlying a case of diffuse erythematous PPK associated with peeling of the skin. METHODS Whole exome and direct sequencing, RT-qPCR, protein modeling and a cathepsin B enzymatic assay were used. RESULTS We studied an individual with severe diffuse erythematous palmoplantar keratoderma transgrediens. Pedigree analysis suggested an autosomal dominant mode of inheritance. Whole exome sequencing revealed a heterozygous missense mutation in the CTSB gene, encoding the cysteine protease cathepsin B. Genomic duplications in a non-coding region which regulates the expression of CTSB, were recently found to cause erythrokeratolysis hiemalis (EH), a rare autosomal dominant disorder of cornification. The mutation affects a highly conserved residue and is predicted to be pathogenic. Protein modelling indicated that the mutation is likely to lead to increased endopeptidase cathepsin B activity. Accordingly, the CTSB variant was found to result in increased cathepsin B proteolytic activity. CONCLUSIONS In summary, we report the identification of the first gain-of-function missense mutation in CTSB, which was found to be associated in one individual with a dominant form of diffuse palmoplantar keratoderma.