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

Abstract

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. To delineate the genetic defect underlying a case of diffuse erythematous PPK associated with peeling of the skin. Methods. Whole exome and direct sequencing, real-time quantitative PCR, protein modelling and a cathepsin B enzymatic assay were used. Results. The patient studied had severe diffuse erythematous PPK 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 noncoding region, which regulates the expression of CTSB, were recently found to cause erythrokeratolysis hiemalis, a rare autosomal dominant disorder of cornification. This 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. Conclusion. 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 PPK.

Cathepsin B Gene Knockout Improves Behavioral Deficits and Reduces Pathology in Models of Neurologic Disorders

“…Palmoplantar keratoderma (PPK) is a heterogeneous group of keratinization skin disorders classified as sporadic or genetically inherited forms, with the latter caused by a plethora of mutations in many genes (reviewed in Schiller et al, 2014). A genetic analysis of the CTSB gene was conducted in a patient with PPK who presented with a KWE-like phenotype, finding a mutation in the CTSB gene that caused the disease (Mohamad et al, 2021). A family pedigree analysis suggested an autosomal dominant mode of gene inheritance in the disease, and gene sequencing found a single nucleotide mutation in the CTSB gene that resulted in substitution of a methionine residue for valine at position 255 at the active site.…”