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.

• Authors: J Mohamad, L Samuelov, L Malki, A Peled, M Pavlovsky, K Malovitski, S Taiber, N Adir, T Rabinowitz, N Shomron, J D Milner, G Lestringant, O Sarig, E Sprecher
• Journal: Clinical and experimental dermatology (Clin Exp Dermatol) Vol. 46 Issue 1 Pg. 103-108 (Jan 2021) ISSN: 1365-2230 [Electronic] England
• PMID: 32683719 (Publication Type: Case Reports, Journal Article)
• Copyright: © 2020 British Association of Dermatologists.

Chemical References

• CTSB protein, human
• Cathepsin B

Topics

• Adult
• Cathepsin B (genetics, ultrastructure)
• Female
• Humans
• Keratoderma, Palmoplantar (genetics, pathology)
• Male
• Molecular Structure
• Mutation, Missense
• Pedigree
• Skin (pathology)
• Exome Sequencing