Keratolytic winter erythema (KWE) is a rare autosomal-dominant skin disorder characterized by recurrent episodes of palmoplantar erythema and epidermal peeling. KWE was previously mapped to 8p23.1-p22 (KWE critical region) in South African families. Using targeted resequencing of the KWE critical region in five South African families and SNP array and whole-genome sequencing in two Norwegian families, we identified two overlapping tandem duplications of 7.67 kb (South Africans) and 15.93 kb (Norwegians). The duplications segregated with the disease and were located upstream of CTSB, a gene encoding cathepsin B, a cysteine protease involved in keratinocyte homeostasis. Included in the 2.62 kb overlapping region of these duplications is an enhancer element that is active in epidermal keratinocytes. The activity of this enhancer correlated with CTSB expression in normal differentiating keratinocytes and other cell lines, but not with FDFT1 or NEIL2 expression. Gene expression (qPCR) analysis and immunohistochemistry of the palmar epidermis demonstrated significantly increased expression of CTSB, as well as stronger staining of cathepsin B in the stratum granulosum of affected individuals than in that of control individuals. Analysis of higher-order chromatin structure data and RNA polymerase II ChIA-PET data from MCF-7 cells did not suggest remote effects of the enhancer. In conclusion, KWE in South African and Norwegian families is caused by tandem duplications in a non-coding genomic region containing an active enhancer element for CTSB, resulting in upregulation of this gene in affected individuals.

Keratolytic winter erythema (KWE) is a rare autosomal dominant keratoderma affecting primarily the palms and soles, manifesting with recurrent waves of erythema followed by epidermal peeling. The condition is so named in view of its anecdotal worsening during the winter months. It is highly penetrant but shows considerable individual clinical variability, waning and reappearing throughout the life course. Histologically, early established lesions of KWE manifest with degenerative changes involving the Malpighian layer, with associated absence of the stratum granulosum. The damaged zone undergoes parakeratotic transformation and subsequent centrifugal ejection. Thick peeling occurs when the stratum corneum eventually separates off as a result of a keratolytic split occurring above, through or below the parakeratotic zone. Reconstitution of the stratum granulosum ensues. KWE is caused by a duplication of an intergenic enhancer element upstream of the cathepsin B gene on chromosome 8. This leads to the upregulation of cathepsin B in the stratum granulosum and subsequent peeling of the epidermis as the end result. With elucidation of the molecular pathology of KWE, new therapeutic approaches to KWE may be considered.

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