Duplicated Enhancer Region Increases Expression of CTSB and Segregates with Keratolytic Winter Erythema in South African and Norwegian Families

Thandiswa Ngcungcu, Martin Oti, Jan C. Sitek, Bjorn I. Haukanes, Bolan Linghu, Robert Bruccoleri, Tomasz Stokowy, Edward J. Oakeley, Fan Yang, Jiang Zhu, Marc Sultan, Joost Schalkwijk, Ivonne M. J. J. van Vlijmen-Willems, Charlotte von der Lippe, Han G. Brunner, Kari M. Ersland, Wayne Grayson, Stine Buechmann-Moller, Olav Sundnes, Nanguneri NirmalaThomas M. Morgan, Hans van Bokhoven, Vidar M. Steen, Peter R. Hull, Joseph Szustakowski, Frank Staedtler, Huiqing Zhou, Torunn Fiskerstrand*, Michele Ramsay*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

24 Citations (Web of Science)


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.

Original languageEnglish
Pages (from-to)737-750
Number of pages14
JournalAmerican Journal of Human Genetics
Issue number5
Publication statusPublished - 4 May 2017


  • GENE

Cite this