The identification and characterisation of the causative gene mutation for keratolytic winter erythema (KWE) in South African families
Date
2017
Authors
Ngcungcu, Thandiswa
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Keratolytic winter erythema (KWE) is a rare autosomal dominant skin disorder characterized
by recurrent episodes of palmoplantar erythema and epidermal peeling, and symptoms
worsen in winter. KWE is relatively common in South African (SA) Afrikaners and was
mapped to 8p23.1-p22 through a common haplotype in SA families. The aim of this study
was to identify and characterize the causal mutation for KWE in SA families.
Targeted resequencing of 8p23.1-22 was performed in three families and seven unrelated
controls. Reads were aligned to the reference genome using BWA. GATK and Pindel were
used to call small and large structural variants, respectively. A 7.67 kb tandem duplication
was identified upstream of the CTSB gene and encompassing an enhancer element that is
active in a keratinocytes (based on H3K27ac data). The tandem duplication segregated
completely with the KWE. The tandem duplication overlaps with a 15.93 kb tandem
duplication identified in two Norwegian families at a 2.62 kb region encompassing the active
enhancer suggesting that the duplication of the enhancer leads to the KWE phenotype.
Existing chromatin structure, CTCF binding and chromatin interaction data from several cell
lines, including keratinocytes were analysed and three potential topological subdomains
were identified, all containing the enhancer and CTSB, or CTSB and FDFT1 or both genes and
NEIL2. Additionally, we showed that the enhancer’s activity correlated with CTSB expression,
but not with FDFT1 and NEIL2 expression in differentiating keratinocytes and other cell lines.
RNA polymerase II ChIA-PET interaction data in cancer cell lines showed that the enhancer
interacts with CTSB but not FDFT1 or NEIL2. These data suggest that the enhancer normally
regulates CTSB expression. Relative gene expression and immunohistochemistry from
palmar biopsies from South African and Norwegian participants (7 Affected and 7 Controls)
showed a significantly higher expression of CTSB, but not FDFT1 and NEIL2, in affected
individuals compared to the controls and that CTSB was significantly more abundant in the
granular layer of affected individuals compared to controls. We conclude that the enhancer
duplication causes KWE by upregulating CTSB expression and causing an overabundance of
CTSB in the granular layer of the epidermis.
Description
A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand,
Johannesburg, in fulfilment for the degree of Doctor of Philosophy
Johannesburg, 2017
Keywords
Citation
Ngcungcu, Thandiswa Goodness (2017) The identification and characterisation of the causative gene mutation for keratolytic winter erythema (KWE) in South African families, University of the Witwatersrand, Johannesburg, http://hdl.handle.net/10539/23084