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Am J Hum Genet. 2017 May 4;100(5):737-750. doi: 10.1016/j.ajhg.2017.03.012. Epub 2017 Apr 27.

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

Author information

1
Division of Human Genetics, School of Pathology and the Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa.
2
Department of Molecular Developmental Biology, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen 6525 GA, the Netherlands; Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.
3
Department of Dermatology, Oslo University Hospital, Oslo 0424, Norway; Centre for Rare Disorders, Oslo University Hospital, Oslo 0424, Norway.
4
Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen 5021, Norway.
5
Computational Biomedicine, WRD Genome Sciences & Technologies, Pfizer Worldwide R&D, Cambridge, MA 02139, USA.
6
Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA; Congenomics, Glastonbury, CT 06033, USA.
7
Department of Clinical Science, University of Bergen, Bergen 5020, Norway.
8
Novartis Institutes for BioMedical Research, Basel 4056, Switzerland.
9
Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
10
Department of Dermatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen 6525 GA, the Netherlands.
11
Centre for Rare Disorders, Oslo University Hospital, Oslo 0424, Norway.
12
Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen 6525 GA, the Netherlands; Maastricht UMC, Department of Clinical Genetics and School for Oncology and Developmental Biology (GROW), Maastricht 6202 AZ, the Netherlands.
13
Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen 5021, Norway; Department of Clinical Science, University of Bergen, Bergen 5020, Norway.
14
School of Pathology, Faculty of Health Sciences, University of the Witwatersrand and Ampath National Laboratories, Johannesburg 2193, South Africa.
15
Department of Dermatology, Oslo University Hospital, Oslo 0424, Norway; Laboratory for Immunohistochemistry and Immunopathology, Department of Pathology, Oslo University Hospital, Oslo 0424, Norway.
16
Institute for Clinical Research and Policy Studies, Tufts University School of Medicine, Boston, MA 02111, USA.
17
Department of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen 6525 GA, the Netherlands.
18
Division of Clinical Dermatology and Cutaneous Science, Dalhousie University, Halifax, NS B3H 1V7, Canada.
19
Translational Medicine, Bristol-Myers Squibb, Pennington, NJ 08534, USA.
20
Department of Molecular Developmental Biology, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen 6525 GA, the Netherlands; Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen 6525 GA, the Netherlands.
21
Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen 5021, Norway; Department of Clinical Science, University of Bergen, Bergen 5020, Norway. Electronic address: torunn.fiskerstrand@helse-bergen.no.
22
Division of Human Genetics, School of Pathology and the Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa. Electronic address: michele.ramsay@wits.ac.za.

Abstract

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.

KEYWORDS:

CTSB; KWE; Norway; South Africa; autosomal-dominant trait; enhancer duplication; gene regulation; keratoderma; keratolytic winter erythema; topological domains

PMID:
28457472
PMCID:
PMC5420352
DOI:
10.1016/j.ajhg.2017.03.012
[Indexed for MEDLINE]
Free PMC Article

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