Dataset Information

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

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.

SUBMITTER: Ngcungcu T

PROVIDER: S-EPMC5420352 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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

Ngcungcu Thandiswa T Oti Martin M Sitek Jan C JC Haukanes Bjørn I BI Linghu Bolan B Bruccoleri Robert R Stokowy Tomasz T Oakeley Edward J EJ Yang Fan F Zhu Jiang J Sultan Marc M Schalkwijk Joost J van Vlijmen-Willems Ivonne M J J IMJJ von der Lippe Charlotte C Brunner Han G HG Ersland Kari M KM Grayson Wayne W Buechmann-Moller Stine S Sundnes Olav O Nirmala Nanguneri N Morgan Thomas M TM van Bokhoven Hans H Steen Vidar M VM Hull Peter R PR Szustakowski Joseph J Staedtler Frank F Zhou Huiqing H Fiskerstrand Torunn T Ramsay Michele M

American journal of human genetics 20170427 5

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 (Nor ...[more]

PMID: 28457472

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Project description:BACKGROUND: Large scale gene analysis of most organisms is hampered by incomplete genomic sequences. In many organisms, such as soybean, the best source of sequence information is the existence of expressed sequence tag (EST) libraries. Soybean has a large (1115 Mbp) genome that has yet to be fully sequenced. However it does have the 6th largest EST collection comprised of ESTs from a variety of soybean genotypes. Many EST libraries were constructed from RNA extracted from various genetic backgrounds, thus gene identification from these sources is complicated by the existence of both gene and allele sequence differences. We used the ESTminer suite of programs to identify potential soybean gene transcripts from a single genetic background allowing us to observe functional classifications between gene families as well as structural differences between genes and gene paralogs within families. The identification of potential gene sequences (pHaps) from soybean allows us to begin to get a picture of the genomic history of the organism as well as begin to observe the evolutionary fates of gene copies in this highly duplicated genome. RESULTS: We identified approximately 45,000 potential gene sequences (pHaps) from EST sequences of Williams/Williams82, an inbred genotype of soybean (Glycine max L. Merr.) using a redundancy criterion to identify reproducible sequence differences between related genes within gene families. Analysis of these sequences revealed single base substitutions and single base indels are the most frequently observed form of sequence variation between genes within families in the dataset. Genomic sequencing of selected loci indicate that intron-like intervening sequences are numerous and are approximately 220 bp in length. Functional annotation of gene sequences indicate functional classifications are not randomly distributed among gene families containing few or many genes. CONCLUSION: The predominance of single nucleotide insertion/deletions and substitution events between genes within families (individual genes and gene paralogs) is consistent with a model of gene amplification followed by single base random mutational events expected under the classical model of duplicated gene evolution. Molecular functions of small and large gene families appear to be non-randomly distributed possibly indicating a difference in retention of duplicates or local expansion.

Dataset Information

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

Publications

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

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