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; Bjørn 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 Nirmala; Thomas M. Morgan; Hans van Bokhoven; Vidar M. Steen; Peter R. Hull; Joseph Szustakowski; Frank Staedtler; Huiqing Zhou; Torunn Fiskerstrand; Michele Ramsay

doi:10.1016/j.ajhg.2017.03.012

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, Bjørn 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

Medicine

Résultat de recherche: Article › examen par les pairs

29 Citations (Scopus)

Résumé

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.

Langue d'origine	English
Pages (de-à)	737-750
Nombre de pages	14
Journal	American Journal of Human Genetics
Volume	100
Numéro de publication	5
DOI	https://doi.org/10.1016/j.ajhg.2017.03.012
Statut de publication	Published - mai 4 2017

Note bibliographique

Funding Information:
The authors wish to thank all the participants of this joint study. Technical assistance from Rita Holdhus, Jorunn Bringsli, Hilde Eldevik Rusaas, Atle Brendehaug, Anita Fernandez, Virginie Petitjean, Marc Altorfer, and Moritz Frei and contributions from Jayne Hehir-Kwa, Christian Gilissen, Alexander Hoischen, Kjell Petersen, Shaun Aron, Karen Koch, and Laeeka Moosa were highly appreciated. The South African study was supported by the South African Medical Research Council, the National Research Foundation, the University of the Witwatersrand, and the National Health Laboratory Service. The South African next-generation sequencing (NGS) study was funded by the Novartis Next Generation Scientist Program, and T.N. was supported by this program and the Novartis Visiting Scholars Program. M.R. is a South African Research Chair in Genomics and Bioinformatics of African populations, which is hosted by the University of the Witwatersrand, funded by the Department of Science and Technology, and administered by the National Research Foundation of South Africa. The Norwegian NGS study was performed by the Genomics Core Facility at the University of Bergen and supported by a grant from the Bergen Research Foundation (807964), including funding of the postdoctoral scholarship of T.S.

Publisher Copyright:
© 2017 American Society of Human Genetics

ASJC Scopus Subject Areas

Genetics
Genetics(clinical)

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10.1016/j.ajhg.2017.03.012

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Ngcungcu, T., Oti, M., Sitek, J. C., Haukanes, B. I., Linghu, B., Bruccoleri, R., Stokowy, T., Oakeley, E. J., Yang, F., Zhu, J., Sultan, M., Schalkwijk, J., van Vlijmen-Willems, I. M. J. J., von der Lippe, C., Brunner, H. G., Ersland, K. M., Grayson, W., Buechmann-Moller, S., Sundnes, O., ... Ramsay, M. (2017). Duplicated Enhancer Region Increases Expression of CTSB and Segregates with Keratolytic Winter Erythema in South African and Norwegian Families. American Journal of Human Genetics, 100(5), 737-750. https://doi.org/10.1016/j.ajhg.2017.03.012

Ngcungcu, T, Oti, M, Sitek, JC, Haukanes, BI, Linghu, B, Bruccoleri, R, Stokowy, T, Oakeley, EJ, Yang, F, Zhu, J, Sultan, M, Schalkwijk, J, van Vlijmen-Willems, IMJJ, von der Lippe, C, Brunner, HG, Ersland, KM, Grayson, W, Buechmann-Moller, S, Sundnes, O, Nirmala, N, Morgan, TM, van Bokhoven, H, Steen, VM, Hull, PR, Szustakowski, J, Staedtler, F, Zhou, H, Fiskerstrand, T & Ramsay, M 2017, 'Duplicated Enhancer Region Increases Expression of CTSB and Segregates with Keratolytic Winter Erythema in South African and Norwegian Families', American Journal of Human Genetics, vol. 100, n° 5, pp. 737-750. https://doi.org/10.1016/j.ajhg.2017.03.012

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title = "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.",

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

note = "Funding Information: The authors wish to thank all the participants of this joint study. Technical assistance from Rita Holdhus, Jorunn Bringsli, Hilde Eldevik Rusaas, Atle Brendehaug, Anita Fernandez, Virginie Petitjean, Marc Altorfer, and Moritz Frei and contributions from Jayne Hehir-Kwa, Christian Gilissen, Alexander Hoischen, Kjell Petersen, Shaun Aron, Karen Koch, and Laeeka Moosa were highly appreciated. The South African study was supported by the South African Medical Research Council, the National Research Foundation, the University of the Witwatersrand, and the National Health Laboratory Service. The South African next-generation sequencing (NGS) study was funded by the Novartis Next Generation Scientist Program, and T.N. was supported by this program and the Novartis Visiting Scholars Program. M.R. is a South African Research Chair in Genomics and Bioinformatics of African populations, which is hosted by the University of the Witwatersrand, funded by the Department of Science and Technology, and administered by the National Research Foundation of South Africa. The Norwegian NGS study was performed by the Genomics Core Facility at the University of Bergen and supported by a grant from the Bergen Research Foundation (807964), including funding of the postdoctoral scholarship of T.S. Publisher Copyright: {\textcopyright} 2017 American Society of Human Genetics",

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doi = "10.1016/j.ajhg.2017.03.012",

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T1 - Duplicated Enhancer Region Increases Expression of CTSB and Segregates with Keratolytic Winter Erythema in South African and Norwegian Families

AU - Ngcungcu, Thandiswa

AU - Oti, Martin

AU - Sitek, Jan C.

AU - Haukanes, Bjørn I.

AU - Linghu, Bolan

AU - Bruccoleri, Robert

AU - Stokowy, Tomasz

AU - Oakeley, Edward J.

AU - Yang, Fan

AU - Zhu, Jiang

AU - Sultan, Marc

AU - Schalkwijk, Joost

AU - van Vlijmen-Willems, Ivonne M.J.J.

AU - von der Lippe, Charlotte

AU - Brunner, Han G.

AU - Ersland, Kari M.

AU - Grayson, Wayne

AU - Buechmann-Moller, Stine

AU - Sundnes, Olav

AU - Nirmala, Nanguneri

AU - Morgan, Thomas M.

AU - van Bokhoven, Hans

AU - Steen, Vidar M.

AU - Hull, Peter R.

AU - Szustakowski, Joseph

AU - Staedtler, Frank

AU - Zhou, Huiqing

AU - Fiskerstrand, Torunn

AU - Ramsay, Michele

N1 - Funding Information: The authors wish to thank all the participants of this joint study. Technical assistance from Rita Holdhus, Jorunn Bringsli, Hilde Eldevik Rusaas, Atle Brendehaug, Anita Fernandez, Virginie Petitjean, Marc Altorfer, and Moritz Frei and contributions from Jayne Hehir-Kwa, Christian Gilissen, Alexander Hoischen, Kjell Petersen, Shaun Aron, Karen Koch, and Laeeka Moosa were highly appreciated. The South African study was supported by the South African Medical Research Council, the National Research Foundation, the University of the Witwatersrand, and the National Health Laboratory Service. The South African next-generation sequencing (NGS) study was funded by the Novartis Next Generation Scientist Program, and T.N. was supported by this program and the Novartis Visiting Scholars Program. M.R. is a South African Research Chair in Genomics and Bioinformatics of African populations, which is hosted by the University of the Witwatersrand, funded by the Department of Science and Technology, and administered by the National Research Foundation of South Africa. The Norwegian NGS study was performed by the Genomics Core Facility at the University of Bergen and supported by a grant from the Bergen Research Foundation (807964), including funding of the postdoctoral scholarship of T.S. Publisher Copyright: © 2017 American Society of Human Genetics

PY - 2017/5/4

Y1 - 2017/5/4

N2 - 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.

AB - 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.

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AN - SCOPUS:85018186492

SN - 0002-9297

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JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

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ER -

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

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