Jiang, Simon H. and Athanasopoulos, Vicki and Ellyard, Julia I. and Chuah, Aaron and Cappello, Jean and Cook, Amelia and Prabhu, Savit B. and Cardenas, Jacob and Gu, Jinghua and Stanley, Maurice and Roco, Jonathan A. and Papa, Ilenia and Yabas, Mehmet and Walters, Giles D. and Burgio, Gaetan and McKeon, Kathryn and Byers, James M. and Burrin, Charlotte and Enders, Anselm and Miosge, Lisa A. and Canete, Pablo F. and Jelušić, Marija and Tasic, Velibor and Lungu, Adrian C. and Alexander, Stephen I. and Kitching, Arthur R. and Fulcher, David A. and Shen, Nan and Arsov, Todor and Gatenby, Paul A. and Babon, Jeff J. and Mallon, Dominic F. and de Lucas Collantes, Carmen and Stone, Eric A. and Wu, Philip and Field, Matthew A. and Andrews, Thomas D. and Cho, Eun and Pascual, Virginia and Cook, Matthew C. and Vinuesa, Carola G. (2019) Functional rare and low frequency variants in BLK and BANK1 contribute to human lupus. Nature Communications, 10 (1). ISSN 2041-1723
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Abstract
Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease. It is thought that many common variant gene loci of weak effect act additively to predispose to common autoimmune diseases, while the contribution of rare variants remains unclear. Here we describe that rare coding variants in lupus-risk genes are present in most SLE patients and healthy controls. We demonstrate the functional consequences of rare and low frequency missense variants in the interacting proteins BLK and BANK1, which are present alone, or in combination, in a substantial proportion of lupus patients. The rare variants found in patients, but not those found exclusively in controls, impair suppression of IRF5 and type-I IFN in human B cell lines and increase pathogenic lymphocytes in lupus-prone mice. Thus, rare gene variants are common in SLE and likely contribute to genetic risk.
| Item Type: | Article | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Additional Information: | Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| MeSH: | Adaptor Proteins, Signal Transducing / genetics * Adaptor Proteins, Signal Transducing / metabolism ; Adolescent ; Adult ; Animals ; B-Lymphocytes / cytology ; B-Lymphocytes / immunology ; B-Lymphocytes / metabolism ; Case-Control Studies ; Cell Line ; Cell Nucleus / immunology ; Cell Nucleus / metabolism ; Child ; Disease Models, Animal ; Female ; Gene Frequency ; Genetic Predisposition to Disease ; HEK293 Cells ; Healthy Volunteers ; Humans ; Interferon Regulatory Factors / immunology ; Interferon Regulatory Factors / metabolism ; Interferon Type I / immunology ; Interferon Type I / metabolism ; Lupus Erythematosus, Systemic / blood ; Lupus Erythematosus, Systemic / genetics ; Lupus Erythematosus, Systemic / immunology ; Male ; Membrane Proteins / genetics ; Membrane Proteins / metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mutation, Missense ; Whole Exome Sequencing ; src-Family Kinases / genetics ; src-Family Kinases / metabolism | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Departments: | Katedra za pedijatriju | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Depositing User: | Kristina Berketa | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Status: | Published | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Date: | 17 May 2019 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Date Deposited: | 12 Feb 2020 11:21 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Last Modified: | 12 Feb 2020 11:21 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Subjects: | / | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| URI: | http://medlib.mef.hr/id/eprint/3569 |
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