Jiang, SimonAthanasopoulos, VickiEllyard, JuliaChuah, Lay HongCappello, JeanCook, AmeliaPrabhu, SavitCardenas, JacobGu, JinghuaStanley, MauriceRoco Alegre, JonathanPapa, IleniaYabas, MehmetWalters, GilesBurgio, GaetanMcKeon, KathrynByers, JamesBurrin, CharlotteEnders, AnselmMiosge, LisaCanete, PabloJelusic, MarijaTasic, VeliborLungu, Adrian C.Alexander, StephenKitching, ArthurFulcher, DavidShen, NanArsov, TodorGatenby, PaulBabon, Jeffrey J.Mallon, Dominic F.de Lucas Collantes, CarmenStone, EricWu, PhilipField, MatthewAndrews, Thomas (Dan)Cho, EunPascual, VirginiaCook, MatthewGarcia De Vinuesa, Maria Carola2020-04-282020-04-2820411723http://hdl.handle.net/1885/203442Systemic 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.FLAG-TRAF6 was a gift from Robert Brink and plasmids for BANK1 were a kind gift from Casamiro CastillejoLopez. RACP Jacquot NHMRC Award for Excellence, Jacquot Research Entry Scholarship, and NHMRC project grants to SHJ. NHMRC Program and project grants, and Elizabeth Blackburn Fellowship to CGV. This research/project was undertaken with the assistance of resources and services from the National Computational Infrastructure (NCI), which is supported by the Australian Government. This research and generation of CRISPR mice were also supported by funding of the Australian Government’s National Collaborative Research Infrastructure Strategy to the Australian Phenomics Facility and Bioplatforms Australia.12 pagesapplication/pdfen-AU© The Author(s) 2019https://creativecommons.org/licenses/by/4.0/2019-05-1710.1038/s41467-019-10242-92023-10-22This 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/.