Functional rare and low frequency variants in BLK and BANK1 contribute to human lupus.

TitleFunctional rare and low frequency variants in BLK and BANK1 contribute to human lupus.
Publication TypeJournal Article
Year of Publication2019
AuthorsJiang SH, Athanasopoulos V, Ellyard JI, Chuah A, Cappello J, Cook A, Prabhu SB, Cardenas J, Gu J, Stanley M, Roco JA, Papa I, Yabas M, Walters GD, Burgio G, McKeon K, Byers JM, Burrin C, Enders A, Miosge LA, Canete PF, Jelusic M, Tasic V, Lungu AC, Alexander SI, Kitching AR, Fulcher DA, Shen N, Arsov T, Gatenby PA, Babon JJ, Mallon DF, Collantes Cde Lucas, Stone EA, Wu P, Field MA, Andrews TD, Cho E, Pascual V, Cook MC, Vinuesa CG
JournalNat Commun
Date Published2019 05 17
KeywordsAdaptor Proteins, Signal Transducing, Adolescent, Adult, Animals, B-Lymphocytes, Case-Control Studies, Cell Line, Cell Nucleus, Child, Disease Models, Animal, Female, Gene Frequency, Genetic Predisposition to Disease, Healthy Volunteers, HEK293 Cells, Humans, Interferon Regulatory Factors, Interferon Type I, Lupus Erythematosus, Systemic, Male, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Missense, src-Family Kinases, Whole Exome Sequencing

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.

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Alternate JournalNat Commun
PubMed ID31101814
PubMed Central IDPMC6525203

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