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

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  • Additional Information
    • Source:
      Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
    • Publication Information:
      Original Publication: [London] : Nature Pub. Group
    • Subject Terms:
      Genetic Predisposition to Disease*; Adaptor Proteins, Signal Transducing/*genetics ; Lupus Erythematosus, Systemic/*genetics ; Membrane Proteins/*genetics ; src-Family Kinases/*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 ; 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/immunology ; Male ; Membrane Proteins/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mutation, Missense ; Exome Sequencing ; src-Family Kinases/metabolism
    • 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.
    • Comments:
      Comment in: Nat Rev Rheumatol. 2019 Jul;15(7):384. (PMID: 31164735)
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    • Accession Number:
      0 (Adaptor Proteins, Signal Transducing)
      0 (BANK1 protein, human)
      0 (IRF5 protein, human)
      0 (Interferon Regulatory Factors)
      0 (Interferon Type I)
      0 (Irf5 protein, mouse)
      0 (Membrane Proteins)
      EC 2.7.10.2 (B lymphoid kinase, mouse)
      EC 2.7.10.2 (BLK protein, human)
      EC 2.7.10.2 (src-Family Kinases)
    • Publication Date:
      Date Created: 20190519 Date Completed: 20190606 Latest Revision: 20221207
    • Publication Date:
      20221213
    • Accession Number:
      PMC6525203
    • Accession Number:
      10.1038/s41467-019-10242-9
    • Accession Number:
      31101814