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

Nat Commun. 2019 May 17;10(1):2201. doi: 10.1038/s41467-019-10242-9.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Exome Sequencing
  • 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
  • src-Family Kinases / genetics*
  • src-Family Kinases / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • BANK1 protein, human
  • IRF5 protein, human
  • Interferon Regulatory Factors
  • Interferon Type I
  • Irf5 protein, mouse
  • Membrane Proteins
  • B lymphoid kinase, mouse
  • BLK protein, human
  • src-Family Kinases