Loss of the Immunomodulatory Transcription Factor BATF2 in Humans Is Associated with a Neurological Phenotype

Cells. 2023 Jan 5;12(2):227. doi: 10.3390/cells12020227.


Epilepsy and mental retardation are known to be associated with pathogenic mutations in a broad range of genes that are expressed in the brain and have a role in neurodevelopment. Here, we report on a family with three affected individuals whose clinical symptoms closely resemble a neurodevelopmental disorder. Whole-exome sequencing identified a homozygous stop-gain mutation, p.Gln19*, in the BATF2 gene in the patients. The BATF2 transcription factor is predominantly expressed in macrophages and monocytes and has been reported to modulate AP-1 transcription factor-mediated pro-inflammatory responses. Transcriptome analysis showed altered base-level expression of interferon-stimulated genes in the patients' blood, typical for type I interferonopathies. Peripheral blood mononuclear cells from all three patients demonstrated elevated responses to innate immune stimuli, which could be reproduced in CRISPR-Cas9-generated BATF2-/- human monocytic cell lines. BATF2 is, therefore, a novel disease-associated gene candidate for severe epilepsy and mental retardation related to dysregulation of immune responses, which underscores the relevance of neuroinflammation for epilepsy.

Keywords: epilepsy; mental retardation; neuroinflammation; transcription factor; type I interferonopathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / metabolism
  • Humans
  • Immunity
  • Intellectual Disability*
  • Leukocytes, Mononuclear / metabolism
  • Phenotype
  • Transcription Factors* / genetics


  • Transcription Factors
  • Basic-Leucine Zipper Transcription Factors

Grants and funding

This research was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation): ZS 99/3-2 and ZS 99/4-1 to G.Z., KU 911/21-2 and KU 911/22-1 to W.S.K., TRR237-369799452 to G.H. and E.B. This work was also funded under Germany’s Excellence Strategy, EXC2151-390873048 of which G.H. and E.B. are members. M.N. received funding from BONFOR (University Bonn). M.L.T.A. received funding from BonnNI (University Bonn).