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

Abstract

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.

Long-term effects of myo-inositol on traumatic brain injury: Epigenomic and transcriptomic studies

“…Recently it has been shown that loss of BATF2 in humans is associated with a neurological phenotype. Authors of the study consider BATF2 as a novel disease-associated gene for severe epilepsy and mental retardation related to dysregulation of immune responses ( Zsurka et al, 2023 ). In our study, the level of BATF2 is significantly upregulated in the ipsilateral hippocampus of the TBI+MI group compared with the TBI+SAL group.…”

BATF2 is a regulator of interferon-γ signaling in astrocytes during neuroinflammation

“…Finally, loss of BATF2 has been linked with hyperactive interferon signaling and subsequent development of epilepsy and severe cognitive disability. Specifically, patients with a homozygous stop-gain mutation of BATF2 presented with upregulated interferon-specific gene signatures in whole blood, resembling a type I interferon phenotype that is closely associated with interferonopathy 48 . Additionally, peripheral immune cells of patients with non-functional BATF2 were hyper-responsive to toll like receptor activation and overexpressed inflammatory cytokines including IFNa, TNF, IL-6 and IL-23 48 .…”

“…Specifically, patients with a homozygous stop-gain mutation of BATF2 presented with upregulated interferon-specific gene signatures in whole blood, resembling a type I interferon phenotype that is closely associated with interferonopathy 48 . Additionally, peripheral immune cells of patients with non-functional BATF2 were hyper-responsive to toll like receptor activation and overexpressed inflammatory cytokines including IFNa, TNF, IL-6 and IL-23 48 . This may indicate that BATF2 has the ability to cross regulate other inflammatory pathways in addition to those directly downstream of interferons.…”