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

• Published in: Cells (Basel, Switzerland) Vol. 12; no. 2; p. 227
• Main Authors: Zsurka, Gábor, Appel, Maximilian L T, Nastaly, Maximilian, Hallmann, Kerstin, Hansen, Niels, Nass, Daniel, Baumgartner, Tobias, Surges, Rainer, Hartmann, Gunther, Bartok, Eva, Kunz, Wolfram S
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 05.01.2023; MDPI
• Subjects: Activator protein 1; Basic-Leucine Zipper Transcription Factors - genetics; Basic-Leucine Zipper Transcription Factors - metabolism; Cell lines; Convulsions & seizures; CRISPR; Disease; Epilepsy; Experiments; Genes; Genomics; Genotype & phenotype; Humans; Immune response; Immunity; Immunomodulation; Infections; Inflammation; Intellectual disabilities; Intellectual Disability; Leukocytes (mononuclear); Leukocytes, Mononuclear - metabolism; Macrophages; mental retardation; Monocytes; Mutation; Neurodevelopment; Neurodevelopmental disorders; neuroinflammation; Neurosciences; Patients; Peripheral blood mononuclear cells; Phenotype; Phenotypes; Plasmids; Proteins; Siblings; transcription factor; Transcription factors; Transcription Factors - genetics; Transcriptomes; Tuberculosis; type I interferonopathy; France; United States > US; Germany; epilepsy; mental retardation; transcription factor; type I interferonopathy; neuroinflammation
• ISSN: 2073-4409; 2073-4409
• 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 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 human monocytic cell lines. 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.