Mikko R. Seppänen, Finland
HUS Helsinki University Hospital Rare Disease Center, Children and Adolescents and Adult Immunodeficiency Unit, Inflammation CenterPresenter of 6 Presentations
WELCOME AND INTRODUCTION
STOP THE DELAY – SIMPLIFYING DIAGNOSIS IN PID
Q&A
SUMMARY AND CLOSE
INTRODUCTION
GAIN-OF-FUNCTION CEBPE MUTATION CAUSES NON-CANONICAL AUTOINFLAMMATORY INFLAMMASOMOPATHY
Abstract
Background and Aims
C/EBPε is a transcription factor involved in late myeloid lineage differentiation and cellular function previously known to cause neutrophil-specific granule deficiency. To molecularly characterize the effects of C/EBPε transcription factor gene’s p.Arg219His mutation in an autoinflammatory and immunodeficiency syndrome.
Methods
Genetic analysis, proteomics, genome-wide transcriptional profiling by RNAsequencing, ChIP-sequencing and assessment of the inflammasome function of primary macrophages were performed.
Results
Studies revealed a novel mechanism of genome-wide gain-of-function that dysregulated transcription of 464 genes. Mechanisms involved dysregulated non-canonical inflammasome activation due to decreased association with transcriptional repressors leading to increased chromatin occupancy and considerable changes in transcriptional activity, including increased expression of NLRP3 and constitutively expressed caspase-5 in macrophages.
Conclusions
We describe a novel autoinflammatory disease with defective neutrophil function caused by homozygous p.Arg219His mutation in transcription factor CEBPE. Mutated CEBPE acts as a regulator of both the inflammasome and interferome, and the Arg219His mutation causes the first human monogenic neomorphic and non-canonical inflammasomopathy/immunodeficiency. The same mutation causes both LOF and GOF, i.e. there is variation-of-function (VOF). This widely dysregulated transcription is likely not unique for C/EBPε. Similar multiomics approaches should be utilized when studying other transcription factor-associated diseases.